A Randomized, Double-blind, Placebo-controlled Phase III Multi-center Study of Azacitidine With or Without MBG453 for the Treatment of Patients With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2)
Phase: PHASE3
Conditions: Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic
Sponsor: Novartis Pharmaceuticals



Novartis
Confidential
Page 2 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Amendment 3 (23-Jun-2022) ............................................................................................13
Amendment 2 (14-Jul-2021) .............................................................................................15
Amendment 1 (06-Aug-2020)...........................................................................................18
Protocol summary..............................................................................................................21
1
Introduction .......................................................................................................................25
1.1
Background............................................................................................................25
1.2
Purpose ..................................................................................................................28
2
Objectives and endpoints...................................................................................................28
3
Study design ......................................................................................................................30
4
Rationale............................................................................................................................32
4.1
Rationale for study design .....................................................................................32
4.2
Rationale for dose/regimen and duration of treatment ..........................................33
4.3
Rationale for choice of combination drugs............................................................35
4.3.1
Rationale for azacitidine .......................................................................35
4.3.2
Rationale for MBG453..........................................................................36
4.3.3
Rationale for combining MBG453 with azacitidine.............................37
4.4
Purpose and timing of interim analyses.................................................................37
4.5
Risks and benefits..................................................................................................38
...................................................39
...........................................................39
..........................................39
4.7
Rationale for Public Health Emergency mitigation procedures ............................40
5
Study Population ...............................................................................................................40
5.1
Inclusion criteria ....................................................................................................40
5.2
Exclusion criteria...................................................................................................41
6
Treatment...........................................................................................................................43
6.1
Study treatment......................................................................................................43
6.1.1
Investigational and control drugs..........................................................44
6.1.2
Additional study treatments ..................................................................44
6.1.3
Treatment arms/group ...........................................................................44
6.1.4
Guidelines for continuation of treatment ..............................................45

Novartis
Confidential
Page 3 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
6.1.5
Treatment duration................................................................................45
6.2
Other treatment(s)..................................................................................................46
6.2.1
Concomitant therapy.............................................................................46
6.2.2
Prohibited medication ...........................................................................47
6.3
Subject numbering, treatment assignment, randomization....................................48
6.3.1
Subject numbering ................................................................................48
6.3.2
Treatment assignment, randomization ..................................................48
6.4
Treatment blinding.................................................................................................49
6.5
Dose escalation and dose modification..................................................................50
6.5.1
Dose modifications................................................................................50
6.5.2
Follow-up for toxicities.........................................................................52
6.6
Additional treatment guidance...............................................................................56
6.6.1
Treatment compliance...........................................................................56
6.6.2
Emergency breaking of assigned treatment code..................................56
6.7
Preparation and dispensation.................................................................................57
6.7.1
Handling of study treatment and additional treatment..........................57
6.7.2
Instruction for prescribing and taking study treatment .........................58
7
Informed consent procedures ............................................................................................58
8
Visit schedule and assessments .........................................................................................60
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.............................................75
8.3
Efficacy..................................................................................................................76
8.3.1
Efficacy assessments.............................................................................76
8.3.2
Appropriateness of efficacy assessments..............................................79
8.4
Safety.....................................................................................................................79
8.4.1
Laboratory evaluations..........................................................................80
8.4.2
Local Electrocardiogram (ECG) ...........................................................81
8.4.3
Pregnancy and assessments of fertility .................................................82
8.4.4
Additional safety monitoring and considerations .................................83
8.4.5
Appropriateness of safety measurements..............................................83
8.5
Additional assessments..........................................................................................84
8.5.1
Clinical Outcome Assessments (COAs) ...............................................84
8.5.2
Pharmacokinetics ..................................................................................86
............................................................................................89
9
Study discontinuation and completion ..............................................................................91

Novartis
Confidential
Page 4 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
9.1
Discontinuation......................................................................................................91
9.1.1
Discontinuation of study treatment .......................................................91
9.1.2
Withdrawal of informed consent/Opposition to use data/biological 
samples..................................................................................................92
9.1.3
Lost to follow-up...................................................................................93
9.1.4
Early study termination by the sponsor.................................................93
9.1.5
Post treatment follow-up.......................................................................94
9.1.6
Survival follow-up ................................................................................94
9.2
Study completion and post-study treatment ..........................................................94
10 Safety monitoring and reporting........................................................................................95
10.1
Definition of adverse events and reporting requirements......................................95
10.1.1
Adverse events ......................................................................................95
10.1.2
Serious adverse events ..........................................................................97
10.1.3
SAE reporting........................................................................................98
10.1.4
Pregnancy reporting ..............................................................................99
10.1.5
Reporting of study treatment errors including misuse/abuse................99
10.2
Additional Safety Monitoring..............................................................................100
10.2.1
Data Monitoring Committee ...............................................................100
10.2.2
Steering Committee.............................................................................101
11 Data Collection and Database management....................................................................102
11.1
Data collection.....................................................................................................102
11.2
Database management and quality control..........................................................102
11.3
Site monitoring ....................................................................................................103
12 Data analysis and statistical methods ..............................................................................103
12.1
Analysis sets ........................................................................................................104
12.2
Subject demographics and other baseline characteristics....................................104
12.3
Treatments ...........................................................................................................104
12.4
Analysis of the primary endpoint(s) ....................................................................105
12.4.1
Definition of primary endpoint(s).......................................................105
12.4.2
Statistical model, hypothesis, and method of analysis........................105
12.4.3
Handling of missing values/censoring/discontinuations.....................106
12.4.4
Supportive analyses.............................................................................106
12.5
Analysis of secondary endpoints .........................................................................106
12.5.1
Key secondary objectives....................................................................106
12.5.2
Efficacy and/or Pharmacodynamic endpoint(s)..................................113
12.5.3
Safety endpoints..................................................................................114
12.5.4
Pharmacokinetics ................................................................................115

Novartis
Confidential
Page 5 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
12.5.5
Patient reported outcomes...................................................................117
.......................................................................117
..................................................................................117
............................................................................117
..........................................................................................117
...................................................................118
..................................................119
12.7
Interim analyses...................................................................................................119
12.8
Sample size calculation........................................................................................121
12.8.1
Primary endpoint(s).............................................................................121
12.8.2
Secondary endpoint(s).........................................................................122
13 Ethical considerations and administrative procedures ....................................................122
13.1
Regulatory and ethical compliance......................................................................122
13.2
Responsibilities of the investigator and IRB/IEC................................................123
13.3
Publication of study protocol and results.............................................................123
13.4
Quality Control and Quality Assurance...............................................................123
14 Protocol adherence ..........................................................................................................123
14.1
Protocol amendments...........................................................................................124
15 References .......................................................................................................................125
16 Appendices ......................................................................................................................130
16.1
Appendix 1: Specific Renal Alert Criteria and Actions and Event Follow-up....130
16.2
Appendix 2: Guidance to support eligibility evaluation based on serologic 
markers for hepatitis B.........................................................................................131
16.3
Appendix 3: Statistical details of leveraging phase II study 
CMBG453B12201 data in the futility interim analysis.......................................132
16.3.1
Background .........................................................................................132
16.3.2
Statistical Models................................................................................133
16.3.3
Hypothetical scenarios ........................................................................135
16.3.4
Operating characteristics.....................................................................136
List of tables
Table 2-1
Objectives and related endpoints ..........................................................28
Table 6-1
Investigational and control drug............................................................44
Table 6-2
Criteria for dose interruption and re-initiation of MBG453 or 
placebo for adverse drug reactions........................................................51
Table 6-3
Follow-up of abnormal liver chemistry results .....................................54
Table 6-4
Action required for isolated total bilirubin elevation............................55
Table 6-5
Dose and treatment schedule.................................................................58

