Clinical trial NCT03946670
Conditions: Myelodysplastic Syndromes
Keywords: Sabatolimab Placebo Phase II MBG453 TIM-3 decitabine azacitidine myelodysplastic syndrome (MDS)
Sponsor: Novartis Pharmaceuticals
Start date: 2019-06-04; Completion date: 2024-07-15
Enrollment: 127 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase II is a multicenter, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to hypomethylating agents (azacitidine or decitabine) in adult subjects with IPSS-R intermediate, high or very high risk myelodysplastic syndrome (MDS) not eligible for Hematopoietic Stem Cell Transplant (HSCT) or intensive chemotherapy.

Detailed description:
The 2 primary objectives are as follows:

To determine if MBG453 combined with standard HMA therapy improves complete remission in subjects with intermediate, high, or very high risk MDS.

To determine if MBG453 combined with standard HMA therapy improves progression free survival (PFS) in subjects with intermediate, high or very high risk MDS.

This Phase II is a multicenter, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to hypomethylating agents (azacitidine or decitabine, as per investigators' choice based on local standard of care (SOC)) in adult subjects with IPSS-R intermediate, high or very high risk MDS not eligible for HSCT or intensive chemotherapy. A total of 127 subjects were randomized in a 1:1 ratio to treatment arms as follows:

MBG453 400 mg IV Q2W and decitabine or azacitidine Placebo IV Q2W and decitabine or azacitidine

The randomization was stratified by 2 stratification factors: a) HMA (decitabine or azacitidine) selected by the investigator as per the local SOC and b) IPSS-R prognostic risk categories (intermediate, high or very high) at randomization. Crossover between treatment arms was not permitted at any time during the study.

Arms: arm 1: Patients are taking MBG453 plus hypomethylating agents arm 2: Patients are taking placebo plus hypomethylating agents
Interventions: intervention 1: MBG453 intervention 2: Placebo intervention 3: Hypomethylating agents
Intervention descriptions: intervention 1: MBG453 is being administered i.v. intervention 2: Placebo is being administered i.v. intervention 3: Decitabine is being administered i.v. Azacitidine is being administered i.v or s.c.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
MBG453/Sabatolimab 
Clinical Trial Protocol CMBG453B12201 / NCT03946670
A randomized, double-blind, placebo-controlled phase II 
multi-center study of intravenous MBG453 added to 
hypomethylating agents in adult subjects with 
intermediate, high or very high risk myelodysplastic 
syndrome (MDS) as per IPSS-R criteria 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2018-004479-11 
Version number: 
04 (Clean) 
Clinical Trial Phase: 
II 
Release date: 
02-Sep-2021
Property of Novartis Pharmaceuticals Corporation 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Template Version 4.0 dated 15-Feb-2021 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 11 
Amendment 4 (02-Sep-2021) ............................................................................................ 14 
Amendment 3 (06-May-2020) ........................................................................................... 18 
Amendment 2 (13-Jan-2020) ............................................................................................. 19 
Amendment 1 (10-Apr-2019) ............................................................................................ 23 
Protocol summary .............................................................................................................. 24 
1 
Introduction ....................................................................................................................... 28 
1.1 
Background ............................................................................................................ 28 
1.2 
Purpose .................................................................................................................. 30 
2 
Objectives and endpoints ................................................................................................... 31 
3 
Study design ...................................................................................................................... 32 
4 
Rationale ............................................................................................................................ 34 
4.1 
Rationale for study design ..................................................................................... 34 
 
 .......................................... 35 
4.3 
Rationale for choice of the combination drugs ...................................................... 37 
4.3.1 
Rationale for HMA (azacitidine or decitabine) ..................................... 37 
4.3.2 
Rationale for MBG453 .......................................................................... 38 
4.3.3 
Rationale for combining MBG453 with HMA (azacitidine and 
decitabine) ............................................................................................. 39 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 40 
4.5 
Risks and benefits .................................................................................................. 40 
 
 ................................ 41 
 
 ........................................................... 41 
 
 ....................... 42 
4.7 
Rationale for Public Health Emergency mitigation procedures ............................ 42 
5 
Population .......................................................................................................................... 43 
5.1 
Inclusion criteria .................................................................................................... 43 
5.2 
Exclusion criteria ................................................................................................... 43 
6 
Treatment ........................................................................................................................... 46 
6.1 
Study treatment ...................................................................................................... 46 
6.1.1 
Investigational and control drugs .......................................................... 46 


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6.1.2 
Additional study treatments .................................................................. 47 
6.1.3 
Treatment arms/group ........................................................................... 47 
6.1.4 
Guidelines for continuation of treatment .............................................. 47 
6.1.5 
Treatment duration ................................................................................ 48 
6.2 
Other treatment(s) .................................................................................................. 48 
6.2.1 
Concomitant therapy ............................................................................. 48 
6.2.2 
Prohibited medication ........................................................................... 50 
6.3 
Subject numbering, treatment assignment, randomization .................................... 50 
6.3.1 
Subject numbering ................................................................................ 50 
6.3.2 
Treatment assignment, randomization .................................................. 51 
6.4 
Treatment blinding ................................................................................................. 51 
6.5 
Dose modification .................................................................................................. 52 
6.5.1 
Dose modifications ................................................................................ 52 
6.5.2 
Follow-up for toxicities ......................................................................... 55 
6.6 
Additional treatment guidance ............................................................................... 59 
6.6.1 
Treatment compliance ........................................................................... 59 
6.6.2 
Emergency breaking of assigned treatment code .................................. 59 
6.7 
Preparation and dispensation ................................................................................. 60 
6.7.1 
Handling of study treatment and additional treatment .......................... 60 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 61 
7 
Informed consent procedures ............................................................................................ 61 
8 
Visit schedule and assessments ......................................................................................... 62 
8.1 
Screening ............................................................................................................... 74 
8.1.1 
Eligibility screening .............................................................................. 74 
8.1.2 
Information to be collected on screening failures ................................. 74 
8.2 
Subject demographics/other baseline characteristics ............................................. 74 
8.3 
Efficacy .................................................................................................................. 75 
8.3.1 
Efficacy assessments ............................................................................. 75 
8.3.2 
Appropriateness of efficacy assessments .............................................. 79 
8.4 
Safety ..................................................................................................................... 79 
8.4.1 
Laboratory evaluations .......................................................................... 80 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 81 
8.4.3 
Pregnancy and assessments of fertility ................................................. 82 
8.5 
Additional assessments .......................................................................................... 83 
 
 ............................................... 83 
8.5.2 
Pharmacokinetics .................................................................................. 84 


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 ............................................................................................ 86 
9 
Study discontinuation and completion .............................................................................. 88 
9.1 
Discontinuation ...................................................................................................... 88 
9.1.1 
Discontinuation of study treatment ....................................................... 88 
9.1.2 
Withdrawal of informed consent/Opposition to use data/biological 
samples .................................................................................................. 90 
9.1.3 
Lost to follow-up ................................................................................... 90 
9.1.4 
Early study termination by the sponsor ................................................. 91 
9.1.5 
Survival follow-up ................................................................................ 91 
9.1.6 
Post-treatment follow-up ....................................................................... 91 
9.2 
Study completion and post-study treatment .......................................................... 91 
10 Safety monitoring and reporting ........................................................................................ 92 
10.1 
Definition of adverse events and reporting requirements ...................................... 92 
10.1.1 
Adverse events ...................................................................................... 92 
10.1.2 
Serious adverse events .......................................................................... 94 
10.1.3 
SAE reporting........................................................................................ 95 
10.1.4 
Pregnancy reporting .............................................................................. 96 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 96 
10.2 
Additional Safety Monitoring ................................................................................ 96 
10.2.1 
Data Monitoring Committee ................................................................. 97 
10.2.2 
Steering Committee ............................................................................... 98 
11 Data Collection and Database management ...................................................................... 98 
11.1 
Data collection ....................................................................................................... 98 
11.2 
Database management and quality control ............................................................ 99 
11.3 
Site monitoring ...................................................................................................... 99 
12 Data analysis and statistical methods .............................................................................. 100 
12.1 
Analysis sets ........................................................................................................ 100 
12.2 
Subject demographics and other baseline characteristics .................................... 101 
12.3 
Treatments ........................................................................................................... 101 
12.4 
Analysis of the primary endpoint(s) .................................................................... 101 
12.4.1 
Definition of primary endpoint(s) ....................................................... 101 
 
 103 
 
 104 
12.4.4 
Supportive analyses ............................................................................. 105 
12.5 
Analysis of secondary endpoints ......................................................................... 105 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................. 105 




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List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 31 
Table 6-1 
Investigational and control drug ............................................................ 46 
Table 6-2 
Criteria for dose interruption and re-initiation of study drug 
MBG453 or placebo for adverse drug reactions ................................... 54 
Table 6-3 
Guidance on specific clinical and diagnostic assessments to be (OR 
which can be) performed to rule out possible alternative causes of 
the observed LFT abnormalities............................................................ 58 
Table 8-1 
Assessment Schedule ............................................................................ 64 
Table 8-2 
Modified response classification per IWG criteria in MDS 
(Platzbecker et al 2018, Cheson et al 2006, Cheson et al 2000) ........... 76 
Table 8-3 
Assessments & Specifications ............................................................... 79 
Table 8-4 
ECOG performance status ..................................................................... 80 
Table 8-5 
Local clinical laboratory parameters collection plan ............................ 81 
Table 8-6 
Central ECG collection plan ................................................................. 82 
Table 8-7 
Local ECG collection plan .................................................................... 82 
Table 8-8 
Blood (serum) collection schedule for PK, IG 
 .................. 85 
 
 ......................................................... 87 
Table 10-1 
Guidance for capturing the study treatment errors including misuse ... 96 
Table 12-1 
Operating characteristics of the group-sequential design ................... 114 
Table 16-1 
Liver event and laboratory trigger definitions .................................... 120 
Table 16-2 
Follow up requirements for liver events and laboratory triggers ........ 121 
Table 16-3 
Specific Renal Alert Criteria and Actions ........................................... 123 
Table 16-4 
Renal Event Follow Up ....................................................................... 125 
Table 16-5 
Eligibility based on serologic markers for hepatitis B ........................ 126 
List of figures 
Figure 3-1 
Study design .......................................................................................... 33 
Figure 3-2 
Study flow ............................................................................................. 34 
Figure 12-1 
Graphical gate-keeping procedure to test primary endpoints in 
order to control overall type I error ..................................................... 103 
 
 ........................................................................ 111 
Figure 16-1 
Decision tree to determine eligibility based on serologic markers 
for hepatitis B ...................................................................................... 126 
 


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List of abbreviations 
ADA 
Anti-drug Antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANA 
Antinuclear antibodies  
ASCO 
American Society of Clinical Oncology 
ASMA 
Anti-smooth muscle antibodies 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
AUC 
Area Under the Curve 
BLQ 
Below the Limit of Quantitation  
BMA 
Bone marrow aspirate  
BSA 
Body surface area 
BUN 
blood urea nitrogen 
C1D1 
Cycle 1 Day 1 
CFR 
Code of Federal Regulation 
CG 
Cockcroft-Gault 
CMML 
Chronic myelomonocytic leukemia 
CMV 
Cytomegalovirus 
COVID-19 
Coronavirus disease of 2019 
CR 
Complete Remission 
CRF 
Case Report/Record Form (paper or electronic) 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DDI 
Drug-Drug Interaction 
DILI 
Drug Induced Liver Injury 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
EBV 
Epstein–Barr virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
EDC 
Electronic Data Capture 
EFS 
Event Free Survival 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 


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EOT 
End of treatment  
ERCP 
Endoscopic Retrograde Cholangio-Pancreatography 
ESA 
Erythropoiesis Stimulating Agent 
ESMO 
European Society for Medical Oncology 
FA 
Final Analysis 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FUP  
Follow Up 
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 
i.v. 
intravenous 
IA 
Interim Analysis 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin (Ig-M; Ig-G; Ig-A; Ig-E) 
INR 
International normalized ratio 
IPSS-R 
International Prognostic Scoring System 
irAE 
immune related adverse event 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine Device  
IUS 
Intrauterine System 


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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 
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 
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 
PAS 
Pharmacokinetic Analysis Set  
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 
PS 
Performance status 
PTA 
Post Trial Access 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
RBC 
red blood cell(s) 


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RNA 
Ribonucleic acid  
s.c. 
subcutaneous 
SAE 
serious adverse event 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SSC 
Steering committee 
SD 
Stable disease 
SOC 
Standard of Care 
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) 
WoC 
Withdrawal of Consent 
WHO 
World Health Organization 


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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biological Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of all 
clinical trial activities. Examples of team members include the Study Lead, 
Medical Monitor, Trial Statistician etc. 
Coded Data 
Personal Data which has been de-identified by the investigative center team 
by replacing personal identifiers with a code. 
Cohort 
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed up or traced over time  
Control drug 
Any drug (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the investigational drug being tested in the trial 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days) 
Discontinuation from 
the study 
Point/time when the subject permanently stops receiving the study treatment 
and further protocol required assessments or follow-up, for any reason. No 
specific request is made to stop the use of their samples or data. 
Discontinuation from 
study treatment 
Point/time when the subject permanently stops receiving the study treatment 
for any reason (prior to the planned completion of study drug administration, 
if any). Subject agrees to the other protocol required assessments including 
follow-up. No specific request is made to stop the use of their samples or 
data. 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used 
to capture data transcribed from source data/documents used at the point of 
care 
End of the clinical trial 
The end of the clinical trial is defined 4 years after last subject randomized, 
which is the data cut-off date of the final OS analysis. 
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained The action of enrolling one or more subjects. 
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to sponsors 
and other oversight authorities, as appropriate 
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” 


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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. 
Medication number 
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system. 
Patient 
An individual with the condition of interest 
Period 
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc. 
Personal data 
Subject information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
subject identifier information, study information and biological samples. 
Premature subject 
withdrawal 
Point/time when the subject 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. 
Randomization 
number 
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment 
Re-screening 
If a subject fails the initial screening and is considered as a Screen Failure, 
he/she can be invited once for a new Screening visit after medical judgment 
and as specified by the protocol 
Screen Failure 
A subject who is screened but is not treated or randomized 
Stage 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Study completion 
Point/time at which the subject came in for a final evaluation visit or when 
study drug was discontinued whichever is later. 
Study drug 
discontinuation 
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal. 
Study treatment 
Any drug administered to the study subjects as part of the required study 
procedures; includes investigational drug (s), control(s) or non-
investigational medicinal product(s) 
Treatment arm/group 
A treatment arm/group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts. 
Study treatment 
discontinuation 
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date 
Subject 
An individual who has consented to participate in this study. The term 
Subject may be used to describe either a healthy volunteer or a patient. 
Subject number 
A number assigned to each subject who enrolls in the study. When 
combined with the center number, a unique identifier is created for each 
subject in the study. 
Variable 
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints. 
Withdrawal of consent 
(WoC)/ Opposition to 
Withdrawal of consent from the study occurs when the subject explicitly 
requests to stop use of their data and biological samples (opposition to use 
data and biological samples) AND no longer wishes to receive study 
treatment, AND does not agree to further protocol required assessments. 


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use of data/biological 
samples 
This request should be in writing (depending on local regulations) and 
recorded in the source documentation. Opposition to use data/biological 
samples occurs in the countries where collection and processing of personal 
data is justified by a different legal reason than consent. 