Novartis
Confidential
Page 6 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Table 8-1
Assessment Schedule ............................................................................62
Table 8-2
Modified response classification per IWG-MDS criteria 
(Platzbecker 2019, Cheson et al 2006, Cheson et al 2000)...................76
Table 8-3
Assessments & Specifications...............................................................80
Table 8-4
ECOG performance status.....................................................................80
Table 8-5
Clinical laboratory parameters collection plan .....................................81
Table 8-6
Local ECG collection plan....................................................................82
Table 8-7
Blood (serum) collection schedule for PK, IG and sTIM-3..................87
Table 8-8
Blood (serum) collection schedule for PK subgroup (in China only)...88
.............................................................................90
..............................................90
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................................100
Table 12-1
Noncompartmental pharmacokinetic parameters................................116
Table 12-2
Estimated timelines for interim and primary analysis assuming 5 
months delayed effects........................................................................121
Table 16-1
Specific Renal Alert Criteria and Actions...........................................130
Table 16-2
Renal Event Follow Up.......................................................................131
Table 16-3
Eligibility based on serologic markers for hepatitis B........................131
Table 16-4
Futility interim decision recommended by PoS..................................135
Table 16-5
Operating characteristics.....................................................................137
List of figures
Figure 3-1
Study design..........................................................................................31
Figure 3-2
Study Flow ............................................................................................32
Figure 12-1
Study flow of analyses and testing strategy........................................109
Figure 12-2
Graphical gate-keeping procedure in order to control overall type I 
error.....................................................................................................110
Figure 16-1
Decision tree to determine eligibility based on serologic markers 
for hepatitis B......................................................................................132
Figure 16-2
Critical HR in Ph3 as a function of the HR estimate observed in 
Ph2 (PoS=15% threshold)...................................................................136

Novartis
Confidential
Page 7 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
List of abbreviations
ADA
Anti-drug Antibody
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AML
Acute myeloid leukemia
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
AUC
Area Under the Curve
BLQ
Below the limit of quantitation
BMA
Bone marrow aspirate
BSA
Body surface area
BUN
Blood urea nitrogen
CBC
Complete Blood Count
CFR
Code of Federal Regulation
CI
Confidence interval
CK
Creatinine kinase
CMML
Chronic myelomonocytic leukemia
COA
Clinical Outcome Assessment
COVID-19
Coronavirus disease of 2019
CR
Complete Remission
CRi
Complete Remission with incomplete hematologic recovery
CSR
Clinical Study Report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTLA4
Cytotoxic T-lymphocyte-associated Protein 4
CV
Coefficient of variation
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
EC
Ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report/Record Form
EDC
Electronic Data Capture
eGFR
estimated Glomerular Filtration Rate
EHA
European Hematology Association
EMA
European Medicines Agency
EORTC QLQ-
C30
European Organisation for Research and Treatment of Cancer - Quality of Life 
Questionnaire
EOT
End of treatment
ePRO
Electronic Patient Reported Outcome
EQ-5D-5L
EuroQol Group - standardized measure of health status questionnaire
ESMO
European Society for Medical Oncology
FACIT
Functional Assessment of Chronic Illness Therapy

Novartis
Confidential
Page 8 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
FAS
Full Analysis Set
FDA
Food and Drug Administration
FUP
Follow Up
G-CSF
Granulocyte Colony Stimulating Factor 
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GLDH
Glutamate dehydrogenase
h
Hour
HBcAB
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HgB
Hemoglobin
HI
Hematologic improvement
HIV
Human immunodeficiency virus
HMA
Hypomethylating agent
HR
Hazard ratio
HSCT
Hematopoietic Stem-Cell Transplantation
i.v. or IV
Intravenous
IA
Interim Analysis
IB
Investigator's brochure
ICF
Informed consent form
ICH
International Council for Harmonization
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IG
Immunogenicity
INR
International normalized ratio
IPSS-R
Revised International Prognostic Scoring System
irAE
Immune related adverse event
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine System
IWG
International Working Group
LDH
Lactate dehydrogenase
LFT
Liver function test
LPLV
Last Patient Last Visit
MAP
Meta-analytic-predictive
MCH
Mean cell hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
mCR
marrow Complete Remission
MCV
Mean corpuscular volume
MDS
Myelodysplastic syndromes
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)

Novartis
Confidential
Page 9 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
mL
milliliter(s)
NB
negative binomial
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
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
PD-L1
Programmed cell death 1 ligand
PD-L2
Programmed cell death 2 ligand
PFS
Progression Free Survival
PK
Pharmacokinetic(s)
PoS
Probability of Success
PR
Partial remission
PRO
Patient Reported Outcome
PS
Performance status
PSDS
Post Study Drug Supply
PTA
Post Trial Access
Q2W
Every 2 weeks
Q4W
Every 4 weeks
Q8W
Every 8 weeks
QoL
Quality of life
QTcF
Corrected QT interval by Fridericia
RBC
Red blood cell(s)
RNA
Ribonucleic acid
s.c.
Subcutaneous
SAE
Serious adverse event
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2
SC
Steering Committee
sCR
serum creatinine
SCT
Stem cell transplant
SD
Stable disease
SOC
Standard of Care
sTIM-3
Soluble T-cell immunoglobulin domain and mucin domain-3
SUSAR
Suspected Unexpected Serious Adverse Reactions

Novartis
Confidential
Page 10 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
TBL
Total bilirubin
TFI
Transfusion-free interval
TFR
Transfusion-free rate
TIM-3
T-cell immunoglobulin domain and mucin domain-3
TLS
Tumor lysis syndrome
TSH
Thyroid-Stimulating Hormone
TTDD
Time to definitive deterioration
ULN
Upper limit of normal
VAS
Visual analogue scale
WBC
White blood cell(s)
WHO
World Health Organization

Novartis
Confidential
Page 11 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Glossary of terms
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 participant
Clinical Outcome 
Assessment (COA)
A measure that describes or reflects how a participant feels, functions, or survives
Coded Data
Personal Data which has been de-identified by the investigative center team by 
replacing personal identifiers with a code
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
Combination drug
Any drug that is combined to a specified regimen
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)
Discontinuation from 
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 participant permanently stops receiving the study treatment for 
any reason (prior to the planned completion of study drug administration, if any). 
Participants agrees to the other protocol required assessments including follow-up. 
No specific request is made to stop the use of their samples or data.
Enrollment
Point/time of subject entry into the study; the point at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the protocol).
Epoch
Interval of time in the planned conduct of a study. An epoch is associated with a 
purpose (e.g. screening, randomization, treatment, follow-up), which applies across 
all arms of a study.
Estimands
As defined in the ICH E9(R1) addendum, estimand is a precise description of the 
treatment effect reflecting the clinical question posed by the trial objective. It 
summarizes at a population-level what the outcomes would be in the same 
participants under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, as 
well as the specification of how the remaining intercurrent events are addressed and 
a population-level summary for the variable
Intercurrent Events
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest
Investigational drug
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational 
new drug” or “investigational medicinal product”.
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.
Part
A single component of a study which contains different objectives or populations 
within that single study. Common parts within a study are: a single dose part and a 
multiple dose part, or a part in patients with established disease and in those with 
newly-diagnosed disease.
Patient
An individual with the condition of interest
Patient Reported 
Outcome (PRO)
A measurement based on a report that comes directly from the patient about the 
status of a participant's health condition without amendment or interpretation of the 
patient's report by a clinician or anyone else

Novartis
Confidential
Page 12 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Period
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Randomization
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the assignments 
in order to reduce bias
Randomization number
A unique identifier assigned to each randomized subject, corresponding to a specific 
treatment arm assignment
Remote
Describes any trial activities performed at a location that is not the investigative site 
where the investigator will conduct the trial, but is for example a home or another 
appropriate location
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 participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational 
medicinal product(s)
Study treatment 
discontinuation
When the 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 unique number assigned to each subject upon signing the informed consent. This 
number is the definitive, unique identifier for the subject and should be used to 
identify the subject throughout the study for all data collected, sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed subject, 
corresponding to a specific treatment arm 
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 
use of data /biological 
samples
Withdrawal of consent from the study occurs when a 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. 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. 

Novartis
Confidential
Page 13 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Amendment 3 (23-Jun-2022) 
Amendment rationale 
The purpose of this protocol amendment is to adjust the group-sequential statistical plan based 
on independent information that became available from the final progression free survival (PFS) 
analysis of CMBG453B12201 which was conducted in a similar patient population and study 
treatment. Based on these data, a delayed treatment effect is considered for this study which 
justifies an increase in overall survival (OS) events to retain statistical power for the primary 
analysis at 85%. 
As of the release of this amendment, accrual was completed: 530 patients have been randomized. 
The DMC, who has been informed about the outcome of CMBG453B12201, had completed the 
safety & preplanned futility assessment of this study at 74 OS events (data cutoff as of 
20Nov2021) and recommended to continue the trial.

CMBG453B12201 is a phase II randomized study in 127 patients with MBG453 or 
placebo added to hypomethylating agents in adult subjects with intermediate, high or very 
high risk myelodysplastic syndrome as per IPSS-R criteria. Final PFS analysis results 
from CMBG453B12201 indicated an unanticipated possible 5-months delayed treatment 
effect for PFS in the investigational arm compared to the control arm. Also, for OS a 
delayed onset of effect is suspected.

If a delayed treatment effect of this magnitude be found in this study, it would result in a 
substantial loss of statistical power for the OS analysis (refer to Section 12.8 for statistical 
analysis and assumptions); therefore, the study design is revised to preserve statistical 
power at 85%. 

In order to achieve a statistical power of 85%, based on assumption of 5 months delayed 
treatment effect and followed by an effect of the same magnitude as assumed in the
protocol version 00 (i.e. HR=0.6), the number of OS events for the primary analysis is 
increased from 180 to approximately 282 events.

The interim analysis on survival will be conducted when 135 OS events have been 
documented as per protocol v00 planned number of events. This interim analysis is 
planned to be conducted shortly after protocol amendment 03 finalization. 

The delay of the primary analysis timepoint is not likely to present an additional risk for 
patients based on MBG453 safety profile. Regular safety reviews will be conducted by the 
DMC.
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, Section 3, Section 4.4 and Section 12: Revised the number of OS 
events for the primary analysis and updated Table 12-2

Section 9.1.1: Removed reporting period for concomitant treatments (to avoid 
inconsistency with Section 6.2.1)

Section 10.1.3: Added that SAE reporting timelines may be adjusted as per local 
requirements

Novartis
Confidential
Page 14 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301

Section 12.7: With increase from 180 to 282 OS events, the information fraction 
corresponding to the 135 events planned for efficacy IA changed from 75% to 48% and 
thus hazard ratio threshold and alpha had to be changed. Since the futility analysis was 
already conducted under the design of protocol version 00 (40% information fraction out 
of 180 events), no changes were made to the threshold for declaring futility or its
calculation.
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 Informed Consent.

Novartis
Confidential
Page 15 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Amendment 2 (14-Jul-2021)
Amendment rationale
As of the release of this amendment, approximately 324 subjects have been randomized in this 
trial.
The main purpose of this amendment is to clarify inclusion criterion #3 related to MDS/CMML-
2 status of the patient and exclusion criterion #9 related to myelofibrosis. It was clarified that 
the IPSS-R score used for MDS patients in this study is solely based on the publication from 
Greenberg et al 2012 to ensure consistency across the participating sites. For CMML-2, it was 
clarified that in alignment with the WHO classification 2016 (Arber et al 2016), the diagnosis 
of CMML-2 contains the presence of monocytosis ≥ 1 x109/L and monocytes accounting for 
≥10% of the WBC differential count. The requirement of WBC < 13 x109/L applies to the time 
of initial diagnosis; the WBC value may be higher at time of randomization. Exclusion criterion 
#9 has been updated to clarify that patients with grade 1 myelofibrosis without symptoms of 
concurrent myeloproliferative neoplasm can be enrolled. Fibrosis is often seen in MDS patients 
and fibrosis grade 0 and 1 does not affect overall survival (Ramos et al 2016).
Furthermore, new Novartis standard language, referred to as disruption proofing language, has 
been added to specify trial conduct during public health emergencies. The added language 
addresses study participant safety and trial integrity. In case subjects cannot come to the site 
during the follow-up period to complete the PROs at site, an alternative way of completion was 
included in order to minimize the risk of missing assessments for the key secondary objectives. 
In addition, guidance was added about PRO collection for illiterate subjects.
Additional guidance for COVID-19 vaccinations was added to avoid overlapping adverse 
events with study treatment, and several updates were made to clarify the visit windows in case 
of delay of administration of study treatment and time windows for certain assessments. 
Lastly, the definition of withdrawal of consent and management of biological samples was 
updated as per latest protocol template. 
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.

Updated glossary of terms and list of abbreviations related to changes in other sections of 
the document

Section 4.7 (Rationale for Public Health Emergency mitigation procedures) added

Section 5.1: Inclusion criterion #3 updated to highlight that the IPSS-R score for MDS used 
in this study is solely based on the publication from Greenberg et al 2012. 
For CMML-2, it was clarified that diagnosis per WHO classification 2016 contains the 
presence of monocytosis ≥ 1 x109/L and monocytes accounting for ≥ 10% of the WBC 
differential count, and the requirement of WBC < 13 x109/L applies to the time of initial 
diagnosis 

Novartis
Confidential
Page 16 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301

Section 5.2: Exclusion criterion #9 updated to myelofibrosis grade 2 or higher. Patients with 
myelofibrosis grade 1 without symptoms of concurrent myeloproliferative neoplasm can be 
enrolled into the study.