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Section 4.3.2:  
• Clarification that MBG453 was well tolerated as a single agent or when it is administered 
intravenously in combination with decitabine or azacitidine to MDS/AML subjects.  
• Additional efficacy data from study CPDR001X2105 with data cut-off 25-Jun-2020 
included. 
Section 4.3.3: Added information based on CPDR001X2105 study data. 
Section 4.4: Clarifies timelines for final PFS analysis, interim OS analysis and final OS analysis. 
Section 4.5:  
• Added information based on CPDR001X2105 study 
• Language added no substantial risk identified for subjects' safety due to the SARS-CoV-2 
virus (Severe Acute Respiratory Syndrome Corona Virus) and the COVID-19 
(Coronavirus disease of 2019) pandemic. 
Section 4.7: Section added “Rationale for Public Health Emergency Mitigation Procedures” 
Section 6.1.5: Addition of Post-Trial Access (PTA) information. 
Section 6.2.2: Vaccination against COVID-19 is allowed during screening and during the 
treatment phase, unless these are live vaccines, but should not be administered on the same day 
of study treatment administration to avoid potential overlapping adverse events.  
Section 6.4: Clarification on treatment unblinding criteria and parameters following PFS IA, 
PFS FA and Interim OS analysis. 
Section 7: Allowance of informed consent discussion remotely due to Public Health Emergency 
(e.g. telephone, videoconference) if allowable by a local Heath Authority. 
Section 8: 
• Allowance of alternative methods of providing continuing care by the investigator due to 
Public Health Emergency as the situation dictates and if allowable by a local Health 
Authority and depending on operational capabilities. Response assessments (bone marrow 
and PB smear), collection of PK/PD/IG 
 samples as well as administration 
of investigational drug always have to be conducted at the investigational site. 
• Unscheduled pre-dose ECG timepoint moved from the Central ECG Collection Plan to 
Local ECG Collection Plan. Unscheduled timepoints should be performed on local ECG 
machine if clinically indicated. In case of new abnormalities, a cardiologist should be 
consulted, as needed. 
Section 8.3.1:  
• Clarifies that pathology reports should be collected and sent to the Novartis designated 
central laboratory for storage until final PFS analysis data cut-off date. 
• Updated with new Withdrawal of Consent (WoC) language 
Section 8.4: 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 




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Section 15: References for the Rho Family and Pocock spending functions removed. Reference 
for the O’Brien and Fleming spending function added.  
Appendix 2: Table 16-1 and Table 16-2 – update on liver events ALP to ≥ 2 × ULN instead of 
ALP to > 2 × ULN 
In addition, editorial changes and text corrections were made for clarification, where required. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 3 (06-May-2020) 
Amendment rationale  
As of the release of this amendment, 61 sites have been initiated and 96 subjects have been 
randomized to the study. 
The purpose of this amendment is to update the definitions of the RBC or platelet transfusion 
dependence and transfusion independence in Section 8.3, Table 8-2 based on FDA feedback. 
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 high-risk MDS patients at baseline (IWG 2006, IWG 2018). Transfusion 
independence will be defined as absence of any transfusion during a given period of 
observation.  
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. 
Section 5.2: Exclusion criteria numbering was adjusted due to a typo on Amendment 2. 
Section 6.1.1: Sentence was removed as instructions for the preparation and dispensation of 
MBG453 or placebo will be provided in the Pharmacy Manual.  
Section 8.3.1 - Table 8-2: Transfusion independence and dependence definition were updated. 
Section 8.4.1: Footnote was added to Table 8-5 to allow Troponin I to be performed in case 
Troponin T is not available. 
Section 10.1.1: Adverse event collection language in patients starting new antineoplastic 
therapy was updated.  
Section 12.3: Transfusions will be summarized using 8 weeks intervals prior and post baseline.  
Section 12.5.1: Transfusion independence definition was updated as per Table 8-2. 
In addition, editorial changes and text corrections were made for clarification, where required. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein do NOT affect the trial specific model ICF. 
 


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Amendment 2 (13-Jan-2020) 
Amendment rationale 
As of the release of this amendment, 52 sites have been initiated and 39 subjects have been 
randomized to the study. 
The primary purpose of this amendment is to address Heath Authorities’ requests and Study 
Steering Committee’s (SSC) recommendations.  
Based on FDA feedback, Event Free Survival (EFS) was added as secondary endpoint. This 
endpoint is defined in analogy with the EFS definition used for AML. Events will include lack 
of reaching complete remission within the first 6 months, relapse from complete remission or 
death due to any cause, whichever occurs first.  
In addition, PK and IG samples collection was prolonged and the time-points for collection 
were updated accordingly 
The table 8-2 relating to efficacy response assessment has been updated as follows:  
The SSC recommended to prohibit use of erythropoietin stimulating agents and thrombopoietic 
agents during the course of the study as their use could mask cytopenias. However, G-CSF 
cannot be prohibited, because it is part of the SOC in the context of infection or septicemia. 
Therefore, the note in the table for complete remission was updated accordingly. Confirmation 
of CR by peripheral blood at 4 weeks was removed as retreatment with HMA every 4 weeks 
could potentially bias results. CR is considered confirmed if progression or relapse from CR are 
not observed within 4 weeks (see Section 12.4.1.1). Assessment hematological improvements 
based on IWG 2006 criteria were added in the table and the definitions of transfusion 
independence/dependence status were adapted to reflect the IWG 2018 criteria. Reference 
values to determine significant increase in blasts or decrease in blood values have been added.  
Change has been made in the inclusion criterion No 9 relating to the adequate renal function. 
The most recent Modification of Diet in Renal Disease (MDRD) formula instead of the 
Cockcroft-Gault (CG) formula should be used to estimate the renal function. MDRD formula 
is more accurate than the CG formula below an eGFR of 60 milliliters per minute per 1.73 
meters squared and is generally more appropriate to identify renal impairment in older 
population such the MDS population (median age around 70 years old) 
A modification has been made in the exclusion criterion No 14 relating to previous cancer to 
clarify that low-risk MDS subjects who were adequately treated with lenalidomide and failed 
are eligible. Per exclusion criterion No 2, lenalidomide must not have been administered for 
intermediate, high or very high-risk MDS 
The safety information has been updated to be in alignment with the Investigator’s Brochure 
Edition 5.1 (cut-off 15-Oct-2019). 
In addition, clarifications and corrections are made throughout the protocol as well as editorial 
change to improve flow and consistency. Other minor editorial changes and corrections were 
made throughout the protocol for consistency and/or clarifications.  


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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. 
Protocol Summary: secondary objective, key inclusion and exclusion criteria, efficacy 
assessment were updated. 
Section 2 - Table 2-1 
• Secondary objective, to assess EFS in each treatment arm, was added 
• Endpoint for secondary objective, Leukemia free survival was updated to add diagnosis of 
extramedullary acute leukemia as an event. 
• Endpoint for secondary objective, to assess HI responses rate was added  
• Endpoint for secondary objective, to assess the duration of RBC/platelet transfusion 
independence was added 
Section 4.2 and 4.3.2 –Updated with the data from latest version of the Investigator Brochure 
Edition 5.1 (data cut-off, 15-Oct-2019) 
Section 5.1  
• Inclusion criteria No 4, 5, have been slightly modified to be more clearly aligned with the 
study population definition in section 5. Subjects who can be enrolled into the present trial 
are subjects who are not eligible for transplant or intensive chemotherapy).  
• The adequate limit for bilirubin for isolated Gilbert Syndrome was added in inclusion 
criterion No 8 
• Change has been made in the inclusion criterion No 9 relating to the adequate renal 
function 
Section 5.2 – Exclusion criteria No 1, 2, 3, 10, 14, 15, 16, 18, 20 were updated. The exclusion 
No 11 has been deleted as it is not relevant in the MDS patient population. Such a criterion is 
more pertinent for AML patients, who are excluded per exclusion criterion No 8 
Section 6.1.1 – Table 6-1 – footnote was added to include other locally available HMA dose 
strengths  
Section 6.1.4 – Typo was corrected, to indicate the correct referenced section  
Section 6.2.1 - Editorial changes to the protocol language to enhance clarity 
Section 6.2.2 – Updated per SSC recommendation to prohibit use of erythropoietin stimulating 
agents and thrombopoietic agents during the course of the study. Editorial changes to the 
protocol language to enhance clarity 
Section 6.3.1 - Editorial changes to the protocol language to enhance clarity 
Section 6.4 – Added clarification for samples received by bio-analyst. Added 
 
 
Section 6.5.1 – Table 6-2 - Editorial changes to enhance clarity 


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Section 8 – Treatment window, laboratory test window (hematology and chemistry) and 
procedure window (bone marrow) were added. Clarity was provided for safety follow up 
Table 8-1 – Assessment Schedule:  
• Thyroid, urine pregnancy, PK and IG assessment collection time-points were added  
• Row was added for Peripheral blood collection to enhance clarity  
• Row for Antineoplastic therapies was updated 
• Time points were updated for Prior/concomitant medications, surgery and medical 
procedures assessment; and Adverse Events assessments  
• Screening time point was removed for Response Assessment  
• Footnote No 2, 5, 9, 11, 12, 14, 18, 19 and 20 were updated to enhance clarity 
Section 8.2 - Editorial changes to the protocol language to enhance clarity 
Section 8.3 – Response criteria section was updated and hematological improvement definition 
was added. Editorial changes to the protocol language to enhance clarity 
Section 8.3.1 – Response confirmation was removed. Editorial changes to the protocol language 
was added to enhance clarity 
Section 8.3.1 - Table 8-2 
• Response category: CR, definition was updated 
• Response category: Relapse from CR, Disease progression were updated to enhance 
clarity. In order to ensure standardization, the reference values to determine significant 
increase in blasts or decrease in blood values have been added 
• Hematological improvement category based on Modified Hematological Improvement per 
IWG-MDS criteria in MDS (Cheson et al 2006) were added. Transfusion independence 
and dependence definition were updated  
Section 8.4.1 – Table 8-5 – Test category: Chemistry – Troponin T test; Additional tests – Free 
T3, Free T4, were added to the chemistry collection panel 
Section 8.4.2 – Information related to ECG collection time points was updated  
Section 8.4.3 – Urine / serum pregnancy test collection during safety follow up period was 
updated 
Section 8.5.1 - Editorial changes were made 
Section 8.5.2.1 
• text related to PK, IG 
 collection time-point was updated 
• Table 8-8: PK and IG collection time-points were updated. Footnote was added to clarify 
PK, IG 
 samples will be analyzed only in subjects receiving MBG453 
Section 8.5.3.1 - Editorial changes to the protocol language to enhance clarity. Information 
regarding storage of biological samples was added 
Section 9.1.5 - Editorial changes to the protocol language to enhance clarity 
Section 9.2  




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Amendment 1 (10-Apr-2019) 
Amendment rationale 
As of the release of this amendment, no site has been initiated, no subject has been screened 
and no subject has received study treatment in this trial. 
The primary purpose of this amendment is to add a general guideline for dosing modifications 
of the investigational drug (MBG453/placebo) in relation to non-hematologic non-immune-
related toxicities that are clinically significant according to the investigator and possibly 
attributable to the investigational drug. This guideline does not apply to non-hematologic non-
immune-related toxicities that are attributable to decitabine/azacitidine or the myelodysplastic 
syndrome and its complications.  
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. 
Section 4.5 – A reference was added to the general guideline in Section 6.5.1. 
Section 6.5.1 – Table 6-2 – General guideline was added for non-hematologic non-immune-
related toxicities possibly attributable to the investigational drug; and the text of the section has 
been updated accordingly. 
Section 8 – Table 8-1 – Typo corrected related to antineoplastic therapies including transplant 
since discontinuation of study treatment. 
IRB Section 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.  
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein do NOT affect the trial specific model ICF. 


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Protocol summary 
Protocol number 
CMBG453B12201 
Full Title 
A randomized, double-blind, placebo-controlled Phase II multi-center study of 
intravenous MBG453 added to hypomethylating agents in adult subjects with 
intermediate, high or very high risk myelodysplastic syndrome (MDS) as per 
IPSS-R criteria. 
Brief title 
A Phase II efficacy and safety study of MBG453 in combination with 
hypomethylating agents in subjects with IPSS-R intermediate, high or very 
high-risk myelodysplastic syndrome (MDS). 
Sponsor and 
Clinical Phase 
Novartis 
Phase II 
Investigation 
type 
Biological 
Study type 
Interventional 
Purpose and 
rationale 
The anti-TIM-3 monoclonal antibody MBG453 is a novel immunotherapeutic 
agent with promising activity in AML and MDS. The purpose of the current 
study is to assess clinical effects of MBG453 in combination with HMA 
(azacitidine or decitabine) in adult subjects with IPSS-R intermediate, high, 
very high risk MDS. The justification for a double blind randomized placebo-
controlled trial is to determine the efficacy of adding MBG453 to the current 
standard of care on the primary efficacy endpoints (complete remission and 
progression free survival). The randomized, double-blind placebo-controlled 
design minimizes the risk of bias introduced by assessments of efficacy, safety 
.  
Primary 
Objective(s)  
The 2 primary objectives are as follow: 
To determine if MBG453 combined with standard HMA therapy improves 
complete remission in subjects with intermediate, high, or very high risk MDS. 
To determine if MBG453 combined with standard HMA therapy improves PFS 
in subjects with intermediate, high or very high risk MDS. 
Secondary 
Objectives 
The secondary objectives are as follow: 
• 
To assess Overall Survival in each treatment arm. 
• 
To assess EFS in each treatment arm. 
• 
To assess Leukemia-free survival in each treatment. 
• 
To assess responses rate in each treatment arm. 
• 
To assess duration of complete remission in each treatment arm. 
• 
To assess time to complete remission in each treatment arm. 
• 
To assess the improvement in RBC/platelets transfusion 
independence in each treatment arm. 
• 
To assess the safety profile of MBG453 when given in combination 
with HMA. 
• 
To characterize the pharmacokinetics of MBG453 when given in 
combination with HMA. 
• 
To evaluate immunogenicity of MBG453 when given in combination 
of HMA. 


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Study design 
This Phase II is a multicenter, randomized, two-arm parallel-group, double-
blind, placebo-controlled study of MBG453 or placebo added to 
hypomethylating agents (azacitidine or decitabine, as per investigators' choice 
based on local standard of care (SOC)) in adult subjects with IPSS-R 
intermediate, high or very high risk myelodysplastic syndrome (MDS) not 
eligible for HSCT or intensive chemotherapy. Approximately 120 subjects will 
be randomized in a 1:1 ratio to treatment arms as follow: 
MBG453 400 mg IV Q2W and decitabine or azacitidine 
Placebo IV Q2W and decitabine or azacitidine 
The randomization will be stratified by 2 stratification factors: a) HMA 
(decitabine or azacitidine) selected by the investigator as per the local 
standard of care (SOC) and b) IPSS-R prognostic risk categories 
(intermediate, high or very high) at randomization. Crossover between 
treatment arms is not permitted at any time during the study. 
Population 
The study population will include adult subjects to be treated in first-line 
setting, with intermediate, high or very high risk per IPSS-R prognostic risk 
categories for myelodysplastic syndromes who do not qualify according to 
medical judgement for intensive chemotherapy or HSCT. Subjects with chronic 
myelomonocytic leukemia are not eligible for this trial. 
Key Inclusion 
criteria 
Subjects eligible for inclusion in 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) 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): 
• 
Very high (> 6 points) 
• 
High (> 4.5-6 points) 
• 
Intermediate (> 3-4.5 points): a subject determined to be in the 
Intermediate Prognostic Risk Category is only allowable in the setting 
of ≥ 5% bone marrow blast 
• 
Not eligible at the time of screening for intensive chemotherapy according 
to the investigator, based on local standard medical practice and 
institutional guidelines for treatment decision 
• 
Not eligible at the time of screening, for allogeneic stem-cell 
transplantation (HSCT) according to the investigator, based on local 
medical practice and institutional guidelines for treatment decisions  
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 
or 2 
Key Exclusion 
criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in 
this study: 
1. Prior exposure to TIM-3 directed therapy at any time. Prior therapy 
with immune check point inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-
PD-L1, or anti-PD-L2), cancer vaccines are allowed except if the drug 
was administered within 4 months prior to randomization. 


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2. Previous first-line treatment for intermediate, high or very high risk 
myelodysplastic syndromes (based on IPSS-R) with chemotherapy or 
any other antineoplastic agents including lenalidomide and 
hypomethylating agent (HMAs) such as decitabine or azacitidine.  
3. History of severe hypersensitivity reactions to any ingredient of the 
study treatment (azacitidine, decitabine or MGB453) or their 
excipients, or to monoclonal antibodies (mAbs). 
4. Currently using or used within 14 days prior to randomization 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 prior to 
randomization. In case of a checkpoint inhibitor: 4 months minimum 
prior to randomization 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 randomization. 
Study treatment 
MBG453, placebo, decitabine, azacitidine. 
Efficacy 
assessments 
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 as Complete 
remission (CR), marrow Complete remission (mCR), Partial Remission (PR), 
Stable Disease (SD), Relapse from CR, Disease Progression including 
transformation to acute leukemia. Response assessment will be performed by 
investigator according to the assessment schedule. Investigators will assess 
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 randomization. Bone marrow assessments will be 
performed at screening and pre-dose during treatment period at C4D1, C7D1, 
C10D1, and C13D1 and hematology assessments will be performed at 
screening, D1, D8 and D22 of each cycle until end of treatment and if clinically 
indicated at any time during the study. After C13D1, bone marrow 
assessments are to be done every 6 cycles (C19D1, C25D1, etc.) and 
hematology assessments every 2 months and if clinically indicated at any time 
during the study. Subjects can be assessed for disease response (bone 
marrow assessment, hematology, transfusion) at any time if clinically indicated 
for example if there is a clinical suspicion of progression/relapse, in particular 
after a subject has achieved a CR. In order to confirm that a subject achieves 
a CR, no progression or relapse from CR should be reported within the 
following 4 weeks. 
Pharmacokinetic 
assessments  
Pharmacokinetic (PK) samples will be obtained and evaluated in all subjects.  
Key safety 
assessments 
Adverse event monitoring, physical examination, vital signs, ECOG PS, 
monitoring of laboratory evaluations in blood and urine, 12-lead 
electrocardiograms (ECGs), monitoring of laboratory markers in blood and 
urine. 