Section 6.1.1 and Section 6.7.2: Duration of administration of MBG453 or placebo 
specified to be preferably over 30 minutes, with a maximum administration time of 2 hours

Section 6.2.1: Duration for recording of concomitant medications during follow-up phase 
updated. Clarification added that G-CSF is also allowed for prophylaxis but should not be 
given within 2 weeks before response assessment.

Section 6.2.2: Clarification added for the timing of vaccination against COVID-19 in 
relation to the study treatment and for prophylactic G-CSF use. Corticosteroids should be 
tapered to 10 mg/day or less before the start of the next treatment cycle.

Section 6.5.1: Clarification added that interruption of study treatment and delay of cycle 
start for 56 consecutive days does not necessarily lead to permanent discontinuation of the 
subject. Exceptions may be granted based on discussions with study team. 

Section 7: Remote ICF procedure allowed in case of public health emergency

Section 8: Coagulation testing was added into the list of assessments which do not need to 
be repeated at C1D1 if done within 7 days of randomization. Visit window for bone marrow 
and PRO assessments was corrected to clarify that these assessments have to be done before 
administration of study treatment at the corresponding visit. Additional guidance was added 
for time windows for assessments in case of delay of administration of study treatment. In 
case of public health emergency, the option to perform some assessments remotely was 
added.

Table 8-1: Clarified that efficacy peripheral blood collection includes conducting pathology 
assessment of this sample

Section 8.2: Reference to IPSS-R score used in this study added. Clarification added that 
subjects should not receive blood transfusion for at least 7 days before the blood samples 
for randomization are collected. Clarification added on cytogenetics and blood smears.

Table 8-5: Definition for blast in MDS/CMML-2 added

Section 8.4.1 and Section 8.4.3: updated to allow alternative local labs and remote urine 
pregnancy testing in case of public health emergency

Section 8.4.2: Number of ECG reads clarified in case of a safety finding

Section 8.5.1.1: Alternative way completion of PROs during follow-up period added. 
Guidance added about PRO collection for illiterate subjects and during public health 
emergency situations

Section 8.5.2: Update of target population for extensive PK sampling in Chinese subjects

Table 8-7 and Table 8-8: Time window for pre-dose PK/PD/IG sample extended to up to 2 
hours on Day 8 when azacitidine and MBG453/placebo are administered on the same day

Section 9.1.2: Definition of withdrawal of consent was updated and clarifications added 
about the management of biological samples; this change was also included as appropriate 
in Sections 3, 8.3.1, Section 9.1.1, Section 9.1.3 and Section 9.1.5

Section 10.1.3: SAE reporting timeframe updated with additional instructions and 
clarification for randomized subjects who were not treated with study treatment

Novartis
Confidential
Page 17 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301

Appendix 1 “Liver event and Laboratory trigger Definitions and Follow-up Requirements” 
was removed 

Appendix 2: Guidance regarding hepatitis B updated to clarify that it is sufficient to measure 
either HBsAG or HBV DNA and that the Novartis study team should be consulted if local 
management of hepatitis B differs from suggestions in the protocol
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.

Novartis
Confidential
Page 18 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Amendment 1 (06-Aug-2020)
Amendment rationale
As of the release of this amendment, 13 subjects have been randomized in this trial.
The purpose of this amendment is to clarify, in particular, the inclusion criteria related to the 
eligibility for intensive chemotherapy and stem cell transplantation, as well as the exclusion 
criteria related to cardiac abnormalities. Additionally, as new treatment options may be 
available for patients with AML, study treatment beyond progression in case of acute leukemia 
(per WHO 2016, as defined as ≥20% blasts in bone marrow and/or peripheral blood) is not 
permitted any longer. Definitions of the RBC or platelet transfusion dependence and transfusion 
independence in Section 8.3, Table 8-2 were updated. The same pre-specified period of 
observation (i.e., 8 weeks) will be used to determine the transfusion status throughout the study. 
The interval of 8 weeks is selected, as it is in line with the assessment of transfusions for 
hematologic improvement and is acceptable to evaluate the transfusion status of higher-risk 
MDS patients at baseline (IWG 2006, IWG 2018) (Cheson et al 2006, Platzbecker 2019). 
Transfusion independence will be defined as absence of any transfusion during a given period 
of observation. Furthermore, clarifications about the estimand definition and methods for 
statistical analyses of PRO data were added. In addition, the need for TLS risk monitoring was 
further emphasized. Lastly, additional PK samples will be collected in a subset of Chinese 
patients to obtain extensive PK profile in Chinese patient population. 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Glossary of terms: Definition for combination drug was added.

Protocol Summary: Key Inclusion criteria regarding assessment of eligibility for intensive 
chemotherapy or stem cell transplantation updated. Key Exclusion criteria amended to 
exclude patients who received investigational treatment within 5 half-lives of this treatment.

Section 3: Term ‘Post Trial Access (PTA)’ was introduced. 

Section 4.2 and Section 4.3.2: Efficacy and safety data were updated based on new data 
acquired.

Section 4.5: Evaluation of risk due to COVID-19 pandemic added.

Section 5.1: Inclusion criteria 5 and 6 were amended to specify that assessment of eligibility 
for intensive chemotherapy or stem cell transplantation will include individual clinical 
factors such as age, comorbidities and performance status. 

Section 5.2: Exclusion criterion 3 was amended to exclude also patients who received 
investigational treatment within 5 half-lives of this treatment. Wording of exclusion 
criterion 12b modified for more clarity. Exclusion criterion 14 was amended to exclude 
patients with history of prolongation or QTcF > 470 ms at screening from this trial.

Section 6.1.5: Text updated to clarify that continuation of study treatment or components of 
study treatment beyond progression is not allowed in case of transformation to acute 
leukemia. Clarification on post trial access (PTA) added. 

Novartis
Confidential
Page 19 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301

Section 6.1.5.1: Criteria for continuation of study treatment or components of study 
treatment beyond progression modified. Guidance for assessment of clinical benefit added.

Section 6.5.1, Table 6-2: Guidance for non-hematologic, non-immune-related toxicities was 
amended to clarify that this refers to any non-hematologic, non-immune-related toxicities 
that are at least possibly attributable to the investigational drug.

Section 6.5.2.1: Time-point of PK sample clarified as part of the follow-up actions for 
potential drug-induced liver injury cases. 

Section 6.7.1.1: Clarification added that azacitidine can be administered outside of 
investigational site as per local regulations.

Section 6.7.2: Wording updated to clarify that azacitidine dose and route of administration 
should be applied as per local package insert. Reference to the pharmacy manual was added 
for investigational drug handling instructions.

Section 7: Informed Consent will be obtained in case of continuing study treatment or 
components of the study treatment beyond progression in absence of transformation to acute 
leukemia.

Section 8: Definition of time windows was amended for more clarity. Time window for 
ePRO assessments and for bone marrow samples at end of treatment was extended. 
Clarification added that safety follow-up visits at Day 90 and Day 150 can be performed via 
telephone call or onsite visits.

Section 8, Table 8-1: List of cytokines was removed. Clarification added that efficacy bone 
marrow sample can be an aspirate and/or a biopsy sample.

Section 8.2: Clarification added that the last available laboratory results during screening 
should be used to confirm eligibility. Rationale for collection of subjects' race and ethnicity 
data added.

Section 8.3.1: Transfusion independence and dependence definitions were updated in 
Table 8-2. In addition, a clarification was added that bone marrow samples, blood smears 
and pathology reports from the diagnosis should be sent to the central laboratory even if 
done during regular work-up of the subject before study start. 

Section 8.4.1, Table 8-5: Addition of cytokines types to be analyzed. Collection of Troponin 
I added as alternative for Troponin T.

Section 8.4.4: New section added to emphasize monitoring of patients for signs and 
symptoms of TLS under azacitidine treatment.

Section 8.5.2: Addition of extensive PK sampling in a subgroup of Chinese patients. 
Clarification added that PK, IG and sTIM-3 samples will be analyzed only in subjects 
receiving MBG453.

Section 8.5.2.2: Additional details about immunogenicity testing method added


Section 9.1.1: Progression of disease (including transformation to acute leukemia) was 
added as reason for discontinuation of study treatment, unless criteria to continue study 
treatment beyond progression as per Section 6.1.5 are met. Incorrect reference to section 
6.1.4 was removed. 

Section 9.2: Updated wording for post trial access (PTA) added.

Novartis
Confidential
Page 21 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Protocol summary
Protocol number
CMBG453B12301
Full Title
A randomized, double-blind, placebo-controlled phase III multi-center study of azacitidine
with or without MBG453 for the treatment of patients with intermediate, high or very high risk 
myelodysplastic syndrome (MDS) as per IPSS-R, or Chronic Myelomonocytic Leukemia-2 
(CMML-2)
Brief title
Study of efficacy and safety of MBG453 in combination with azacitidine in subjects with 
intermediate, high or very high risk myelodysplastic syndrome (MDS) as per IPSS-R, or 
Chronic Myelomonocytic Leukemia-2 (CMML-2)
Sponsor and 
Clinical Phase
Novartis 
Phase III
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 azacitidine in adult subjects with IPSS-R intermediate, 
high, very high risk MDS and CMML-2. The justification for a double-blind randomized 
placebo-controlled trial is to determine the efficacy of adding MBG453 to azacitidine on the 
primary efficacy endpoint (Overall survival). 
Primary 
Objective(s) 
The primary objective of this study is to compare overall survival (OS) in the MBG453 plus 
azacitidine arm versus placebo plus azacitidine arm where OS is the time from randomization 
until death due to any cause. If the subject is not known to have died, then OS will be 
censored at the latest date the subject was known to be alive (on or before the cut-off date).
Secondary 
Objectives
Key secondary objectives

To compare time to definitive deterioration of fatigue in the MBG453 plus azacitidine arm 
versus placebo plus azacitidine arm as measured by FACIT-Fatigue

To compare RBC transfusion-free intervals in the MBG453 plus azacitidine arm versus 
placebo plus azacitidine arm

To compare improvement of fatigue in the MBG453 plus azacitidine arm versus placebo 
plus azacitidine arm using FACIT-Fatigue

To compare improvement of physical functioning in the MBG453 plus azacitidine arm 
versus placebo plus azacitidine arm using EORTC QLQ-C30

To compare improvement of emotional functioning in the MBG453 plus azacitidine arm 
versus placebo plus azacitidine arm using EORTC QLQ-C30
Secondary objectives

To assess response rate in each treatment arm as per investigator assessment

To assess PFS in each treatment arm, including transformation to acute leukemia per 
WHO 2016 classification, relapse from complete remission (CR) according to IWG-MDS 
or death due to any cause as per investigator assessment

To assess Leukemia-free survival in each treatment arm

To assess the safety profile of MBG453 when given in combination with azacitidine

To assess the improvement in RBC/Platelets transfusion independence in each 
treatment arm

To characterize the pharmacokinetics of MBG453

To evaluate immunogenicity of MBG453

To assess overall quality of life in each treatment arm by testing change from baseline 
in EQ-5D-5L scores and VAS scores over time and change from baseline to C12D1 of 
Global Health Status/QoL scores using EORTC QLQ-C30

Novartis
Confidential
Page 22 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Study design
This is a Phase III multi-center, randomized, two-arm parallel-group, double-blind, placebo-
controlled study of MBG453 or placebo added to azacitidine in adult subjects with 
intermediate, high or very high risk myelodysplastic syndrome (MDS) as per IPSS-R, or 
Chronic Myelomonocytic Leukemia-2 (CMML-2).
Subjects will be randomized in a 1:1 ratio to treatment arms as follow:

MBG453 800 mg IV Q4W plus azacitidine

Placebo IV Q4W plus azacitidine
The randomization will be stratified into 4 groups: intermediate risk MDS, high risk MDS, very 
high risk MDS and CMML-2.
All subjects who discontinued both study treatments will enter a long-term post-treatment 
follow-up including response and PRO assessments, and/or survival follow-up for up to 
5 years after the last subject was randomized.
Study 
Population
The study population will include approximately 500 adult subjects with intermediate, high or 
very high risk (per IPSS-R prognostic risk categories) myelodysplastic syndrome or with 
Chronic Myelomonocytic Leukemia - 2 (CMML-2). These subjects have an indication for 
treatment with azacitidine in first-line setting and are not eligible for intensive chemotherapy 
or hematopoietic stem cell transplantation (HSCT) according to medical judgment by the 
investigator.
Key Inclusion 
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 myelodysplastic syndrome (MDS) based on WHO 
2016 classification (Arber et al 2016) by local investigator assessment with one of the 
following Prognostic Risk Categories, based on the revised International Prognostic 
Scoring System (IPSS-R) as per Greenberg et al 2012:

Very high (> 6 points)

High (> 4.5 - ≤ 6 points)

Intermediate (> 3 - ≤ 4.5 points)
Or
Morphologically confirmed diagnosis of Chronic Myelomonocytic Leukemia -2 based on 
WHO 2016 classification (Arber et al 2016 - persistent PB monocytosis ≥ 1 x109/L and 
monocytes accounting for ≥ 10% of the WBC differential count) by local investigator 
assessment with WBC < 13 x 109/L at time of initial diagnosis

Indication for azacitidine treatment according to the investigator, based on local standard 
medical practice and institutional guidelines for treatment decisions

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 including assessment of individual clinical factors such as age, 
comorbidities and performance status (de Witte et al 2017)

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 including assessment of individual clinical factors such 
as age, comorbidities, performance status, and donor availability (de Witte et al 2017)

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
Key Exclusion 
criteria

Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune 
checkpoint inhibitors (e.g, anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer 
vaccines is allowed except if the drug was administered within 4 months prior to 
randomization

Previous first-line treatment for intermediate, high, very high risk myelodysplastic 
syndromes (based on IPSS-R) or CMML-2 with any antineoplastic agents including for 
example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as 
decitabine or azacitidine. However, previous treatment with hydroxyurea or 
leukapheresis to reduce WBC count is allowed prior to randomization.