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Data analysis 
The CR rate analysis is planned when the last randomized subject has 
reached cycle 7 (or discontinued earlier). No interim analysis (IA) is planned 
for CR rate. The intent of this CR rate analysis is to assess whether MBG453 
+ HMA has superior efficacy than Placebo + HMA based on the CR rate. The 
other primary endpoint PFS will not be tested at this time point and is following 
a group sequential design.  
One interim analysis for PFS is planned after approximately 81 of the targeted 
108 PFS events (i.e. at approximately 75% information fraction) have been 
documented. 
If the PFS is not already significant at IA, the final PFS analysis will be 
conducted after observing approximately 108 PFS events or approximately 4 
months after the PFS IA data cut-off date, whichever comes first. The final 
PFS analysis if applicable, and the interim OS analysis will be performed 
approximately 4 months after the PFS IA data cut-off date. The final OS 
analysis will be conducted at end of study, i.e. with a data cut-off date of 4 
years after the last subject randomized. 
Key words 
Phase II, MBG453, TIM-3, decitabine, azacitidine, placebo, myelodysplastic 
syndrome (MDS). 
 
 


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1 
Introduction 
1.1 
Background 
It is estimated that 15,000 to 20,000 new cases of Myelodysplastic Syndromes (MDS) are 
diagnosed annually in the USA (Klepin 2016). 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 
candidates for HSCT (Passweg et al 2011; and see Section 4.1). 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 regimens or HSCT. 
However, despite these improvements, prognosis for patients treated with HMA remains poor. 


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Complete Remission rate (CR) with azacitidine or decitabine in higher-risk (IPSS; intermediate-
2 & 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 reported CR rate in MDS patients 
ranging from 7% to 25% with azacitidine and from 9% to 35% with decitabine 
(Saunthararajah 2013). 
Treatment failure, relapse and transformation to acute myeloid leukemia (AML) are frequent 
events. Once a patient with higher risk MDS has failed treatment with HMAs or has transformed 
to AML, survival generally will not exceed 6 months. Thus, improved treatments in addition to 
HMA and/or as an alternative to HMAs are urgently needed in this patient population. 
The primary goals for treatment of higher-risk (intermediate/high risk/very high risk) MDS 
patients are to improve overall survival (OS) and delay/prevent AML evolution. International 
Working Group (IWG) 2006 response criteria were developed to predict clinical outcomes in 
general practice and clinical trials for MDS patients treated with standard of care (HMA). 
Validation of IWG response criteria has shown that the best responses to first line therapy in 
higher-risk MDS correlate with OS. This finding suggests that CR rate may be considered as a 
relevant primary endpoint in Phase II clinical trials investigating novel therapies, especially 
when other time related endpoints will evaluate disease progression or transformation to acute 
leukemia 
(progression 
free 
survival 
(PFS)) or 
transfusion 
free 
intervals 
(Cheson et al 2006, Komrokji et al 2015, Nazha et al 2016, Bell et al 2018). 
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 T-
cells in murine models of AML/MDS. In addition, there is evidence of pharmacodynamic 
activity and promise for checkpoint inhibition in MDS (Chen et al 2008, Zhang et al 2009, 
Yang et al 2014, Kong et al 2015, Ørskov et al 2015); however, it will be important to 
determine the ideal checkpoint inhibitor strategy and to consider combination therapies in order 
to optimize anti-tumor immunity. A few clinical trials have investigated immune checkpoint 
inhibitors in MDS and AML patients. An ongoing Phase II study investigates the clinical effects 
of 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. Overall response rate was observed in 15/20 (75%), 15/21 
(71%), 2/15 (13%), and 7/20 (35%) of patients treated with azacitidine+nivolumab, 
azacitidine+ipilimumab, nivolumab, and ipilimumab, respectively; CR/CRp was observed in 
10/20 (50%), 8/21 (38%), 0 (0%), and 3 (15%) in patients treated with azacitidine+nivolumab, 
azacitidine+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 


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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 pre-treated (n = 45) patients, 
respectively. Duration of response among responders was 5.2 months. 3 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 3/4 immune 
related adverse events (irAE) occurred in 8 (11%) patients (Daver et al 2018). 
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 diseases were reported and 
transplants were possible in some patients. 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. 5 
patients underwent allografting without excessive toxicity (Zeidan et al 2018).  
T-cell immunoglobulin and mucin domain-containing 3 (TIM-3; also known as hepatitis A 
virus cellular receptor 2) 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 overexpressed in MDS patients and detection on 
blasts increases as MDS progresses. Therefore the blockade of this other immune checkpoint 
constitutes a potential target for novel therapies in MDS, and promising preclinical and clinical 
anti-cancer activity has been reported for TIM-3 blockade (Kikushige et al 2010, 
Sakuishi et al 2010, 
Ngiow et al 2011, 
Sakuishi et al 2011, 
Jing et al 2015, 
Asayama et al 2017). MBG453 is a high-affinity, ligand-blocking, humanized anti-TIM-3 IgG4 
monoclonal antibody which blocks the binding of TIM-3 to phosphatidylserine (PtdSer). First 
in human trials have shown that MBG453 can be safely administered with decitabine in 
MDS/AML subjects suggesting that MBG453 may be combined with hypomethylating agents 
(decitabine or azacitidine). Preliminary clinical activity has been observed particularly in high 
and very high risk MDS subjects (see clinical responses in Section 4.3.2).   
For further details about MBG453, refer to the IB [MBG453 Investigator's Brochure]. 
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. 
The humanized anti-TIM-3 IgG4 monoclonal antibody (mAb) MBG453 is a novel 
immunotherapeutic agent with promising activity in AML and MDS. The purpose of the current 
study is to assess clinical effects of MBG453 in combination with HMA (azacitidine or 
decitabine) in adult subjects with IPSS-R intermediate, high, very high risk MDS. This 
randomized, two-arm, parallel-group, double-blind, placebo-controlled study will compare 
MBG453 plus HMA or placebo plus HMA. Objectives and endpoints of the study are detailed 
in Section 2. 


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2 
Objectives and endpoints 
The objectives and associated endpoints are presented in Table 2-1 below: 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To determine if MBG453 
combined with standard HMA 
therapy improves complete 
remission in subjects with 
intermediate, high, or very 
high risk MDS 
• 
Complete remission (CR) rate according to International 
Working Group (IWG) for MDS (Section 8.3) as per 
investigator assessment (Section 12.4.1.1) 
• 
To determine if MBG453 
combined with standard HMA 
therapy improves PFS in 
subjects with intermediate, 
high or very high risk MDS 
• 
PFS is defined as time from randomization to disease 
progression (including transformation to acute leukemia 
per WHO 2016 classification), relapse from CR according 
to IWG-MDS (Section 8.3) or death due to any cause, 
whichever occurs first, as per investigator assessment 
(Section 12.4.1.2) 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess Overall Survival in 
each treatment arm 
• 
Time from randomization to death due to any cause 
• 
To assess EFS in each 
treatment arm 
• 
EFS is defined as time from randomization to lack of 
reaching CR within the first 6 months, relapse from CR or 
death due to any cause, whichever occurs first. CR and 
relapse from CR are defined according to International 
Working Group (IWG) for MDS (Section 8.3) as per 
investigator assessment.  
• 
To assess Leukemia-free 
survival in each treatment 
• 
Time from randomization to ≥ 20% blasts in bone-
marrow/peripheral blood (per WHO 2016 classification) or 
diagnosis of extramedullary acute leukemia or death due 
to any cause 
• 
To assess responses rate in 
each treatment arm 
• 
Percentage of CR/mCR/PR according to IWG-MDS as per 
investigator assessment and HI according to IWG-MDS  
• 
To assess duration of 
complete remission in each 
treatment arm 
• 
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 
• 
To assess time to complete 
remission in each treatment 
arm 
• 
Time from randomization to the first documented CR 
• 
To assess the improvement in 
RBC/platelets transfusion 
independence in each 
treatment arm. 
• 
Number and percent of subjects who are 
RBC/platelets transfusion independent and duration of 
transfusion independence (Section 8.3) after 
randomization as per IWG-MDS 
• 
To assess the safety profile of 
MBG453 when given in 
combination with HMA 
• 
Incidence and severity of AEs and SAEs, changes in 
laboratory values and vital signs, incidence of notable 
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Objective(s) 
Endpoint(s) 
• 
To characterize the 
pharmacokinetics of MBG453 
when given in combination 
with HMA 
• 
Serum concentrations and pharmacokinetic parameters 
for MBG453  
• 
To evaluate immunogenicity of 
MBG453 when given in 
combination of HMA 
• 
Anti-drug Antibody (ADA) prevalence at baseline and ADA 
incidence on-treatment 
3 
Study design 
This Phase II is a multicenter, randomized, two-arm parallel-group, double-blind, placebo-
controlled study of MBG453 or placebo added to hypomethylating agents (azacitidine or 
decitabine, as per investigators' choice based on local standard of care (SOC)) in adult subjects 
with IPSS-R intermediate, high or very high risk myelodysplastic syndrome (MDS) not eligible 
for HSCT or intensive chemotherapy. 


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Approximately 120 subjects will be randomized in a 1:1 ratio to treatment arms as described in 
the Figure 3-1. The randomization will be stratified by 2 stratification factors: a) HMA 
(decitabine or azacitidine) selected by the investigator as per the local standard of care (SOC) 
and b) IPSS-R prognostic risk categories (intermediate, high or very high) at randomization. 
Crossover between treatment arms is not permitted at any time during the study. 
The study treatment consists of cycles of MBG453 or placebo in combination with HMA 
administered to the subjects until treatment discontinuation (Section 6.1.5 and Section 9.1.1). 
Treatment options and dosing information is provided in Section 6.1.1. The planned duration 
of a cycle is 28 days. 
After the end of study treatment, all subjects must be followed for adverse events (AEs) for 30 
days following the last dose of azacitidine or decitabine, or 150 days following the last dose of 
MBG453 or placebo, whichever is later. In addition, all subjects who discontinued study 
treatment will enter a long-term follow-up (for efficacy and/or survival status) for up to 4 years 
from the last subject randomized. Subjects who are scheduled for hematopoietic stem-cell 
transplant (HSCT) or intensive chemotherapy at any time during the course of the study will be 
discontinued from study treatment but will also enter a long term follow-up (for efficacy and/or 
for survival status) for up to 4 years from the last subject randomized (Section 12.8.1).  
Figure 3-1 
Study design 
 


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Figure 3-2 
Study flow 
 
4 
Rationale 
4.1 
Rationale for study design 
The justification for a double-blind, randomized, placebo-controlled trial is to determine the 
efficacy of adding MBG453 to the current standard of care on the primary efficacy endpoints 
(complete remission and progression free survival). The randomized, double-blind placebo-






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4.3 
Rationale for choice of the combination drugs 
4.3.1 
Rationale for HMA (azacitidine or 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 of 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 subjects achieved a significantly 
higher overall response rate (17%), including 9% complete remissions, compared with 
supportive care (0%) (p < 0.001). An additional 12 subjects 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 subjects 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 (See Section 6.1.1.).  
4.3.2 
Rationale for MBG453 
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 subjects with solid tumors or hematological malignancies. 
Abnormal upregulation of PD-L1, PD-L2, PD-1, and CTLA4 in CD34+ cells in MDS subjects 
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 subjects 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 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 
are ongoing in solid tumors and hematological malignancies. 
Safety data indicate that the compound was well tolerated overall in 291 subjects with solid 
tumors or hematological malignancies exposed to MBG453. Two trials are ongoing: one 
Phase I/II open label, multicenter study of the safety and efficacy of MBG453 as single agent 
and in combination with PDR001 in adult subjects with advanced malignancies 
[CMBG453X2101] and a Phase Ib multi-arm, open label study of PDR001 and/or MBG453 in 
combination with decitabine in subjects with AML or high risk MDS [CPDR001X2105]. 


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In particular, the compound was well tolerated as a single agent or when it is administered 
intravenously in combination with decitabine or azacitidine to MDS/AML subjects. Please refer 
to Section 4.2 and the [MBG453 Investigator's Brochure] for more details. 
Preliminary efficacy data reported in higher risk MDS subjects are showing high response rates. 
At the time of the latest data cut-off on 25-Jun-2020 among 35 evaluable patients with high-
risk MDS, overall response rate (ORR) was 62.9% (22 patients) including 8 CR, 8 mCR 
(including 5 mCR with hematologic improvement [HI]) and 6 stable disease with HI. Median 
time to response was 2.0 months and estimated 6-month Duration of response rate for 
CR/mCR/PR was 90% (95% CI: 73.2-100%). Encouraging response rates were achieved in 
both patients with high-risk per IPSS-R MDS (ORR 50% [11/22]) and very high-risk per IPSS-
R MDS (ORR 84.6% [11/13]) [CPDR001X2105]. 
 
4.3.3 
Rationale for combining MBG453 with HMA (azacitidine and 
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 1.1) strongly supports the evaluation of the 
novel anti-TIM-3 antibody MBG453 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 subjects indicate that MGB453 plus decitabine or azacitidine combination is feasible, well 
tolerated and produces clinical responses (see Section 4.3.2). Please refer to Section 4.2 and to 
the [MBG453 Investigator's Brochure] for more details. 


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Azacitidine and decitabine exhibit a similar safety profile and share a similar mechanism of 
action. As a result, the combination of MBG453 with azacitidine is likely to be feasible and as 
tolerated as the combination MBG453 with decitabine. Immunomodulators, such as MBG453, 
may regulate CYP enzymes and may cause Drug-Drug Interaction (DDI) with small molecule 
drugs because of the potential to alter CYP mediated metabolism. However, cytochrome P450 
mediated degradation is minor for HMA and therefore DDI between MBG453 and HMA is not 
expected. When MBG453 was administered in combination with decitabine in the 
CPDR001X2105 study, MBG453 PK were similar to that observed in the CMBG453X2101 
study, while decitabine PK was similar to the label reported value. 
In CPDR001X2105 study, a signal of a relevant clinical activity is being reported with high 
response rate, durable response and absence of disease progression in all high risk MDS and 
newly diagnosed AML subjects who were treated with MBG453 and HMA (see above). 
4.4 
Purpose and timing of interim analyses/design adaptations 
The statistical basis for claim of efficacy in favor of the MBG453 arm is based on either 
statistical significance for CR rate or statistical significance for PFS as detailed in 
Section 12.4.2. 
There was one analysis of the CR rate, with a data cut-off date fixed at 7 months after the last 
randomized subject. It has taken place in May-2021 and the DMC recommended to continue 
the study blinded without changes. PFS was not tested at this time point. A PFS interim analysis 
will be performed after 75% of the planned target PFS events have been observed. If the PFS is 
not already significant at IA, the final PFS analysis will be conducted after observing 
approximately 108 PFS events or at approximately 4 months after the PFS IA data cut-off date, 
whichever comes first. The final PFS analysis if applicable, and the interim OS analysis will be 
performed approximately 4 months after the PFS IA data cut-off date. The final OS analysis will 
be performed with a data cut-off date of 4 years after the last subject randomized. The timing 
of the CR rate analysis, the interim and final PFS analyses and OS analyses are detailed 
in Section 12.4.2 and Section 12.7. Figure 12-2 described the study flow of the analyses. 
4.5 
Risks and benefits 
The potential benefit of MBG453 combined with HMA in MDS is suggested by early efficacy 
results from the study [PDR001X2105], which showed achievement of durable complete 
remission or bone marrow CR in high risk MDS subjects receiving MBG453 in combination 
with decitabine (Section 4.3.2). The proportion of higher-risk MDS patients achieving CR/mCR 
and durable CR/mCR under treatment with MBG453 combined with HMA appears to be larger 
as compared to historic and published data on similar MDS patients treated with decitabine or 
azacitidine alone. 
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring. The MBG453 dose established in 
other studies will be used in combination with HMA, dose modifications must be applied per 
protocol based on clinical or laboratory findings, and a close safety monitoring will be 
performed during the study. 


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Occurrence of an immune-related event is an anticipated risk in subjects treated with checkpoint 
inhibitors, such as MBG453. In the case of an immune-related event, 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 6.5.1 and Section 6.5.2). 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 Section 6.5.1). 
Based on currently available data, there are no known significant overlapping toxicities between 
decitabine or azacitidine and MBG453. However, there may be unforeseen risks from 
combining decitabine or azacitidine with MBG453, 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 subjects enrolled will be monitored closely for these 
potential toxicities. Furthermore, as safety data of the azacitidine + MBG453 combination are 
not yet available from the ongoing [CPDR001X2105] study, the protocol of the trial stipulates 
that a data monitoring committee (DMC) (Section 10.2.1) will meet regularly to review safety 
data and initially when at least 10 subjects have received azacitidine combined with the study 
drug MBG453 or placebo for at least one cycle (approximately 5 subjects in each blinded 
treatment arm). Safety data from subjects receiving decitabine combined with the study drug 
MBG453 or placebo available will be reviewed as well at the same time. 
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 
subject 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 (Coronavirus disease of 2019) 
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. 
 