Novartis
Confidential
Page 24 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
The primary analysis will be performed after approximately 282 OS events have been 
documented. The final analysis will occur at the end of study. 
If OS is statistically significant at the efficacy interim or at the primary analysis, the key 
secondary endpoints will be tested according to a specific testing strategy, and using a 
separate alpha spending function.
Key words
Phase III, MBG453, TIM-3, azacitidine, placebo, myelodysplastic syndrome (MDS), chronic 
myelomonocytic leukemia-2 (CMML-2)

Novartis
Confidential
Page 25 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
1
Introduction
1.1
Background
It is estimated that 15,000 to 20,000 new cases of Myelodysplastic Syndromes (MDS) are 
diagnosed annually in the USA (Klepin 2016). In Europe, the incidence rate of MDS is about 2 
new cases per 100,000 each year (Visser et al 2012). The incidence of MDS is more frequent 
in male patients and increases with age, with a median age at diagnosis of about 70 years.
Myelodysplastic syndromes (MDS) correspond to a heterogeneous group of hematological 
malignancies that are associated with impaired bone marrow function, ineffective 
hematopoiesis, elevated bone marrow blasts and persistent peripheral blood cytopenias. Anemia 
is the most common peripheral blood abnormality reported in up to 85% of the patients at 
diagnosis (Steensma and Bennett 2006). As a result, most patients with MDS require red blood 
cell transfusion support at some time during their illness and some are transfusion-dependent 
from the time of diagnosis onward. Frequent use of transfusions may have a negative impact on 
survival in patients with high risk MDS engaged in routine care (Bell et al 2019). Additionally, 
anemia is frequently associated with fatigue which represents a significant concern for MDS 
patients impacting their quality of life (Heptinstall 2006). Cytogenetic abnormalities are 
frequently present at time of diagnosis and 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 median time until 25% of the MDS population developed AML 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), intensive 
chemotherapy 
or 
hypomethylating 
agents 
(HMAs; 
azacitidine 
and 
decitabine) 
(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 and may precede HSCT (Steensma 2018). 
HSCT remains the only curative option for MDS patients; however, many MDS patients are 
not candidates for HSCT (Passweg et al 2011; and see Section 4.1). In MDS patients without 
major co-morbidities who are classified as higher risk by IPSS-R , and who do not qualify for 
transplantation 
or 
intensive 
chemotherapy, 
HMAs 
are 
the 
first-line 
reference 
treatment. Azacitidine is the sole HMA which showed a prolongation of overall survival (OS) 
compared to conventional care regimens among patients with higher risk MDS [median OS, 

Novartis
Confidential
Page 26 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
24.5 versus 15 months, respectively, hazard ratio (HR) = 0.58; P < 0.0001] in the pivotal 
AZA001 randomized phase III trial (Fenaux et al 2009). Other controlled clinical trials reported 
median OS between 19 to 20 months in patients receiving azacitidine (Silverman et al 2002, 
Garcia-Manero et al 2018).
Azacitidine is generally administered for a minimum of 6 cycles (repeat cycle after 4 weeks), 
and continued for as long as the patient benefits. In clinical practice, azacitidine safety profile 
is mainly characterized by bone marrow suppression leading to dose-reduction or
discontinuation of azacitidine, and supportive care, including blood transfusions, is frequently 
required during the course of the disease.
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 HMAs remains poor.  
Median survival in intermediate, high and very high MDS patients are only 3 years, 1.6 years 
and < 1 year respectively (Greenberg et al 2012). Treatment failure, relapse and transformation 
to acute myeloid leukemia (AML) are frequent events. Once a patient with higher risk MDS 
has failed treatment with HMAs or transformation to AML has occurred, survival generally will 
not exceed 6 months. Thus, improved treatments in addition to HMAs and/or as an alternative 
to HMAs are urgently needed in this MDS patient population.
Occurring in 1 in 100,000 people each year, Chronic Myelomonocytic Leukemias correspond 
to the group of myeloid neoplasms according to the 2016 WHO classification (Arber et al 2016) 
with CMML-2 representing approximately 15-20% of the CMML population. Recently an 
international treatment guidelines was published by the European Hematology Association 
(EHA) (Itzykson et al 2018). EHA recommends to treat the myelodysplastic CMML-2 patients 
who are ineligible for transplantation with azacitidine.
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 the checkpoint inhibitors nivolumab (PD1) and ipilimumab (CTLA4) with or without the 
hypomethylating agent azacitidine in front-line and relapsed MDS patients. Front-line MDS 
patients were treated with the combination azacitidine+nivolumab or ipilimumab, whereas 
relapsed MDS patients received single-agent nivolumab or ipilimumab. Twenty patients were 
treated with azacitidine+nivolumab, 21 with azacitidine+ipilumab, 15 with nivolumab, and 20 
with ipilimumab. The observed overall response rate was 75% (15/20), 71% (15/21), 13% 
(2/15), and 35% (7/20) of patients treated with azacitidine combined with nivolumab, 
azacitidine combined with ipilimumab, nivolumab, and ipilimumab, respectively; Complete 
Remission or Complete Remission with residual thrombocytopenia was observed in 10/20 
(50%), 8/21 (38%), 0 (0%), and 3 (15%) in patients treated with azacitidine combined with 
nivolumab, azacitidine combined with ipilimumab, nivolumab, and ipilimumab, respectively. 

Novartis
Confidential
Page 27 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Main toxicities reported were as follows: skin rash (11%); fatigue (9%); pain (7%); infection 
(6%); febrile neutropenia (5%); pruritus (6%); diarrhea (5%); constipation, nausea (4% each), 
alanine aminotransferase (ALT) elevations, anorexia, cough (3% each). This provides 
preliminary evidence that checkpoint inhibition combined with hypomethylating agents is 
feasible in front-line MDS and may have clinical activity (Garcia-Manero et al 2018). A Phase 
Ib/II study involving azacitidine and nivolumab has been conducted in 70 relapsed/refractory 
AML patients. The overall response rate (ORR) in this study was 33%: 23 clinical responses 
were reported including 4 complete remission, 11 complete remission with insufficient recovery 
of counts (CRi), 1 partial remission (PR), and 7 patients with hematologic improvement (HI) 
maintained > 6 months. The ORR was 58% and 22% in HMA-naive (n = 25) and HMA pre-
treated (n = 45) patients, respectively. Duration of response among responders was 5.2 months. 
Three patients in CR/CRi underwent HSCT. Additionally, 6 patients had stable disease lasting 
for more than 6 months.
Overall the combination azacitidine plus nivolumab was well tolerated, Grade 3 or 4 immune 
related adverse events (irAE) occurred in 8 (11%) patients (Daver et al 2019). A Phase Ib study 
reported that ipilimumab in patients with MDS after HMA failure is safe but has limited efficacy 
as monotherapy. However, prolonged stable disease was reported and some patients received 
allo HSCT. Prolonged stable disease for ≥ 46 weeks occurred in 7 patients (24% of the patients), 
including 3 patients with more than a year of stable disease. Five patients underwent allografting 
without excessive toxicity (Zeidan et al 2018).
T-cell immunoglobulin and mucin domain-containing 3 (TIM-3; 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 bone marrow mononuclear cells and detection 
on blasts increases as MDS progresses. Therefore the blockade of TIM-3 constitutes a potential 
target for novel therapies in MDS, and promising preclinical and clinical anti-cancer activity 
has been reported for TIM-3 blockade (Kikushige et al 2010, Sakuishi et al 2010, 
Ngiow et al 2011, Sakuishi et al 2011, Jing et al 2015, Asayama et al 2017). MBG453 is a 
high-affinity, 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). 
There is an ongoing Phase II trial [CMBG453B12201] which is investigating MBG453 
(CR and PFS as primary endpoints) in high risk MDS subjects. The trial is a double-blind, 
placebo-controlled study comparing MBG453 plus HMA versus placebo plus HMA. 
For further details about MBG453, refer to the Investigator's Brochure (IB) [MBG453 
Investigator's Brochure].

Novartis
Confidential
Page 28 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
1.2
Purpose
Prognosis is poor and life expectancy is short in intermediate, high, or very high risk MDS, and 
Chronic Myelomonocytic Leukemia 2 (CMML-2) patients treated with the current standard of 
care based on hypomethylating agents. Very few patients can benefit from a curative option 
with hematopoietic stem cell transplant (HSCT). HMAs represent the standard of care for the 
vast majority of patients who cannot receive HSCT or cannot be treated with intensive 
chemotherapy. Azacitidine is the sole HMA which demonstrated a survival gain over 
conventional care in higher risk MDS and CMML patients (Fenaux et al 2009). Complete 
remission is reported in a minority of patients treated by azacitidine alone, and clinical benefits 
of this drug are frequently transient and when it fails, treatment options in second line are 
limited.
The humanized anti-TIM-3 IgG4 monoclonal antibody MBG453 is a novel immunotherapeutic 
agent with promising activity seen in AML and MDS. The purpose of the current study is to 
assess clinical effects of MBG453 in combination with azacitidine in adult subjects with 
intermediate, high or very high risk MDS, and CMML-2. This randomized, two-arm parallel-
group, double-blind, placebo-controlled study will compare MBG453 plus azacitidine or 
placebo plus azacitidine. Objectives and endpoints of the study are detailed in Section 2.
2
Objectives and endpoints
The objectives and associated endpoints are presented in the 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 compare overall survival (OS) in the 
MBG453 plus azacitidine arm versus 
placebo plus azacitidine arm

OS is the time from randomization until death due to any 
cause. If the subject is not known to have died, then OS will 
be censored at the latest date the subject was known to be 
alive (on or before cut-off date).
Secondary objective(s)
Endpoint(s) for secondary objective(s)

Key Secondary Objective 1: To compare 
time to definitive deterioration of fatigue in 
the MBG453 plus azacitidine arm versus 
placebo plus azacitidine arm

Time from randomization to at least 3 points worsening from 
baseline in FACIT-fatigue scores with no subsequent 
improvement above this threshold or death due to any 
cause, whichever occurs first

Key Secondary Objective 2: To compare 
RBC transfusion-free intervals in the 
MBG453 plus azacitidine arm versus 
placebo plus azacitidine arm

Cumulative time of intervals with no evidence of RBC 
transfusion for at least 8 weeks at any point after 
randomization

Key Secondary Objective 3: To compare 
improvement of fatigue in the MBG453 
plus azacitidine arm versus placebo plus 
azacitidine arm

Percent of subjects with at least 3 point confirmed 
improvement from baseline in FACIT-fatigue scores

Key Secondary Objective 4: To compare 
improvement of physical functioning in the 
MBG453 plus azacitidine arm versus 
placebo plus azacitidine arm

Percent of subjects with at least 10 point confirmed 
improvement from baseline in physical functioning using 
EORTC QLQ-C30

Novartis
Confidential
Page 29 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Objective(s)
Endpoint(s)

Key Secondary Objective 5: To compare 
improvement of emotional functioning in 
the MBG453 plus azacitidine arm versus 
placebo plus azacitidine arm

Percent of subjects with at least 10 point confirmed 
improvement from baseline in emotional functioning using 
EORTC QLQ-C30

To assess response rate in each treatment 
arm

Percentage of CR/mCR/PR/HI according to IWG-MDS as 
per investigator assessment
- Percentage of SD according to IWG-MDS as per 
investigator assessment

To assess PFS in each treatment arm

Time from randomization to disease progression (including 
transformation 
to 
acute 
leukemia 
per 
WHO 
2016 
classification), relapse from complete remission (CR) 
according to IWG-MDS or death due to any cause, 
whichever occurs first, as per investigator assessment

To assess Leukemia-free survival in each 
treatment arm

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 the safety profile of MBG453 
when given in combination 
with azacitidine

Incidence and severity of AEs and SAEs, changes in 
laboratory values and vital signs (per CTCAE version 5)

To assess the improvement in 
RBC/Platelets transfusion independence 
in each treatment arm

Number and percent of transfusion dependent subjects at 
baseline 
who 
become 
RBC/platelets 
transfusion 
independent after randomization as per IWG-MDS criteria

To characterize the pharmacokinetics of 
MBG453

Serum concentrations and pharmacokinetic parameters for 
MBG453

To evaluate immunogenicity of MBG453

Anti-drug Antibody (ADA) prevalence at baseline and ADA 
incidence on-treatment

To assess overall quality of life in each 
treatment arm

Change from baseline in EQ-5D-5L scores and VAS scores 
over time 

Change from baseline to C12D1 of Global Health Status/QoL 
scores using EORTC QLQ-C30 