 


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4.7 
Rationale for Public Health Emergency mitigation procedures 
In the event of a Public Health emergency as declared by Local or Regional authorities i.e. 
pandemic (eg COVID-19), epidemic or natural disaster, mitigation procedures may be required 
to ensure subject safety and trial integrity are listed in relevant sections of the present study 
protocol. 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 
Population 
The study population will include adult subjects 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 to medical judgement for intensive chemotherapy or 
HSCT. Subjects with chronic myelomonocytic leukemia (CMML) are not eligible for this trial. 
The investigator or designee must ensure that only subjects who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Age ≥ 18 years at the date of signing the informed consent form (ICF). 
3. Morphologically confirmed diagnosis of a myelodysplastic syndrome (MDS) 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): 
• Very high (> 6 points) 
• High (> 4.5-6 points) 
• Intermediate (> 3-4.5 points): a subject determined to be in the Intermediate Prognostic 
Risk Category is only allowable with ≥ 5% bone marrow blasts at baseline 
4. Not eligible at the time of screening, for intensive chemotherapy according to the investigator, 
based on local standard medical practice and institutional guidelines for treatment decisions. 
5. Not eligible at the time of screening, for hematopoietic stem-cell transplantation (HSCT) 
according to the investigator, based on local standard medical practice and institutional 
guidelines for treatment decisions. 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. 
7. AST and ALT ≤ 3 × upper limit of normal (ULN). 
8. Total bilirubin ≤ 1.5 × ULN (except in the setting of isolated Gilbert syndrome where subjects 
may only be included with direct bilirubin ≤1.5 × ULN). 
9. Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73m2 (estimation based on 
Modification of Diet in Renal Disease (MDRD) formula, by local laboratory). 
10. Subject is able to communicate with the investigator and has the ability to comply with the 
requirements of the study procedures. 
5.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study 
1. Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune check point 
inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines are 
allowed except if the drug was administered within 4 months prior to randomization. 


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2. Previous first-line treatment for intermediate, high or very high risk myelodysplastic 
syndromes (based on IPSS-R) with chemotherapy or any other antineoplastic agents including 
lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine.  
3. History of severe hypersensitivity reactions to any ingredient of the study treatment 
(azacitidine, decitabine or MGB453) or their excipients, or to monoclonal antibodies (mAbs). 
4. Currently using or used within 14 days prior to randomization 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 prior to randomization. In case of 
a checkpoint inhibitor: 4 months minimum prior to randomization 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 randomization. 
8. Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and 
extra-medullary acute myeloid leukemia based on WHO 2016 classification (Arber et al 
2016). 
9. Diagnosis of Chronic myelomonocytic leukemia (CMML), or primary or secondary 
myelofibrosis based on 2016 WHO classification (Arber et al 2016). 
10. History of organ transplant or allogeneic hematopoietic stem cell transplant.  
11. Exclusion criteria retired. 
12. Any concurrent severe and/or uncontrolled medical condition. Subjects 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 > 470 ms at screening, long QT syndrome or family history of unexplained cardiac 
death 
c) Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third 
degree AV block). 
14. Subjects with prior malignancy, except:  
a) Subjects with history of lower risk MDS treated by supportive care (e.g. growth factors, 
TGF-beta agents) or untreated are eligible 
b) Subjects with history of lower risk MDS who were treated adequately and failed 
lenalidomide are eligible 
c) Subjects with history of adequately treated malignancy for which no anticancer systemic 
therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the 


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course of the study. Subjects 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. Subjects 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 subject to high risk 
of noncompliance with the protocol. 
18. Sexually active males unwilling to use a condom during intercourse while taking azacitidine 
or 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. 
19. Subject is pregnant or breastfeeding. 
20. 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 as per their 
respective local labels, whichever is longer) and 150 days after the last dose of MBG453 or 
placebo. Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). 
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female subjects on the study 
the vasectomized male partner should be the sole partner for that subject. 
• Use of oral (estrogen and progesterone), injected or implanted combined hormonal 
methods of contraception or placement of an intrauterine device (IUD) or intrauterine 
system (IUS) or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception 
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
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 


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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 or 
placebo plus hypomethylating agent (HMA: decitabine or azacitidine). 
The term “investigational drug” refers to the Novartis study drug, MBG453 or placebo. The 
choice of the HMA (as described in the following sections) will be selected by the investigator 
as per local standard of care (SOC) at randomization. The investigator choice for HMA must 
not be changed after randomization. 
All doses prescribed, dispensed to the subject and all dose changes during the study including 
the reason must be recorded on the appropriate electronic case report form (eCRF) page. 
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigationa
l/ Control 
Drug 
(Name and 
Strength) 
Dose 
administrati
on 
Pharmaceuti
cal Dosage 
Form 
Route of 
Administratio
n 
Supply Type 
Sponsor 
(global or 
local) 
MBG453 
100mg/1ml 
/Placebo  
400mg 
Solution for 
infusion 
Intravenous 
use 
Double Blind 
Sponsor 
(global) 
MBG453 
400mg/4ml 
/Placebo* 
400mg 
Solution for 
infusion 
Intravenous 
use 
Double Blind 
Sponsor 
(global) 
Decitabine 
50mg  single vi
al** 
20mg/m2 
Lyophilized 
powder 
Intravenous 
use 
Open Label 
Provided 
Locally 
Azacitidine 100
mg single vial** 
75mg/m2 
Lyophilized 
powder 
Intravenous or 
subcutaneous 
use 
Open label 
Provided 
Locally 
*During the study the MBG453 400mg/4ml/Placebo may be included as additional strength which 
will be globally supplied. 
**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 


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Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), 
Steensma 2018). 
Decitabine should be administered according to 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 day cycle (see local decitabine package insert). MBG453 or placebo 
infusions will be administered on Day 8 and Day 22 out of a 28 day cycle (Section 6.1). 
Azacitidine should be administered according to 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 day cycle (see local azacitidine 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 or placebo infusions will be 
administered on Day 8 and Day 22 out of a 28 day cycle (Section 6.1). 
If the alternative schedule is selected for azacitidine by the investigator, azacitidine and 
MBG453 or placebo will be given on the same Day 8. Azacitidine should be administered first, 
followed by MBG453 or placebo. Further instructions are described in the Pharmacy Manual. 
MBG453 or placebo will be administered at 400 mg via i.v. infusion over 30 minutes (up to 2 
hours, if clinically indicated). There should be a period of at least 1 hour after the infusion 
whereby the subject requires close observation. Further instructions for the preparation and 
dispensation of MBG453 or placebo is described in the Pharmacy Manual. 
6.1.2 
Additional study treatments 
Not applicable 
6.1.3 
Treatment arms/group 
Subjects will be randomized in a 1:1 ratio to: 
• MBG453 + HMA (decitabine or azacitidine) or 
• Placebo + HMA (decitabine or azacitidine) 
The randomization will be stratified by two stratification factors: 
• Hypomethylating agents as per investigators' choice at randomization based on local standard 
of care (SOC): a) decitabine or b) azacitidine 
• IPSS-R Prognostic Risk Categories: a) intermediate, b) high, c) very high 
6.1.4 
Guidelines for continuation of treatment 
The study treatment consists of HMA plus MBG453 or HMA plus placebo (Section 6.1.1). 
Planned duration of a cycle is 28 days. Treatment will continue until a protocol-defined reason 
for discontinuation is met (Section 9.1).  
Per protocol, dose modifications including interruptions for toxicities are permitted 
(Section 6.5.1, Section 6.5.2).  


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6.1.5 
Treatment duration 
A subject may be discontinued from study treatment for reasons of unacceptable toxicity, 
progressive disease (including transformation to acute leukemia per WHO 2016 classification) , 
withdrawal of consent by the subject, pregnancy, failure to adhere the protocol or at the 
discretion of the investigator or if the study is terminated by the Sponsor. Continuation of 
treatment beyond progression (including transformation to acute leukemia) may be possible in 
selected subjects (Section 6.1.5.1). 
Subjects who complete participation in this trial and continue to derive clinical benefit from the 
treatment based on the investigator’s evaluation may receive post-trial access. Post Trial Access 
(PTA) means the provision of treatment to trial subjects following their completion of trial 
participation. PTA will be provided until one of the following is met: subject no longer derives 
clinical benefit, investigator discontinues treatment, launch or reimbursement (where 
applicable), treatment fails to achieve registration in the trial subject’s country, or the clinical 
program is discontinued for any other reason including toxicity. 
Mechanisms for provision of PTA may include an extension phase to this study, a separate 
extension protocol, a rollover protocol, provision of the Novartis investigational product in a 
non-trial setting (known as post-study drug supply [PSDS]) when no further safety or efficacy 
data are required, or any other mechanism appropriate for the country. 
The PTA mechanism must comply with local laws and regulations in the participating trial 
countries. If Novartis discontinues the PTA for this trial, Novartis will work with investigators 
to transition patients onto locally available alternative treatment, or standard of care. 
6.1.5.1 
Treatment beyond disease progression 
Subjects with immunotherapy may get clinical benefit despite initial evidence of disease 
progression. Subjects will be allowed to continue the study treatment, HMA or MBG453 or 
placebo beyond disease progression if all following criteria are met: 
• There is no overt transformation to acute leukemia with ≥ 30 % blast. Regarding subjects with 
low blast count (> 20% and < 30%), subjects may continue the study treatment if the 
benefit/risk remains positive according to the investigator 
• There is a clinical benefit observed per investigator assessment 
• No unacceptable toxicity is reported 
• The subject continues to follow all protocol requirements 
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 
subject (e.g., such as anti-emetics, anti-diarrheal) is permitted (see Section 6.2.1.1), except 
when specifically prohibited (see Section 6.2.2). The subject must be told to notify the 
investigational site about any new medications he/she takes after the start of the study drug. 


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Subjects should not receive pre-medication to prevent infusion reaction before the first infusion 
of MBG453 or placebo. If a subject 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 subject 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 subject experiences a Grade 3 or Grade 4 
anaphylactic/anaphylactoid reaction, the investigational drug should be discontinued. 
MBG453 or placebo should be administered in a facility equipped for cardiopulmonary 
resuscitation. Appropriate resuscitation equipment should be available and a physician should 
be readily available. 
Subjects 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 randomization 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 
randomizing a subject or allowing a new medication to be started. If the subject is already 
randomized, contact Novartis medical monitor to determine if the subject 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. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Anticoagulation therapy is permitted if the subjects 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. Subjects 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 
or placebo. 


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6.2.2 
Prohibited medication 
During the course of the study, subjects 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 
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 subject 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, but should not be administered on the same day of study treatment administration to 
avoid potential overlapping adverse events. 
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 decitabine and azacitidine will apply according to 
local label. 
6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.) that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier unless the 
subject is re-screened. The Subject identifier consists of the Center Number (Center No.), (as 
assigned by Novartis to the investigative site) with a sequential Subject No. suffixed to it, so 
that each subject 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 subject the next 
sequential Subject No. 
The investigator or designated staff will contact the Interactive Response Technology (IRT) and 
provide the requested identifying information to register the subject. Once assigned, the Subject 
No. must not be reused for any other subject and the Subject No. for that individual must not 
be changed unless the subject is re-screened. If the subject fails to be randomized or start 
treatment for any reason, the reason will be entered into the appropriate eCRF page and 
IRT should be notified as soon as possible.  Re-screening is allowed once for subjects that were 






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Dose modifications for HMA will be done according to local practice and country-specific drug 
label. Dose modifications for MBG453 or placebo will be done according to ASCO guidelines 
about management of immune-related AEs (Brahmer et al 2018). Additionally, the guidance 
indicated in Table 6-2 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. 
Deviations to mandatory dose interruptions, reductions and/or permanent discontinuations are 
not allowed. 
• Dose modifications for MBG453 or placebo (See  Table 6-2  and refer to 
Brahmer et al 2018) 
Administration of MBG453 or placebo may be delayed due to toxicities. A scheduled dose may 
be delayed within a cycle by up to seven 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 or placebo are not allowed. 
Overall, for adverse events of potential immune-related etiology (irAE) that do not recover to 
≤ Grade 1 or baseline at a dose of immunosuppression of ≤ 10 mg/day prednisone or equivalent 
(or as indicated in Table 6-2) within 12 weeks after initiation of immunosuppressive therapy, 
MBG453 or placebo must be permanently discontinued 
• Dose modifications for HMA 
If azacitidine or 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 
country-specific label guiding azacitidine or decitabine use. 
• Permanent discontinuation of MBG453 or placebo and HMA 
If the study treatment (i.e. MBG453 + HMA or placebo + HMA) 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 treatment for both, HMA and 
MBG453/placebo) the subject should be discontinued from study treatment. 
• Permanent discontinuation of only one component MBG453/placebo or HMA 
If one component only of the study treatment (HMA OR MBG453, placebo) is discontinued 
for toxicities, then the treatment may continue with the other component of study treatment 
alone (MBG453 or placebo alone or HMA alone) as long as the subject benefits per 
investigator's judgement.  
All dose changes must be recorded on the appropriate CRF. 
 


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Table 6-2 
Criteria for dose interruption and re-initiation of study drug MBG453 
or placebo 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/placebo   
For toxicities thought to be immune-related and not covered in the ASCO Guidelines for the 
management of immune-related adverse events in subjects treated with immune checkpoint 
inhibitor therapy Brahmer et al 2018 
Grade 1 
No change. Continue MBG453/placebo at the 
same dose (400 mg) and schedule (Q2W) 
Grade 2 or Grade 3 ≤ 7 days 
Delay MBG453/placebo until toxicity resolved to 
≤ Grade 1 or baseline. Then resume at the same 
dose (400 mg) and schedule (Q2W) 
Grade 3 lasting > 7 days but < 21 days 
Delay MBG453/placebo until toxicity resolved to 
≤ Grade 1 or baseline. Then resume at the same 
dose (400 mg) but with a longer treatment 
interval (Q4W). Return to the initial treatment 
interval (Q2W) may be possible but only after 
discussion and agreement with Novartis Medical 
Lead 
Grade 3 lasting ≥ 21 days Or Grade 4 
Discontinue MBG453/placebo 
General guideline for non-hematologic, non-immune-related toxicities that are clinically significant** 
and possibly attributable to the investigational drug. 
This guideline does not apply for toxicities attributable to HMA (decitabine or azacitidine) or the 
underlying MDS including its complications. 
Grade 1 
No change. Continue MBG453/placebo at the 
same dose (400 mg) and schedule (Q2W) 
Grade 2 or Grade 3 ≤ 7 days  
Delay MBG453/placebo until toxicity resolved to 
≤ Grade 1 or baseline. Then resume at the same 
dose (400 mg) and schedule (Q2W) 
Grade 3 > 7 days  
Delay MBG453/placebo until toxicity resolved to 
≤ Grade 1 or baseline. Then resume at the same 
dose (400 mg) but with a longer treatment 
interval (Q4W). Return to the initial treatment 
interval (Q2W) may be possible but only after 
discussion and agreement with Novartis Medical 
Lead 


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Worst Toxicity CTCAE v5.0 Grade 
 Dose Modifications 
Grade 4 
Discontinue MBG453/placebo 
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. 
6.5.2 
Follow-up for toxicities 
Subjects whose treatment is interrupted or permanently discontinued due to an AE or clinically 
significant laboratory value, must be followed-up at least once a week (or more frequently if 
required by institutional practices, or if clinically indicated) for 4 weeks, and subsequently at 
approximately 4-week intervals, until resolution or stabilization of the event, whichever comes 
first. Appropriate clinical experts should be consulted as deemed necessary.  
All subjects must be followed up for AEs for 30 days following the last dose of azacitidine or 
decitabine, or 150 days following the last dose of MBG453 or placebo, 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 subjects with signs or 
symptoms of irAEs should be monitored and managed following the ASCO Guidelines for the 
management of immune-related adverse events in subjects treated with immune checkpoint 
inhibitor therapy (Brahmer et al 2018). 
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 8-5 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 subjects receiving MBG453 in 
combination with decitabine. 
During this study, subjects should be closely monitored (including relevant laboratory tests) for 
signs and symptoms of TLS before initiation and during a treatment cycle. 


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To minimize risk of TLS, subjects 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/ i.v. hydration prior to treatment should be given in subjects with elevated uric acid 
or high tumor burden 
• Prompt supportive care in case of acute TLS (i.v. fluids and treatment with rasburicase as 
clinically indicated, when uric acid continues to rise despite allopurinol/febuxostat and 
fluids) 
• During a treatment cycle:  
• Frequent monitoring of the following laboratory tests (per assessment cycle and as 
clinically indicated): potassium, phosphorus, calcium, creatinine, and uric acid 
• Encourage oral hydration 
Based on laboratory and clinical TLS criteria (modified from Cairo and Bishop 2004), the 
following measures for TLS should be also followed: 
Laboratory tumor lysis syndrome 
• Defined as two or more of the following values within 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 
• Phosphorus ≥ 6.5 mg/dL (children) or ≥ 4.5 mg/dL (adults) or 25% increase from 
baseline 
• Calcium ≤ 7 mg/dL or 25% decrease from baseline 
• Regimen:  
• If none or one of the laboratory values above is abnormal, continue to manage with 
allopurinol or a non-allopurinol alternative (e.g., febuxostat) and oral fluids. If uric acid 
remains elevated, consider i.v. fluids, treatment with rasburicase, and hospital monitoring. 
• Laboratory TLS should be managed with i.v. 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 


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• Regimen: Clinical TLS should be managed with i.v. fluids, laboratory blood tests every 6 to 8 
hours, cardiac monitoring, treatment with rasburicase/allopurinol/febuxostat and inpatient care 
(consider intensive care unit (ICU)). 
Subjects 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. 
6.5.2.1 
Follow-up on potential drug-induced liver injury (DILI) cases 
Subjects with transaminase increase combined with TBIL increase may be indicative of 
potential DILI and should be considered as clinically important events and should be assessed 
appropriately to establish diagnosis. The required clinical information, as detailed below, 
should be sought to obtain the medical diagnosis of the most likely cause of the observed 
laboratory abnormalities. 
The threshold for potential DILI may depend on the subject’s baseline AST/ALT and TBIL 
value; subjects meeting any of the following criteria will require further follow-up as outlined 
below: 
• For subjects with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 
• For subjects with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 3.0 x 
baseline] OR  [ALT or AST > 8.0 x ULN] combined with [TBIL > 2 x baseline AND > 2.0 x 
ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before the diagnosis of DILI is confirmed. 
A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected. 
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, gamma-
glutamyl transferase (GGT), glutamate dehydrogenase (GLDH), prothrombin time (PT)/INR, 
alkaline phosphatase, albumin, and creatine kinase. 
Perform relevant examinations (Ultrasound or magnetic resonance imaging (MRI), endoscopic 
retrograde cholangiopancreatography (ERCP) as appropriate, to rule out if liver function tests 
(LFTs) are caused by cholestasis (defined as ALP elevation > 2.0 x ULN with R value < 2). 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R > 2 and < 5) liver injury. 


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Table 6-3 
Guidance on specific clinical and diagnostic assessments to be (OR 
which can be) performed to rule out possible alternative causes of the 
observed LFT abnormalities 
Disease 
Assessment 
Hepatitis A, B, C, E 
• 
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, 
HBV DNA; anti-HCV, HCV RNA, IgM & IgG 
anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
• 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; 
IgM & IgG anti-EBV 
Autoimmune hepatitis 
• 
ANA & ASMA titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
• 
Ethanol history, gGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
• 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
• 
Medical history: acute or chronic CHF, 
hypotension, hypoxia, hepatic venous 
occlusion. Ultrasound or MRI. 
Biliary tract disease 
• 
Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if <40 yrs. old) 
• 
Ceruloplasmin 
Hemochromatosis 
• 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
• 
Alpha-1-antitrypsin 
 
Other causes should also be considered based upon the subjects' medical history 
(Hyperthyroidism/thyrotoxic hepatitis – T3, free T4, thyroid stimulating hormone (TSH); CVD 
/ Ischemic hepatitis – electrocardiogram (ECG), prior hypotensive episodes; T1D/glycogenic 
hepatitis). 
Obtain PK sample to determine exposure to study drug and metabolites. 
Following appropriate causality assessments, as outlined above, the causality of the drug is 
estimated as “probable” i.e. >50% likely, if it appears greater than all other causes combined. 
The term “drug-induced” indicates probably caused by the drug, not by something else, and 
only such a case can be considered DILI case and should be reported as an SAE. 
6.5.2.2 
Follow-up for QTcF Prolongation 
In case of QTcF >480 ms (or QTcF prolongation > 60 ms from baseline): 
• Assess the quality of the ECG recording. Collect two additional ECGs as soon as possible and 
submit the triplicate for central review. 
• Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities. 
• Review concomitant medication use for possible causes for QT prolongation (refer to 
crediblemedicines.org). Record all concomitant medications in the appropriate eCRF page. 
• Monitor ECG per the institutional standards. 


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• Contact Novartis Medical Lead in case QTcF > 500 ms or QTcF prolongation > 60 ms from 
baseline. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
IRT must be contacted to assign a medication (kit) number to the subjects every time the 
MBG453 or placebo is to be administered. The date and time of all study treatment 
administrations during the study and any deviations from the protocol treatment schedule will 
be captured by the investigator staff on the appropriate study treatment dispensing form. 
Compliance with the study treatment and any protocol deviations will be assessed by the field 
monitor on an ongoing basis. All study treatment dispensed and returned (if applicable) must 
be recorded in the Drug Accountability Log. 
Pharmacokinetic 
samples 
will 
be 
taken 
in 
all 
subjects 
as 
detailed 
in 
the 
pharmacokinetic Section 8.5.2. 
6.6.2 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• Protocol number 
• Name (if available) 
• Subject number 
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
Study treatment must be discontinued once emergency unblinding has occurred. The subject 
will have an End of Treatment (EOT) visit completed and will continue to be followed for 
recurrence and survival as specified in the protocol (Section 9.1.5 and Section 9.1.6). 


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6.7 
Preparation and dispensation 
Novartis will supply each study site with the investigational drug (MBG453 or placebo) in 
packaging of identical appearance per product volume. 
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label), immediately before dispensing the medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document. 
MBG453 or placebo 
MBG453 (400 mg) or placebo will be administered i.v. Further instructions for the preparation 
and dispensation of MBG453 or placebo are described in the Pharmacy Manual. 
All dosages for MBG453 or placebo prescribed to the subject and all dose changes during the 
study must be recorded on the Dosage Administration Record eCRF. 
Decitabine 
For details on preparation refer to the country-specific label instructions and/or decitabine 
package insert, if the drug is commercially available. All dosages for decitabine prescribed to 
the subject and all dose changes during the study must be recorded on the Dosage 
Administration Record eCRF. 
Azacitidine 
For details on preparation refer to the country-specific label instructions and/or azacitidine 
package insert, if the drug is commercially available. All dosages for azacitidine prescribed to 
the subject and all dose changes during the study must be recorded on the Dosage 
Administration Record eCRF.   
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 
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 subject 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. 


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At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.7.1.2 
Handling of additional treatment 
Not applicable 
6.7.2 
Instruction for prescribing and taking study treatment 
Refer to Section 6.1.1. 
7 
Informed consent procedures 
Eligible subjects 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 subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her level of understanding. If the subject 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 subject source documents. 
The date when a subject’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. 
The study includes the option for the subjects to continue MBG453 or placebo alone. These 
will require a separate informed consent if the subject agrees to participate. It is required as part 
of this protocol that the investigator presents these options to the subjects, as permitted by local 
governing regulations. The process for obtaining consent should be the same as described above 
for the main informed consent. 
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 subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject. 




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to be administered on the same day as randomization. A visit window of + 3 days is allowed 
for treatment administration for reason other than toxicities. On PK collection days the windows 
are provided in Section 8.5.2.1. 
Subjects who discontinue the study treatment for any reason should be scheduled for an end of 
treatment (EOT) visit within 7 days from the date that the subject discontinued from treatment, 
at which time all of the assessments listed for the EOT visit will be performed (if bone marrow 
aspirate or biopsy was performed within 14 days from the EOT visit, the assessment does not 
have to be repeated).  
All subjects receiving the study treatment must have safety evaluations for 30 days after the 
last dose of decitabine or azacitidine, or 150 days after the last dose of MBG453 or placebo, 
whichever occurs later. After the safety follow-up on site visit on Day 30, subjects will be 
followed via telephone call for the Day 90 and Day 150 (or onsite visit if patient happens to 
be visiting the site). 
For post-treatment follow-up and survival information, please refer to Section 8.3.1, 
Section 9.1.5 and Section 9.1.6. 
As per Section 4.7, 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, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff to the subject´s 
home, can replace on-site study visits, for the duration of the disruption until it is safe for the 
subject to visit the site again. Response assessments (bone marrow and PB smear), collection 
of PK/PD/IG 
 samples as well as administration of investigational drug always 
have to be conducted at the investigational site.


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Table 8-1 
Assessment Schedule 
 
Period Screening 
Treatment 
Cycle 
 
Cycle 1 (28d) 
Cycle 2 (28d) 
Cycle 3 (28d) 
Cycle 4 (28d) 
Cycle 5 (28d) 
Cycle 6 (28d) 
Cycle 7 (28d) 
Days 
-28 to -1 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
IRT Screening  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
IRT Randomization1 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion 
criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical 
history/current 
medical conditions 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Disease History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior antineoplastic 
therapies 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior/concomitant 
medications, 
surgery and medical 
procedures 
(including blood 
transfusions 
requirement)2 
X 
Continuous  
Physical 
Examination 
S 
S 
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 
X 
X 
Body Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
BSA (use height 
from screening) 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Body Weight 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 


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Period Screening 
Treatment 
Cycle 
 
Cycle 1 (28d) 
Cycle 2 (28d) 
Cycle 3 (28d) 
Cycle 4 (28d) 
Cycle 5 (28d) 
Cycle 6 (28d) 
Cycle 7 (28d) 
Days 
-28 to -1 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
ECOG PS 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Hematology3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Coagulation 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Cytogenetics 4 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Thyroid function5 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Urinalysis dipstick 
and sediment 
S 
If clinically indicated 
Serum vitamin B12, 
serum and 
erythrocyte folates, 
iron  
X 
If clinically indicated 
Serum ferritin 
X 
If clinically indicated 
Cytokines for safety 
IFN-γ, IL-6, IL-
1,TNF-α6 
X 
Anytime for a suspected cytokine release syndrome, immediately after the AE, and one week after occurrence of AE 
Virology hepatitis B 
and C 
S 
If clinically indicated 
HIV serology (only if 
required  per local 
regulation) 
S 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum Pregnancy 
test 7 
S 
S8 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Urine Pregnancy 
Test  OR Serum 
Pregnancy Test7 
  
  
  
  
S 
  
  
S 
  
  
S 
  
  
S 
  
  
S 
  
  
S 
Efficacy - Bone 
marrow aspirate 
and/or biopsy and 
X10 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
X 


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Period Screening 
Treatment 
Cycle 
 
Cycle 1 (28d) 
Cycle 2 (28d) 
Cycle 3 (28d) 
Cycle 4 (28d) 
Cycle 5 (28d) 
Cycle 6 (28d) 
Cycle 7 (28d) 
Days 
-28 to -1 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
peripheral blood 
smears 9  
Response 
assessment11 
 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
X 
12-Lead ECG 
(triplicates)12 
X13 
X 
X 
  
S 
  
  
S 
X 
  
S 
  
  
S 
  
  
S 
  
  
S 
Adverse Events 
X 
Continuous 
Decitabine  infusion 
  
on Days 1-5 of every cycle: IV 20mg/m2   
Azacitidine infusion 
  
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 
MBG453/Placebo 
infusion 
  
on Day 8 and Day 22: 400 mg IV Q2W 
IRT - Drug 
Dispensation 
MBG453/Placebo 
  
  
X 
X 
  
X 
X 
  
X 
X 
  
X 
X 
  
X 
X 
  
X 
X 
  
Blood sample for 
PK analysis14 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
Blood sample for IG  
analysis14 
  
  
X 
  
  
  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  


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Period Screening 
Treatment 
Cycle 
 
Cycle 1 (28d) 
Cycle 2 (28d) 
Cycle 3 (28d) 
Cycle 4 (28d) 
Cycle 5 (28d) 
Cycle 6 (28d) 
Cycle 7 (28d) 
Days 
-28 to -1 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
D8 
D22 
D1 
Antineoplastic 
therapies including, 
HSCT and 
transfusions since 
discontinuation of 
study treatment19 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Disposition 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
IRT Discontinuation 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Survival Follow-up 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Period 
Treatment 
EOT 
Safety FU18 
Post- treatment FU Survival (every 3 months) 
Cycle Cycle 7 (28d) 
Cycle 8 (and beyond) (28d) 
 
 
 
 
Days 
D8 
D22 
D1 
D8 
D22 
- 
 
- 
- 
Informed consent 
  
  
  
  
  
  
  
  
  
IRT Screening  
  
  
  
  
  
  
  
  
  


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Period 
Treatment 
EOT 
Safety FU18 
Post- treatment FU Survival (every 3 months) 
Cycle Cycle 7 (28d) 
Cycle 8 (and beyond) (28d) 
 
 
 
 
Days 
D8 
D22 
D1 
D8 
D22 
- 
 
- 
- 
IRT 
Randomization1 
  
  
  
  
  
  
  
  
  
Demography 
  
  
  
  
  
  
  
  
  
Inclusion / 
Exclusion criteria 
  
  
  
  
  
  
  
  
  
Medical 
history/current 
medical 
conditions 
  
  
  
  
  
  
  
  
  
Disease History 
  
  
  
  
  
  
  
  
  
Prior 
antineoplastic 
therapies 
  
  
  
  
  
  
  
  
  
Prior/concomitant 
medications, 
surgery and 
medical 
procedures 
(including blood 
transfusions 
requirement)2 
Continuous  
X 
 
 
Physical 
Examination 
S 
S 
S 
S 
S 
S 
  
  
  
Vital Signs 
X 
X 
X 
X 
X 
X 
  
  
  
Body Height 
  
  
  
  
  
  
  
  
  
BSA (use height 
from screening) 
  
  
X 
  
  
  
  
  
  
Body Weight 
  
  
X 
  
  
X 
  
  
  
ECOG PS 
  
  
X 
  
  
X 
  
  
  
Hematology3 
X 
X 
X 
X 
X 
X 
  
Every 2 months and 
if clinically indicated 
  


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Period 
Treatment 
EOT 
Safety FU18 
Post- treatment FU Survival (every 3 months) 
Cycle Cycle 7 (28d) 
Cycle 8 (and beyond) (28d) 
 
 
 
 
Days 
D8 
D22 
D1 
D8 
D22 
- 
 
- 
- 
Chemistry 
  
  
X 
  
  
X 
  
  
  
Coagulation 
  
  
X 
  
  
X 
  
  
  
Cytogenetics 4 
  
  
  
  
  
  
  
  
  
Thyroid function5 
 
 
On cycle 8 and every 3 cycles thereafter 
 
 
X 
 
 
 
Urinalysis dipstick 
and sediment 
If clinically indicated 
  
  
  
Serum vitamin 
B12, serum and 
erythrocyte 
folates, iron  
If clinically indicated 
  
  
  
Serum ferritin 
If clinically indicated 
  
  
  
Cytokines for 
safety IFN-γ, IL-6, 
IL-1,TNF-α6 
Anytime for a suspected cytokine release syndrome, immediately after the 
AE, and one week after occurrence of AE 
  
  
  
Virology hepatitis 
B and C 
If clinically indicated 
  
  
  
HIV serology (only 
if required  per 
local regulation) 
  
  
  
  
  
  
  
  
  
Serum Pregnancy 
test 7 
  
  
  
  
  
S 
S20 
  
  
Urine Pregnancy 
Test  OR Serum 
Pregnancy Test7 
  
  
S 
  
  
  
Monthly testing20 
S 
  
  
Efficacy - Bone 
marrow aspirate 
and/or biopsy and 
peripheral blood 9  
  
  
On cycle 10, 13, 19, 25 and beyond, and 
if clinically indicated9 
  
  
X 
  
At least every 6 
months and if 
clinically indicated 
  
Response 
assessment11 
  
  
On cycle 10, 13, 19, 25 and beyond, and 
if clinically indicated 
  
  
X 
  
Every 2 months and 
if clinically indicated 
  


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Period 
Treatment 
EOT 
Safety FU18 
Post- treatment FU Survival (every 3 months) 
Cycle Cycle 7 (28d) 
Cycle 8 (and beyond) (28d) 
 
 
 
 
Days 
D8 
D22 
D1 
D8 
D22 
- 
 
- 
- 
12-Lead ECG 
(triplicates)12 
  
  
S 
  
  
S 
  
  
  
Adverse Events 
Continuous 
 Continuous 
  
  
Decitabine  
infusion 
on Days 1-5 of every cycle: IV 20mg/m2   
  
  
  
  
Azacitidine 
infusion 
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 
  
  
  
  
MBG453/Placebo 
infusion 
on Day 8 and Day 22: 400 mg IV Q2W 
  
  
  
  
IRT - Drug 
Dispensation 
MBG453/Placebo 
X 
X 
  
X 
X 
  
  
  
  
Blood sample for 
PK analysis14 
  
  
  
On 
cycles 
9, 12, 
18 
and 
24 
  
X 
D30 and D150 
 
  
Blood sample for 
IG  analysis14 
  
  
  
On 
cycles 
9, 12, 
18 
and 
24 
  
X 
D30 and D150 
 
  


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Period 
Treatment 
EOT 
Safety FU18 
Post- treatment FU Survival (every 3 months) 
Cycle Cycle 7 (28d) 
Cycle 8 (and beyond) (28d) 
 
 
 
 
Days 
D8 
D22 
D1 
D8 
D22 
- 
 
- 
- 
Antineoplastic 
therapies 
including 
transplant, and 
transfusions since 
discontinuation of 
study treatment19 
  
  
  
  
  
  
X 
X 
X 
Disposition 
  
  
  
  
  
X 
  
X 
  
IRT 
Discontinuation 
  
  
  
  
  
X 
  
  
  
Survival Follow-up 
  
  
  
  
  
  
  
  
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 At C1D1 IRT randomization will be performed. MBG453 / placebo will not be dispensed at this visit 
2 Blood transfusion administered within 16 weeks prior to randomization should be collected. 3 During treatment, hematology should be performed at every visit and if 
clinically indicated at any time during the study. During post-treatment follow-up, hematology should be performed every 2 months and if clinically indicated at any time 




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Period 
Treatment 
EOT 
Safety FU18 
Post- treatment FU Survival (every 3 months) 
Cycle Cycle 7 (28d) 
Cycle 8 (and beyond) (28d) 
 
 
 
 
Days 
D8 
D22 
D1 
D8 
D22 
- 
 
- 
- 
20 Should be performed for women of child bearing potential monthly up to D90 after the last dose of azacitidine or decitabine; monthly up to D150 after the last dose of 
MBG453/placebo, and a serum pregnancy test should be performed on D150 after the last dose of MBG453/placebo. If the subject is not coming to the clinic during the 
safety follow-up period, the urine test can be performed at home or at a local doctor’s office, and the results must be communicated to the site staff. If the urine test is 
positive, then the subject will be asked to report to the clinic for a serum test. Please refer to Section 8.4.3.  
 


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8.1 
Screening 
Screening 
All subjects must provide signed ICFs prior to performing any study specific procedures. 
Subjects 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 randomization (Table 8-1). Laboratory parameters may be retested within the 28-day from 
the ICF signature if such parameters does not meet the eligibility criteria. If the repeat value 
remains outside of the specified ranges, the subject must be discontinued from the study and 
will be considered a screen failure. 
A subject may only be re-screened once for the study. A new ICF will need to be signed if the 
investigator chooses to re-screen the subject. For re-screened subjects, a new Subject No. should 
be assigned, and all required screening activities must be perform when the subject is re-
screened for participation in the study. 
Bone marrow and peripheral blood pathology specimens (i.e. bone marrow slides, bone marrow 
biopsy block if applicable, peripheral blood smears) prepared locally for establishing the MDS 
diagnosis at the time of screening, should be sent to the Novartis designated central laboratory 
for storage. A copy of the corresponding pathology reports should be collected and sent to the 
Novartis designated central laboratory for storage. Central morphology review of the pathology 
specimens may be performed, if deemed necessary. 
8.1.1 
Eligibility screening 
Following registering in the IRT for screening, subject eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual. 
8.1.2 
Information to be collected on screening failures 
Subjects who sign an informed consent form and subsequently found to be ineligible prior to 
randomization 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 subjects. No 
other data will be entered into the clinical database for subjects who are screen failures, unless 
the subject experienced a serious adverse event during the screening Phase (see SAE section 
for reporting details, Section 10.1.3). If the subject fails to be randomized, the IRT is to be 
notified as soon as possible that the subject was not randomized. Subjects who are randomized 
are not considered screening failures regardless of eligibility. 
8.2 
Subject demographics/other baseline characteristics 
Demographics and other baseline characteristics data to be collected on all subjects include: 
Other background, relevant medical history or current medical conditions 




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criteria in MDS are described in Table 8-2. Investigators will assess and document 
response/progression at each time point as per the visit schedule. For efficacy analyses, baseline 
is defined as the last non-missing assessment on or before the date of randomization.  
The hematological improvement per modified IWG-MDS criteria (Cheson et al 2006) will be 
assessed in all randomized subjects 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 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] 
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: 


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Response category 
Definition# 
neutrophils counts during periods of active infection will not 
be considered in determining the maximum 
3. 
Decrease of ≥ 50% from maximum remission/response*** 
levels in platelets AND platelets < 100*109/L 
4. 
Decrease from maximum remission/response*** levels in 
Hgb concentration by ≥ 1.5g/dL AND Hgb < 10 g/dL 
5. 
Becoming transfusion dependent** 
Disease progression 
At least 1 of the following criteria is met:  
[in absence of another explanation not due to MDS, such as acute 
infection, bleeding, hemolysis, etc. Note that observation of 
peripheral blasts is not a sufficient criterion for progression. However 
in that case, a bone marrow examination should be made to 
determine whether relapse has occurred] 
Bone marrow according to the number of blasts of the 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. 




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screening and pre-dose during treatment period at C4D1, C7D1, C10D1, and C13D1 and 
hematology assessments will be performed at screening, D1, D8 and D22 of each cycle until 
end of treatment and if clinically indicated at any time during the study. After C13D1, bone 
marrow assessments are to be done every 6 cycles (C19D1, C25D1, etc.) and hematology 
assessments every 2 months 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 
randomization. If a subject's screening BMA/BMB was collected >28 days before 
randomization, then the subject must agree to have a repeat BMA/BMB performed. Clinical 
suspicion of relapse or disease progression at any time after randomization will require a disease 
evaluation promptly, 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. 
Post-treatment efficacy follow-up 
For subjects who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent/opposition to use data/biological samples, 
will enter the post-treatment follow-up phase. Efficacy assessments (hematology and bone 
marrow aspirate/biopsy) should follow Table 8-1. Response 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 documented disease progression/relapse 
(per IWG criteria Table 8-2), death, lost to follow-up, or withdrawal of consent/opposition to 
use data/biological samples. 
8.3.2 
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, the last available assessment on or before the date of start of study 
treatment is taken as ‘‘baseline” assessment. 
For details on AE collection and reporting, refer to AE Section 10.1. 
As per Section 4.7, 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 as necessary for safety monitoring and discussion of the 
subject´s health status until it is safe for the subject to visit the site again. 
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, 


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Assessment 
Specification 
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 . 
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 subject’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. 


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As per Section 4.7, 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, if participants cannot visit the site for protocol specified safety lab assessments, an 
alternative lab (local) collection site may be required for patient’s management and used. 
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 subjects 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) 
Additional tests 
Ferritin, iron, vitamin B12, erythrocyte and/or serum folates **, 
TSH, Free T3, Free T4 
*Virology, urinalysis and pregnancy test will only be reported in the source documentation. 
**Preferred method is erythrocyte folate but in case is not available then serum should be performed. 
However, every effort should be made to perform both test. 
***Preferred cytokine panel should include IFN-γ, IL-6, IL-1, TNF-α, however it may be adjusted as per 
standard local practice. 
****If Troponin T is not available, Troponin I may be performed.  
8.4.2 
Electrocardiogram (ECG) 
Standard triplicate 12-lead ECG recording will be performed according to Table 8-6 and 
Table 8-7. The Fredericia QT corrected (QTcF) values should be used for clinical decisions. 
The ECGs are to be collected with ECG machines supplied by the central laboratory during the 
following timepoints: C1D1 predose, C1D8 post-dose, and C3D8 predose. At the remaining 
time-points ECG will be collected locally including unscheduled ECGs. When triplicate ECG 
is required, collect three serial ECGs approximately 3 minutes apart after the subject has been 
resting comfortably in a supine position for about 10 minutes (it should be obtained before 
blood collection if a blood sample is scheduled at the same time point). Pre-dose ECG to be 


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collected prior to any study drug dosing. Post-dose ECG to be collected at the end of study drug 
infusion. 
Clinically significant ECG abnormalities present at screening should be reported on the 
appropriate CRF and must be discussed with Novartis prior to randomizing the subject in the 
study. New or worsened clinically significant findings occurring after informed consent must 
be recorded as adverse events. All ECGs recorded using the machines supported by the central 
laboratory must be transmitted electronically to the central laboratory and should be centrally 
reviewed by an independent reviewer.  
Any identifier details must be redacted e.g. subject initials, date of birth where local regulations 
require it. 
Additional ECGs may be repeated at the discretion of the investigator locally at any time during 
the study as clinically indicated. In case of new abnormalities, a cardiologist should be 
consulted, as needed.  
Refer to section 'Dose modification' in case of QTcF prolongation (Section 6.5). 
Table 8-6 
Central ECG collection plan 
Cycle 
Day 
Time 
ECG Type 
1 
1 
Pre-dose 
12 Lead Triplicate 
1 
8 
Post-dose** 
12 Lead Triplicate 
3 
8 
Pre-dose*** 
12 Lead Triplicate 
**ECG to be collected after dose of MBG453 or placebo 
***ECG to be collected prior to any study drug dosing 
Table 8-7 
Local ECG collection plan 
Cycle 
Day 
Time 
ECG Type 
Screening** 
-28 to -1 
Anytime 
12 Lead Triplicate 
2 
1 
Pre-dose 
12 Lead Triplicate 
3 
1 
Pre-dose 
12 Lead Triplicate 
4 and subsequent 
cycles 
1 
Pre-dose 
12 Lead Triplicate 
EOT 
NA 
Anytime 
12 Lead Triplicate 
Unscheduled 
Any 
Anytime 
12 Lead Triplicate 
**Results will be collected in the eCRF 
8.4.3 
Pregnancy and assessments of fertility 
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 safety follow up, women of child bearing potential will be 


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tested monthly with urine or serum pregnancy tests up to Day 90 after the last dose of azacitidine 
or decitabine. They will also be tested monthly with urine or serum pregnancy tests up to Day 
150 after the last dose of MBG453/placebo, and a serum pregnancy test should be performed 
on Day 150 after the last dose of MBG453/placebo. If the subject is not coming to the clinic 
during the safety follow-up period, or 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, 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 as per 
their respective local labels, whichever is longer) and 150 days after the last dose of MBG453 
or placebo. 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 
subject regardless of reported reproductive/menopausal status at screening/baseline. 
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 and for 3 months after stopping these drugs. In addition, male 
participants should not donate sperm for the time period specified above. 
Prior to starting treatment, male subjects are advised to seek consultation on sperm storage and 
female subjects of child-bearing potential should seek consultation regarding oocyte 
cryopreservation. 
8.5 
Additional assessments 
 
 




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Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein opposite to the arm used for infusion. 
A single blood sample of approximately 5 mL will be collected. After clotting, the resulting 
serum will be separated in aliquots and will be stored frozen until analysis. The exact date and 
clock times of drug administration and blood draw for PK, 
 IG assessment will be 
recorded on the appropriate eCRF. 
After permanent discontinuation of MBG453 or placebo, the samples scheduled for pre-
MBG453/placebo and end of MBG453/placebo infusion (within 2 hours) should no longer be 
collected with exception of 30 days and 150 days safety follow-up. Refer to the 
[MBG453B12201 Laboratory Manual] for detailed instructions for the collection, handling, and 
shipment of PK, IG 
 samples. 
Table 8-8 
Blood (serum) collection schedule for PK, IG 
 
Cycle 
Day 
Scheduled 
Time Point 
(h) 
PK Sample 
IG Sample 
1 
1 
Pre-HMA 
infusion* 
 
 
1 
8 
Pre-MBG453 
infusion 
x 
x 
1 
8 
End of 
MBG453 
infusion 
(within 2 
hours) 
x 
 
2 
8 
Pre-MBG453 
infusion* 
x 
 
3 
8 
Pre-MBG453 
infusion* 
x 
x 
3 
8 
End of 
MBG453 
infusion 
(within 2 
hours) 
x 
 
4 
8 
Pre-MBG453 
infusion* 
x 
x 
5 
8 
Pre-MBG453 
infusion* 
x 
x 
6 
8 
Pre-MBG453 
infusion* 
x 
x 
9 
8 
Pre-MBG453 
infusion* 
x 
x 
12 
8 
Pre-MBG453 
infusion* 
x 
x 
18 
8 
Pre-MBG453 
infusion* 
x 
x 




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


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Study treatment must be discontinued under the following circumstances: 
• Subject/guardian decision* 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
(Section 6.2.2) 
• Any situation in which study participation might result in a safety risk to the subject 
• Following emergency unblinding 
• Any adverse events or laboratory abnormalities that in the judgement of the 
investigator, taking into consideration the subject’s overall status, prevents the subject from 
continuing participation in the study 
• Protocol-defined reasons for discontinuation (see Section 6.1.4 and Section 6.1.5) 
• Termination of the study by Novartis 
• Subjects who are scheduled for hematopoietic stem-cell transplant (HSCT) or intensive 
chemotherapy at any time during the course of the study  
*If discontinuation from study treatment occurs, the investigator should make a reasonable 
effort to understand the primary reason for the subject’s discontinuation from study treatment 
and record this information. 
Subjects who discontinue from study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent/Opposition to use data/biological samples' 
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 subject/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 subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 
The investigator must also contact the IRT to register the subject’s discontinuation from 
MBG453 or placebo. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code Section 6.6.2. 
For subjects who discontinue from study treatment for reasons other than documented disease 
progression, pregnancy, death, lost to follow-up, or withdrawal of consent/opposition to use 
data/biological samples, 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 documented disease progression, death, lost to follow-up, or 
withdrawal of consent/opposition to use data/biological samples.. 
In some circumstances subjects may be allowed to continue to receive study treatment beyond 
disease progression as per criteria described at Section 6.1.5.1. These subjects will continue 


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assessments as outlined in the assessments section (Section 8), and will complete the EOT visit 
only after permanent discontinuation from study treatment. 
9.1.2 
Withdrawal of informed consent/Opposition to use data/biological 
samples 
Withdrawal of consent/opposition to use data/biological samples occurs when a subject: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
subject’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study related contacts)  
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw their consent/opposition 
to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the subject therefore cannot withdraw consent. However, they still retain the right 
to object to the further collection or use of their Personal Data.  
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
If the subject agrees, a final evaluation at the time of the subject’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition.  
9.1.3 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw/oppose to the use of their data/biological samples, the 
investigator must show "due diligence" by documenting in the source documents steps taken to 
contact the subject, e.g. dates of telephone calls, registered letters, etc. A subject should not be 
considered as lost to follow-up until due diligence has been completed or until the end of the 
study. 




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treatment and be followed as per the schedule of assessments. The end of study is defined as 4 
years after the last subject randomized; which is the data cut-off date for the final OS analysis 
and a final CSR will be produced  (Section 12.4). Also, in the event of an early study termination 
decision, the end of the study is the date of that decision. 
At the end of the study, in alignment with local regulations, Post Trial Access (PTA) will be set 
up to continue provision of the study treatment outside this study through an alternative setting 
to subjects who in the opinion of investigator are still deriving clinical benefit (see Section 
6.1.5).  
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 subject or 
clinical investigation subject 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 subject 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 subject at 
each visit during the study. Adverse events also may be detected when they are reported by the 
subject 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 subject, 
3. its duration (start and end dates or ongoing), and the outcome 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 


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All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. its outcome (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 subject. 
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 150 days following the last 
dose of MBG453 or placebo, whichever is later (After the safety follow-up on site visit on 
Day 30, subjects will be followed via telephone call for the Day 90 and Day 150 (or onsite 
visit if a patient happens to be visiting the site)). 
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 subjects 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 subject 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 subject’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 subject 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 subject 
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 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 
events irrespective if a clinical event has occurred. 


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10.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent to 30 days after the date of the last actual administration of HMA 
or 150 days after the last dose of MBG453 or placebo, whichever is later and it must be reported 
to Novartis safety immediately, without undue delay, and under no circumstances later than 
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 unless otherwise specified by local law/regulations.  
 
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 subject who is screened but is not treated or randomized) SAEs 
occurring after the subject has provided informed consent until the time the subject is deemed 
a Screen Failure must be reported to Novartis 
2. Randomized OR Treated Subjects: SAEs collected between the time the subject signs ICF to 
30 days after the date of the last actual administration of HMA or 150 days after the last dose 
of MBG453 or placebo, 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 
immediately, without undue delay, and under no circumstances later than within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one must be 
reported separately as a new event. 
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 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. 
 


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10.1.4 
Pregnancy reporting 
Pregnancies 
To ensure subject safety, each pregnancy occurring in a female study subject 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 
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 subjects 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, subject 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 
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 
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 
Not applicable 


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10.2.1 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess safety data and recommend to the 
sponsor whether to continue, modify, or terminate a trial. The DMC will be responsible to 
periodically review safety data after the first enrolled subject has started study treatment. The 
DMC will review also efficacy (CR rate and PFS) at the time of the CR rate analysis and interim 
PFS analysis. 
DMC Composition  
It is expected that the DMC will consist at a minimum of two physicians with appropriate 
disease area qualifications and one statistician. 
DMC Responsibilities 
DMC will be responsible to review regularly safety data of subjects treated in the study. 
It is envisioned that the DMC may make recommendations with regard to safety, namely: 
• No safety issues, ethical to continue the study as planned 
• Serious safety concerns precluding further study treatment 
• Recommendation to continue the study but proposing an amendment to the protocol (e.g. 
incorporate an additional safety assessments) 
If the study is recommended to continue by the DMC, no details about the safety results will be 
revealed. 
DMC will be responsible to review CR rate and PFS data of subjects randomized into the study 
at the time of CR rate analysis. 
It is envisioned that the DMC may make recommendations, namely: 
• Recommendation to continue the study blinded as planned, no details about the efficacy 
results will be revealed 
• Recommendation to continue the study blinded as planned but proposing to the Sponsor to 
unblind the interim results, if CR rate is statistically significant 
If CR rate analysis is not statistically significant, the DMC will be responsible to review CR 
rate and PFS data of subjects randomized into the study at the time of PFS IA. 
It is envisioned that the DMC may make recommendations, namely: 
• Recommendation to continue the study blinded as planned, no details about the efficacy 
results will be revealed 
• Recommendation to continue the study blinded as planned but proposing to have the 
Sponsor unblinded to the interim results, if PFS IA is statistically significant 
DMC meetings Frequency  
The DMC will be established prior to the randomization of the first subject. 


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There will be an initial meeting with the DMC describing their roles and responsibilities and 
discussing potential data format and process issues prior to the finalization of DMC charter and 
the study analysis plan. 
The second meeting will occur when at least 10 subjects have received azacitidine combined 
with the study drug MBG453 or placebo for at least one cycle (approximately 5 subjects in each 
blinded treatment arm). Safety data from subjects receiving decitabine combined with the study 
drug MBG453 or placebo available will be reviewed during this meeting as well. 
Thereafter, DMC will meet on a regular basis as described in the DMC Charter to review safety 
data. The frequency of the DMC safety reviews may vary and depend on the recruitment rate, 
the number of subjects on-treatment and upon DMC's request. They may also be notified 
periodically if concerns develop. 
The DMC will review also efficacy (CR rate and PFS) at the time of the CR rate analysis and 
interim PFS analysis. 
More specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC. 
10.2.2 
Steering Committee 
The Steering Committee (SC) will be established comprising of investigators participating in 
the trial, i.e. not being members of the DMC and Novartis representatives from the Clinical 
Trial Team. 
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 
publications of study results including authorship rules. The details of the role of the steering 
committee will be defined in the steering committee charter. The Study Steering Committee 
will not have access to unblinded trial data at the time of the CR rate analysis. The SC will be 
unblinded after the interim OS analysis. 
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. 


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After final database lock, the investigator will receive copies of the subject 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 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. 
Randomization codes and data about all study treatment(s) dispensed to the subject will be 
tracked using an Interactive Response Technology (IRT). The system will be supplied by a 
vendor, who will also manage the database. The data will be sent electronically to Novartis at 
specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of 
Novartis. 
Once all the necessary actions have been completed and the database has been declared 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time 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 will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject 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 subject 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 


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subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject). 
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 
subjects will be disclosed. 
12 
Data analysis and statistical methods 
The CR rate analysis is planned when the last randomized subject has reached cycle 7 (or 
discontinued earlier). No interim analysis (IA) is planned for CR rate. The intent of this CR rate 
analysis is to assess whether MBG453 + HMA has superior efficacy than Placebo + HMA based 
on the CR rate. The other primary endpoint PFS will not be tested at this time point and is 
following a group sequential design.  
One interim analysis for PFS is planned after approximately 81 of the targeted 108 PFS events 
(i.e. at approximately 75% information fraction) have been documented. 
If PFS is not already significant at the interim analysis, the final PFS analysis will be performed 
after approximately 108 PFS events have been documented or at approximately 4 months after 
the interim PFS analysis data cut-off date, whichever comes first. The final PFS analysis if 
applicable, and the interim OS analysis will be performed approximately 4 months after the 
PFS IA data cut-off date. 
The final OS analysis will be performed with the data cut-off date of 4 years after the last subject 
randomized. 
All data will be summarized by treatment group: baseline characteristics, efficacy data for the 
Full Analysis Set, safety and other data (unless specified otherwise) for the Safety Set.  
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum as well as 25th and 75th percentiles will 
be presented. 
12.1 
Analysis sets 
Full Analysis Set: FAS 
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, subjects will be analyzed according 
to the treatment and strata they have been assigned to during the randomization procedure. 
Safety Set 
The Safety Set includes all subjects who received at least 1 dose of any component of the study 
treatment (MBG453 + HMA or placebo + HMA). Subjects will be analyzed according to the 
study treatment they received, either MBG453 + HMA or placebo + HMA. If the subject never 


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received the study drug (i.e. MBG453 or placebo) and took at least 1 dose of HMA, subjects 
will be analyzed in the placebo + HMA treatment arm. 
Pharmacokinetic Analysis Set: PAS 
The Pharmacokinetic Analysis Set (PAS) includes all subjects in the Safety Set, who had at 
least 1 evaluable PK concentration. 
For a concentration to be evaluable: 
• Dosing information must be properly documented (data and time of administration) 
• For post-dose samples: planned dose of MBG453 must be taken prior to sampling 
• For pre-dose samples: the sample is collected before the next dose administration 
12.2 
Subject demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for the FAS.  
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term. 
12.3 
Treatments 
The duration of exposure will be summarized for study treatment and for each study drug 
(MBG453, placebo and HMA (azacitidine and decitabine)). 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 component by descriptive statistics.  
The number of subjects with dose adjustments (reductions for HMA only, interruption, or 
permanent discontinuation) and the reasons will be summarized by study treatment and by study 
drug. 
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. 
RBC and platelets transfusions will be summarized for the period of 8 weeks prior to baseline 
and post-baseline. 
12.4 
Analysis of the primary endpoint(s) 
The 2 primary objectives of the study are to compare complete remission (CR) rate and 
progression-free survival (PFS) as per investigator assessment between the two treatment arms. 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoints are CR rate and PFS as per the International Working Group (IWG) 
criteria for MDS (Cheson et al 2006, Platzbecker et al 2018; Table 8-2): 
- CR rate is defined as the percentage of subjects with best overall response equal to confirmed 
complete remission (CR) 










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Event Free Survival (EFS) 
EFS is defined as time from randomization to lack of reaching CR within the first 6 months, 
relapse from CR or death due to any cause, whichever occurs first. CR and relapse from CR are 
defined according to International Working Group (IWG) for MDS (Section 8.3) as per 
investigator assessment. A subject without EFS event will have their EFS censored at the time 
of the last adequate response assessment performed on or before the cut-off date. For subject 
without reaching CR within the first 6 months, an EFS event at day 1 will be considered.  
Leukemia-free survival 
Leukemia-free survival is defined as the time from date of randomization to ≥ 20% blast in 
bone-marrow/peripheral blood as per WHO 2016 classification or diagnosis of extramedullary 
acute leukemia or death to any cause. For subject without event, the time is censored at the 
latest date the subject was known to be alive and without leukemia (on or before the cut-off 
date).  
Response rate (CR/mCR/PR/HI) 
Response rate is defined as the proportion of subjects with best overall response of either 
complete remission (CR)/marrow remission (mCR)/partial remission (PR)/hematologic 
improvement (HI) as per investigator assessment according to modified MDS-IWG (Table 8-2). 
Response 
rates 
will 
be 
provided 
with 
exact 
95% 
confidence 
intervals 
(Clopper and Pearson 1934). Stable Disease (SD) rate is defined as the proportion of subjects 
with best overall response of SD per investigator assessment. Any hematologic improvement 
rate, based on Table 8-2, will be reported separately with exact 95% confidence intervals 
(Clopper and Pearson 1934). 
Duration of CR 
Duration of CR is only derived for subjects with CR. 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. Subjects continuing without event will be censored at the date of 
their last adequate response assessment. 
Time to CR 
Time to CR is defined as the time from the date of randomization to the first documented CR. 
Subjects without a CR will be censored at the study-maximum follow-up time (i.e. Last Patient 
Last Visit (LPLV)) 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. 
Red blood cells (RBC)/Platelets transfusion independence 
RBC/Platelets transfusion independence rate is defined as the proportion of subjects having 
received 0 units of RBC/Platelets transfusions during at least 8 consecutive weeks after 
randomization (Table 8-2). The number and percentage of subjects will be shown for the overall 
FAS and then also in only those with transfusion dependence at baseline as defined in 
Table 8-2. Percentages 
will 
be 
provided 
with 
exact 
95% 
confidence 
intervals 
(Clopper and Pearson 1934). 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 


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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. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used.  
On-treatment period for safety analyses  
For safety reporting, the overall observation period will be divided into three mutually exclusive 
segments: 
1. Pre-treatment period: from day of subject’s informed consent to the day before first dose of 
study treatment 
2. On-treatment period: from day of first dose of study medication to 30 days after date of last 
administration of study treatment (MBG453, placebo or HMA) 
3. Post-treatment period: starting at day 30 + 1 after date of last administration of study 
treatment (MBG453, placebo 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 or placebo, 
whichever is later.  
Adverse events 
All information obtained on adverse events will be displayed by treatment arm and subject. 
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). 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 subjects with adverse events will be summarized: 
• By treatment arm, 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. 






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12.7 
Interim analyses 
The null hypothesis for CR rate will be tested at alpha-CR significance level (Figure 12-1), and 
the analysis will be scheduled approximately 7 months after the last subject has been 
randomized in the study. This analysis is expected to take place approximately 18 months after 
the date that the first subject is randomized, assuming a recruitment duration of approximatively 
11 months. No interim analysis (IA) is planned for CR rate. 
A maximum of two analyses will be performed for PFS. The interim analysis will be 
scheduled when approximately 81 PFS events (75% of the target number) have been 
documented, expected to occur approximately 28 months after the first subject randomized. 
Based on the pooled observed PFS events, the rate of discontinuations without PFS event, the 
limited number of subjects still at risk to have a PFS event and the predictions of future events, 
there is a risk that the targeted 108 PFS events for FA will not be observed at all or within a 
reasonable time frame. Therefore, the PFS final analysis will be performed using the pre-
defined cut-off date of approximately 4 months after the PFS IA with the number of PFS events 
documented by this date, if PFS is not already significant at IA. The final OS analysis will be 
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13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines 
for Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 


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monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last subject last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects 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. 












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Table 16-5 
Eligibility based on serologic markers for hepatitis B 
 
Figure 16-1 
Decision tree to determine eligibility based on serologic markers for 
hepatitis B  
 
 

SAP_001.pdf: 








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Date 
Time point 
Reason 
for 
update 
Outcome for 
update 
Section and title impacted (Current) 
already significant at IA. The final PFS 
analysis if applicable, and the interim 
OS 
analysis 
will 
be 
performed 
approximately 4 months after the PFS 
IA data cut-off date. Based on FDA’s 
recommendation, the alpha spending 
function for PFS and OS analyses 
were modified to use O’Brien and 
Fleming boundaries. 


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Table of contents 
Table of contents ................................................................................................................. 6 
List of abbreviations ............................................................................................................ 8 
1 
Introduction ....................................................................................................................... 10 
1.1 
Study design........................................................................................................... 10 
1.2 
Study objectives and endpoints ............................................................................. 11 
2 
Statistical methods ............................................................................................................. 13 
2.1 
Data analysis .......................................................................................................... 13 
2.2 
Analysis sets .......................................................................................................... 15 
2.2.1 
Subgroup of interest .............................................................................. 16 
2.3 
Subject disposition, demographics and other baseline characteristics .................. 16 
2.3.1 
Subject disposition ................................................................................ 16 
2.3.2 
Demographic and other baseline characteristics ................................... 16 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 17 
2.4.1 
Study treatment / compliance ................................................................ 17 
2.4.2 
Concomitant and post-treatment therapies / HSCT .............................. 18 
2.5 
Analysis of the primary endpoint(s) ...................................................................... 19 
2.5.1 
Complete remission rate ........................................................................ 21 
2.5.2 
Progression Free Survival (PFS) ........................................................... 22 
2.5.3 
Statistical hypothesis, model, and method of analysis .......................... 24 
2.5.4 
Handling of missing values/censoring/discontinuations ....................... 25 
2.5.5 
Sensitivity analyses ............................................................................... 26 
2.5.6 
Supportive analyses ............................................................................... 26 
2.6 
Analysis of secondary endpoints ........................................................................... 26 
2.6.1 
Efficacy ................................................................................................. 26 
2.6.2 
Safety ..................................................................................................... 29 
2.6.3 
Pharmacokinetics .................................................................................. 32 
 
 ........................................................................ 33 
 
 ............................................................................................ 33 
 
 .......................................... 34 
 
 .............................................................................. 35 
 
 ......................................................... 35 
 
 .................................................... 35 
2.8 
Interim analysis ...................................................................................................... 35 
2.9 
Sample size calculation .......................................................................................... 37 
 
 .............................................................................. 39 


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.. 40 
5 
References ......................................................................................................................... 45 


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List of abbreviations 
ADA 
Anti-drug Antibody 
AE 
adverse event 
 
 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
BLQ 
Below the Limit of Quantitation  
BM 
Bone marrow 
BMI 
Body mass index 
BOR 
Best Overall Response 
BP 
Blood pressure 
BSA 
Body surface area 
CI 
Confidence interval 
CHM 
Cochran-Mantel-Haenszel 
CR 
Complete Remission 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DMC 
Data Monitoring Committee 
DMS 
Document Management System 
DOR 
Duration of response 
eCRF 
Electronic Case Report/Record Form 
 
 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
EOT 
End of treatment  
FAS 
Full Analysis Set 
Hgb 
Hemoglobin 
HLT 
High level terms 
HMA 
Hypomethylating agent 
HR 
Hazard ratio 
HSCT 
Hematopoietic stem cell transplantation 
IV 
Intravenous 
IA 
Interim Analysis 
IG 
Immunogenecity 
IPSS-R 
International Prognostic Scoring System 




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1 
Introduction 
This statistical analysis plan (SAP) describes the planned analyses for the primary Clinical 
Study Report (CSR) of the study CMBG453B12201, a randomized, double-blind, placebo-
controlled, phase II study evaluating the efficacy and safety of MBG453 in combination with 
hypomethylating agents in subjects with IPSS-R intermediate, high or very high-risk 
myelodysplastic syndrome (MDS). 
As specified in the study protocol amendment 4, the CR rate analysis was performed 
approximately 7 months after the last subject has been randomized in the study. The CR rate 
analysis was performed in May 2021 and the DMC recommended to continue the study blinded 
without changes. 
In case the PFS is declared statistically significant at the PFS IA, this analysis will constitute 
the basis for the primary CSR. Otherwise, the final PFS analysis  , will be considered as the 
primary analysis and will constitute the basis of the primary CSR. Updated analyses after the 
primary CSR will be conducted and reported as needed. This SAP will serve as the basis for 
those analyses as well, however, a separate selection of tables, figures and listings (TFL) might 
be done.   
The content of this SAP is based on the CMBG453B12201 protocol including amendment 4 (2-
Sep-2021). All decisions regarding the analysis, as defined in the SAP document, have been 
made prior to database lock and unblinding of the study data. The SAP is written using the 
future tense, as the first version was approved at the start of the study. 
1.1 
Study design 
This Phase II is a multicenter, randomized, two-arm parallel-group, double-blind, placebo-
controlled study of MBG453 or placebo added to a hypomethylating agent (azacitidine or 
decitabine, as per investigators' choice based on local standard of care (SOC)) in adult subjects 
with IPSS-R intermediate, high or very high risk myelodysplastic syndrome (MDS) not eligible 
for HSCT or intensive chemotherapy. 
Subjects will be randomized in a 1:1 ratio as described in Figure 1.1 to one of the following: 
• MBG453 + HMA (decitabine or azacitidine) or 
• Placebo + HMA (decitabine or azacitidine) 
The randomization will be stratified by two stratification factors: 
• Hypomethylating agent (HMA) as per investigators' choice at randomization based on 
local standard of care (SOC): a) decitabine or b) azacitidine 
• IPSS-R Prognostic Risk Categories: a) intermediate, b) high, c) very high 
The study treatment consists of cycles of MBG453 or placebo 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. Crossover between treatment arms is not permitted at 
any time during the study. 




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Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To determine if MBG453 
combined with standard HMA 
therapy improves complete 
remission in subjects with 
intermediate, high, or very high 
risk MDS 
• 
Complete remission(CR) rate according to International 
Working Group (IWG) for MDS as per investigator 
assessment 
• 
To determine if MBG453 
combined with standard HMA 
therapy improves PFS in 
subjects with intermediate, high 
or very high risk MDS 
• 
PFS is defined as time from randomization to disease 
progression (including transformation to acute 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 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess Overall Survival in 
each treatment arm 
• 
Time from randomization to death due to any cause 
• 
To assess EFS in each 
treatment arm 
• 
EFS is defined as time from randomization to lack of 
reaching CR within the first 6 months, relapse from CR or 
death due to any cause, whichever occurs first. CR and 
relapse from CR are defined according to International 
Working Group (IWG) for MDS (Section 2.5) as per 
investigator assessment.  
• 
To assess Leukemia-free 
survival in each treatment 
• 
Time from randomization to ≥ 20% blasts in bone-
marrow/peripheral blood (per WHO 2016 classification) 
or diagnosis of extramedullary acute leukemia or death 
due to any cause 
• 
To assess responses rate in 
each treatment arm 
• 
Percentage of CR/mCR/PR according to IWG-MDS as 
per investigator assessment and HI according to IWG-
MDS  
• 
To assess duration of complete 
remission in each treatment 
arm 
• 
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 
• 
To assess time to complete 
remission in each treatment 
arm 
• 
Time from randomization to the first documented CR 
• 
To assess the improvement in 
RBC/platelets transfusion 
independence in each 
treatment arm. 
• 
Number and percent of subjects who are 
RBC/platelets transfusion independent and duration of 
transfusion independence (Section 2.5)  after 
randomization as per IWG-MDS 
• 
To assess the safety profile of 
MBG453 when given in 
combination with HMA 
• 
Incidence and severity of AEs and SAEs, changes in 
laboratory values and vital signs, incidence of notable 
ECG abnormalities 
• 
To characterize the 
pharmacokinetics of MBG453 
when given in combination with 
HMA 
• 
Serum concentrations and pharmacokinetic parameters 
for MBG453  


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Objective(s) 
Endpoint(s) 
• 
To evaluate immunogenicity of 
MBG453 when given in 
combination of HMA 
• 
Anti-drug Antibody (ADA) prevalence at baseline and 
ADA incidence on-treatment 
2 
Statistical methods 
2.1 
Data analysis   
The primary analysis will be performed by Novartis. However, the DMC analyses will be 
performed by an Independent Statistician and Independent Programmer at a CRO. 
 
   
SAS version 9.4 or later R 3.4.3 or later software will be used to perform all data analyses and 
to generate tables, figures and listings. 
Data included in the analysis / data cut-off handling  
For each of the analyses a data cut-off date will be defined.   


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The CR rate analysis will be done when all randomized subjects have completed 6 cycles of 
treatment or have discontinued the study. In order to allow for confirmation of response at least 
4 weeks after the initial response, the cut-off date will be set to 7 months after the last patient is 
randomized (or earlier depending on when the last patient had achieved CR).  
One interim analysis for PFS is planned after approximately 81 of the targeted 108 PFS events 
(i.e. at approximately 75% information fraction) have been documented. 
If PFS is not already significant at the interim analysis, the final PFS analysis will be performed 
after approximately 108 PFS events have been documented or at approximately 4 months after 
the interim PFS analysis data cut-off date, whichever comes first. The final PFS analysis if 
applicable, and the interim OS analysis will be performed approximately 4 months after the 
PFS IA data cut-off date. 
The final OS analysis will be performed with the data cut-off date of 4 years after the last subject 
randomized. 
For each of the analyses, all statistical analyses will be performed using all data collected in the 
database up to the data cut-off date. All data with an assessment date or event start date (e.g. 
laboratory assessment date or start date of an adverse event) prior to or on the cut-off date will 
be included in the analysis. Any data collected beyond the cut-off date will not be included in 
the analysis and will not be used for any derivations. 
General analysis conventions 
Data will be summarized by treatment arm: demographics and other baseline characteristics as 
well as efficacy data and anti-neoplastic therapies / HSCT for the Full Analysis Set, safety and 
any other data (unless specified otherwise) for the Safety Set.  
Qualitative data (e.g., gender, race) will be summarized by means of contingency tables; a 
missing category will be included as applicable. Percentages will be calculated using the 
number of subjects in the relevant population or subgroup as the denominator. 
Quantitative data (e.g., age, body weight) will be summarized by appropriate descriptive 
statistics (e.g. mean, standard deviation, median, 25th and 75th percentiles, minimum, and 
maximum). 
Study treatment and investigational drug 
MBG453 matching placebo refers to as “placebo” and azacitidine and decitabine as “HMA” 
throughout this document and in the analyses. The treatment arms are MBG453 + HMA and 
placebo + HMA.  
Study treatment refers to the combination of MBG453 or placebo with HMA.  
Investigational drug refers to the individual components: MBG453 or placebo. 


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2.2 
Analysis sets 
Full Analysis Set  
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, subjects will be analyzed according 
to the treatment and strata they have been assigned to during the randomization procedure. 
Safety Set 
The Safety Set includes all subjects who received at least 1 dose of any component of the study 
treatment (MBG453 + HMA or placebo + HMA). Subjects will be analyzed according to the 
study treatment they received, either MBG453 + HMA or placebo + HMA. If the subject never 
received the investigational drug (i.e. MBG453 or placebo) and took at least 1 dose of 
HMA, subjects will be analyzed in the placebo + HMA treatment arm. 
Pharmacokinetic Analysis Set  
The Pharmacokinetic Analysis Set (PAS) includes all subjects in the Safety Set, who had at 
least 1 evaluable PK concentration. 
For a concentration to be evaluable: 
• Dosing information must be properly documented (data and time of administration) 
• For post-dose samples: planned dose of MBG453 must be taken prior to sampling 
• For pre-dose samples: the sample is collected before the next dose administration 
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 set 
Protocol deviations leading to 
exclusion 
Non protocol deviation leading to 
exclusion 
FAS 
No written informed consent 
None 
Safety Set 
No written informed consent 
No dose of any component of study treatment 
PAS 
No written informed consent 
See definition of PAS 
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.  




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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 
summarized.  
Data from the IRT system at randomization will be summarized also: HMA selected 
(azacitidine or decitabine), IPSS-R risk category including the components (blasts in BM, 
number of cytopenias and cytogenetic abnormalities). 
Medical history 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term. Medical history and current medical conditions will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The 
MedDRA version used for reporting will be specified in the CSR and as a footnote in the 
applicable outputs.  
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Duration of exposure 
The duration of exposure (in months) will be summarized for study treatment and for each 
investigational drug individually (MBG453 and placebo) and for HMA (azacitidine or 
decitabine) based on summary statistics and categorical analyses (e.g. exposure <1 month, at 
least 1 month, at least 2 months etc.). 
 
     
Dose intensity 
The actual dose intensity (computed as the ratio of actual cumulative dose received and duration 
in days with at least one component of the combination) and the relative dose intensity 
(computed as the ratio of actual dose intensity and planned dose intensity) will be summarized 
for each study treatment component by descriptive statistics.  
For MBG453/placebo, the actual cumulative dose in mg is the sum of “dose administered” from 
the eCRF of all cycles during the exposure of MBG453/placebo. 
For HMA (azacitidine and 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) = ඥWeight (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 treatment to the end of the last cycle 
initiated irrespective of date of death, last contact date for withdraw consent and cut-off date: 


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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. 
 
 
The relative dose intensity is then comparing the actual dose intensity during subjects’ exposure 
with the protocol planned dose of 400 mg Q2W for MBG453/placebo and 20 mg/m2 for 
decitabine and 75 mg/m2 for azacitidine, e.g. if a subject received 300 mg Q2W on average 
throughout the study, the relative dose intensity for this subject is 0.75.  
Dose reductions, interruptions or permanent discontinuations 
The number (%) of subjects with any dose changes (incl. reductions, interruptions, or permanent 
discontinuations) and the reasons (e.g. AE, dosing error, dispensing error, physician decision) 
will be taken from the ‘Study Treatment eCRF’ and summarized by investigational drug and 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). 
2.4.2 
Concomitant and post-treatment therapies / HSCT 
Prior and concomitant medications/therapies 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system. 
Prior anti-neoplastic therapies 
Prior anti-neoplastic medications will be summarized using the FAS. Medications will be 
summarized by ATC class and preferred term.Radiotherapies and surgeries will be listed using 
the FAS. 
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD). 
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 (e.g. bleeding, surgical procedure, 
hemolysis, infections) of platelet and red blood cells will be summarized using the FAS. For 
that, the number of transfusion units will be normalized by time (fixed 8-weekly interval, 
mentioned below as episode) prior to and on-treatment. The number of subjects with at least 
one transfusion episode and the number of units per episode will also be described. Further 
analyses to summarize transfusion independence and dependence are described in the efficacy 
section.  
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 


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with the source, the type of transplant and the allogeneic donor type. Both analyses will be using 
the FAS.   
2.5 
Analysis of the primary endpoint(s) 
The 2 primary objectives of the study are to compare complete remission (CR) rate and 
progression-free survival (PFS) as per investigator assessment between the two treatment arms. 
The primary endpoints are CR rate and PFS as per the International Working Group (IWG) 
criteria for MDS (see Table 2-2 and further details in sections 2.5.1 and 2.5.2 of this analysis 
plan).  
To conclude for efficacy, the treatment effect needs to be demonstrated in any (or both) of the 
primary endpoints CR rate and/or PFS. The type I error control for this primary endpoint family 
is described in Section 2.8.  
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 2-2 below. 
Table 2-2 
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: 
• Hgb ≥ 10 g/dL AND 
• Platelets ≥ 100*109/L AND 
• Neutrophils ≥ 1.0*109/L AND 
• 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: 


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Response category 
Definition# 
[in absence of another explanation not due to MDS, such as acute 
infection, bleeding, hemolysis, etc. Note that observation of 
peripheral blasts is not a sufficient criterion for 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** 
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: 
• Less than 5% blasts at baseline: ≥ 50% increase in blasts over 
baseline to > 5% blasts 
• 5%-<10% blasts at baseline: ≥ 50% increase over baseline to > 
10% blasts 
• 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: 
• 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 
• Reduction from baseline 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  


















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from the end date of the last transfusion received until the date transfusions are given again or 
last date of treatment administration in case transfusions had not (re-)started during treatment. 
The total duration of all transfusion independence periods is the sum of each period of the 
transfusion independence. 
2.6.2 
Safety 
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). 
All safety analyses will be using the Safety Set. When specified, some analyses will be 
performed not only by treatment arm but also by HMA treatment (azacitidine vs. decitabine), 
provided enough subjects in each treatment arm had received decitabine. 
On-treatment period for safety analyses  
The following section streamlines the on-treatment period definition for safety analyses 
compared to the protocol section 12.5.2.  For safety reporting, the overall observation period 
will be divided into three mutually exclusive segments:  
1. Pre-treatment period: from day of subject’s informed consent to the day before first 
administration of study treatment  
2. On-treatment period: from day of first administration of study treatment to 30 days after 
last administration of study treatment (MBG453, placebo or HMA). 
3. Post-treatment period: starting at day 31 after after last administration of study treatment 
(MBG453, placebo 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 or placebo, 
whichever is later.    
Adverse events (AEs) 
AE summaries will include all AEs occurring during on-treatment period (until 30 days after 
last administration of study treatment). When specified, some AEs summaries will include all 
AEs occurring during the overall safety period.  
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period. The number (and percentage) of subjects with treatment emergent AEs 
will be summarized by primary system organ class, preferred term and maximum severity 
(based on CTCAE grades). 
All AEs reported in the AE eCRF page will be listed along with the information collected on 
those AEs, e.g. toxicity grade, relationship to study treatment, outcome, action taken etc. AEs 
that started during the pre-treatment, post-treatment and after the overall safety period will be 
flagged.   






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Table 2-4 
Notable ECG values 
ECG parameter (unit) 
Clinically notable criteria 
QT or QTcF (ms) 
Increase >30 and <=60 ms 
Increase >60 ms 
New >450 to <=480 ms 
New >480 to <=500 ms 
New >500 ms 
 
HR (bpm) 
Increase >25% and HR >100 bpm 
Decrease >25% and HR<50 bpm 
 
PR (ms) 
Increase from baseline >25% and to a value > 200 ms  
New value of > 200 ms  
 
QRS (ms) 
Increase from baseline >25% and to a value > 120 ms 
New values of QRS > 120 ms  
 
In addition, local ECGs are performed but not used for summary of QTc values. If abnormalities 
are observed based on these local ECGs, these abnormalities are to be reported and thus 
summarized as AEs.    
Clinical laboratory evaluations 
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 
calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low/normal/high based on laboratory normal ranges. 
For laboratory tests where grades are defined by CTCAE v5.0: 
• Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value 
Liver function parameters of interest are total bilirubin, ALT, AST and alkaline phosphatase. 
The number (%) of subjects with worst post-baseline values as per Novartis Liver Toxicity 
guidelines will be summarized. 
 All CTCAE grade 3 or 4 laboratory toxicities will be listed.  
ECOG Performance status  
ECOG PS categorical data will be summarized by timepoint (with visit windows as defined in 
Table 4.1).  
2.6.3 
Pharmacokinetics    
Pharmacokinetic (PK) data analysis will be performed for MBG453 only. The PAS will be used 
for all pharmacokinetic data analyses. 


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Descriptive statistics (n, m (number of non-zero concentrations), mean, coefficient of variation 
(CV%), standard deviation, median, geometric mean, geometric CV%, minimum and 
maximum) for MBG453 will be presented at each scheduled timepoint. PK parameters such as 
those listed in Table 2-5 will be estimated and reported. Below the limit of quantitation (BLQ) 
values will be set to zero by the Bioanalyst and will be displayed in the listing of all PK 
concentrations as zero and flagged. However, BLQ values will be treated as missing for the 
calculation of the geometric means and geometric CV% but included as zero in the other 
summary statistics. Missing values for any PK parameters or concentrations will not be imputed 
and will be treated as missing.  
All concentration data for MBG453 vs. time profiles will be displayed graphically.  
The concentrations collected before dose administration on Day 8 of Cycle 3 (and later cycles) 
are considered steady-state concentrations for MBG453. 
Table 2-5 
Non-compartmental pharmacokinetic parameters 
Cmin* or Ctrough* 
The minimum observed plasma or serum drug concentration (mass x volume-1) 
Cmax* or C2h* 
The maximum (peak) observed plasma or serum drug concentration (mass x volume-1) 
Population pharmacokinetic (PopPK) analysis 
If there is adequate amount of data, a mixed-effects model may be applied to the serum 
MBG453 concentration-time data from this study along with other studies to generate post-hoc 
estimates of pharmacokinetic parameters using appropriate software to characterize MBG453 
exposure and to determine the effects of intrinsic (i.e. demographic factors) and extrinsic 
covariates (e.g. combination partners) on MBG453 exposure. The details of the population 
pharmacokinetic analyses may be provided in a separate reporting and analysis plan, and the 
results may be reported in a separate population pharmacokinetic report. 
Immunogenicity (IG) / anti-drug antibody (ADA) 
Immunogenicity will be characterized descriptively by tabulating ADA prevalence at baseline 
or post-baseline and ADA incidence on-treatment.  
ADA incidence (i.e. ADA-positive subjects) will be calculated as the number of subjects with 
at least one on-treatment ADA-positive sample divided by the number of subjects with a 
determinant baseline IG sample and at least one determinant post-baseline IG sample.  
Listings will be provided of sample ADA status (including titer for positive samples) and 
subject ADA status. 
 
 
 


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2.8 
Interim analysis 
The null hypothesis for CR rate will be tested at alpha-CR significance level 
 and 
the analysis will be scheduled approximately 7 months after the last subject has been 
randomized in the study. This analysis is expected to take place approximately 18 months after 
the date that the first subject is randomized, assuming a recruitment duration of approximatively 
11 months. No interim analysis (IA) is planned for CR rate. 
A maximum of two analyses will be performed for PFS. The interim analysis will be 
scheduled when approximately 81 PFS events (75% of the target number) have been 
documented, expected to occur approximately 28 months after the first subject randomized. 
Based on the pooled observed PFS events, the rate of discontinuations without PFS event, the 
limited number of subjects still at risk to have a PFS event and the predictions of future events, 
there is a risk that the targeted 108 PFS events for FA will not be observed at all or within a 
reasonable time frame. Therefore, the PFS final analysis will be performed using the pre-
defined cut-off date of approximately 4 months after the PFS IA with the number of PFS events 
documented by this date, if PFS is not already significant at IA. The final OS analysis will be 
conducted with a data cut-off date of 4 years after the last subject randomized. 


















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