Novartis
Confidential
Page 30 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
3
Study design
The trial is a randomized, double-blind, placebo-controlled, multi-center phase III study of 
MBG453 or placebo added to azacitidine for the treatment of subjects with intermediate, high 
or very high risk MDS as per IPSS-R or with CMML-2.
Approximately 500 subjects will be randomized in a 1:1 ratio to receive azacitidine 75 mg/m2, 
intravenous or subcutaneous, with or without MBG453 800 mg IV Q4W in 28-day treatment 
cycles (Figure 3-1). The randomization will be stratified into 4 groups: intermediate risk MDS, 
high risk MDS, very high risk MDS, and CMML-2. Crossover between treatment arms is not 
permitted at any time during the study.
Study treatment consists of cycles of MBG453 or placebo 800 mg IV Q4W administered on 
Day 8 of each cycle in combination with azacitidine administered to the subjects on days 1 to 7 
(or on days 1 to 5 and days 8 and 9) of each cycle until treatment discontinuation (for treatment 
duration and reasons for discontinuation, please refer to Section 6.1.5 and Section 9.1.1). 
Treatment options and dosing information are provided in Section 6.1.1. The planned duration 
of a cycle is 28 days.
Subjects who become eligible for hematopoietic stem cell transplant (HSCT) or intensive 
chemotherapy at any time during the course of the study will be discontinued from study 
treatment.
All subjects must be followed for adverse events (AEs) after the last dose of azacitidine, 
MBG453 or placebo as indicated in Section 10.1.1. All women of child-bearing potential must 
be followed for pregnancy safety evaluations as per Table 8-1 and after last dose of azacitidine 
and MBG453/placebo as indicated in Section 10.1.4.
In addition, all subjects who discontinued both study treatments will enter a long-term 
post-treatment and/or survival follow-up. Subjects who discontinued both study treatments due 
to reasons other than progression, death, lost to follow-up, or withdrawal of consent/opposition 
to use data/biological samples will have hematology assessments, Patient Reported Outcomes 
(PRO) and response assessments at defined timepoints until documented disease progression, 
death, lost to follow-up, or withdrawal of consent/opposition to use data/biological samples 
(Figure 3-2). Survival and post-treatment follow-up data will be collected for up to 5 years after 
the last subject was randomized.
Regular safety reviews will be performed by an independent Data Monitoring Committee 
(DMC) throughout the study (see Section 10.2.1). Additionally, efficacy reviews will be 
performed by the DMC when pre-defined number of OS events are documented. 

Novartis
Confidential
Page 33 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
clinical entities: CMML-2, MDS very high, MDS high and MDS intermediate risk according 
to IPSS-R score at baseline.
IPSS-R score at baseline for MDS subjects is a crucial clinical indicator in the sense that it will 
inform about the treatment outcomes and prognosis of each given subject. Each level of risk 
(intermediate/high/very high) is associated with a different estimated survival length and 
potential of leukemic transformation (see Section 1.1).
CMML-2 is considered as a distinct clinical entity according to WHO 2016 classification of 
myeloid neoplasms. Even though treatment paradigms and the clinical outcome in CMML-2 
subjects are generally similar to that of higher risk MDS subjects, it is important to balance the 
treatment-arms regarding distribution of clinical entities by using stratification.
4.2
Rationale for dose/regimen and duration of treatment
The proposed MBG453 dose in the study is 800 mg Q4W based on data accumulated from two 
phase I studies: [CMBG453X2101] in solid tumor patients has a wide MBG453 dose range 
(single agent MBG453 from 80 to 1200 mg every 2 weeks (Q2W) or every 4 weeks (Q4W), 
with a lower 20 mg Q2W MBG453 dose additionally tested in combination with PDR001. 
Because of the data obtained in [CMBG453X2101], study [CPDR001X2105] started evaluating 
MBG453 at 240 mg Q2W and additionally tested 400 mg Q2W and 800 mg Q4W in 
combination with decitabine. 
Clinical Pharmacology: The pharmacokinetics (PK) of MBG453 were similar between studies 
[CMBG453X2101] in solid tumor patients and [CPDR001X2105] in AML and high risk MDS 
patients. At lower doses (at 80 mg and below for Q2W dosing or at 240 mg and below for Q4W 
dosing), the PK was nonlinear, with faster elimination at lower concentrations. PK appeared 
linear with an approximate proportional dose-exposure (AUC and Cmax) relationship at doses 
of 240 mg and above for Q2W dosing and at doses of 800 mg and above for Q4W dosing. 
Accumulation of MBG453 was observed with repeated administrations, and for the Q2W 
regimen, AUCtau during cycle 3 ranged between 1.01-2.78 fold higher than during cycle 1. The 
dose of 800 mg Q4W has similar AUCtau as 400 mg Q2W at the steady state.
Clinical Efficacy: In study [CPDR001X2105], clinical benefit was seen across 3 dose levels 
tested at 240 mg Q2W, 400 mg Q2W and 800 mg Q4W in combination with hypomethylating 
agents, with CR or marrow CR in higher-risk MDS subjects and CR or CRi in newly diagnosed 
AML subjects. Among responding higher-risk MDS subjects, there were durable responses as 
long as 30 months (see Section 4.3.2). No dose-response relationship was observed. In a 
preliminary exposure-response analysis, there was also no clear relationship between exposure 
and response, using steady state exposure metrics of AUCtau or Ctrough and efficacy metrics 
of clinical benefit (CR/mCR/CRi) or percent blast cell reduction.
Clinical Safety: In study [CMBG453X2101], as of 25-Jul-2019, a total of 133 subjects with 
solid tumors have been treated with MBG453 single agent therapy. There were no adverse 
events attributed to study treatment with an incidence >10%. The most frequently reported 
adverse events attributed to study treatment included fatigue (9%), followed by decreased 
appetite and nausea (4.5% each). There were no DLTs during the first cycle. No subjects 
discontinued study treatment due to treatment-related AEs. 

Novartis
Confidential
Page 34 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
In study [CPDR001X2105], as of 26-Jul-2019, a total of 123 subjects with hematological 
malignancies have been treated with MBG453 as a single agent (n=26) or in combination with 
decitabine (n=81) or azacitidine (n=16). In the 26 subjects treated with MBG453 single agent, 
there were no adverse events attributed to study treatment with an incidence >10%. The most 
frequently reported adverse event attributed to study treatment was a rash in two subjects (8%). 
All other adverse events attributed to study treatment were single occurrences. There were no 
DLTs during the first cycle. No subjects discontinued study treatment due to treatment-related 
AEs. In the 81 subjects treated with MBG453 in combination with decitabine, the most frequent 
adverse events (all grades, >10%) attributed to study treatment have included thrombocytopenia, 
anemia, neutropenia, nausea, and fatigue. One subject experienced a DLT during the first 2 
cycles, which consisted of hepatitis manifesting as Grade 3 ALT increase. One subject 
discontinued study treatment due to a treatment-related AE of possible hemophagocytic 
lymphohistiocytosis (HLH). In the 16 subjects treated with MBG453 in combination with 
azacitidine, the most frequent adverse events (all grades, >10%) attributed to study treatment 
have included nausea, vomiting, anemia, constipation, neutrophil count decrease, platelet count 
decrease. There were no DLTs during the first 2 cycles. No subjects discontinued study 
treatment due to treatment-related AEs. No study treatment-related deaths were observed in any 
of the studies mentioned above. 
Preliminary analysis revealed no relationship between dose, incidence and severity of adverse 
events across the different treatment groups. No relationship was observed between Cmax and 
the incidence of potentially immune related adverse events, providing additional support for 
800 mg Q4W regimen which has the highest Cmax among the doses tested. Please refer to the 
[MBG453 Investigator's Brochure] for additional information of AEs reported in subjects with 
solid tumors or with hematologic malignancies treated with MBG453 as a single agent or in 
combination with other drugs.
As per the latest data analysis (cut-off: 10-Apr-2020) of HR-MDS and AML patients treated 
with MBG453 + HMA combination; including 69 patients treated with MBG453+decitabine 
and 37 patients treated with MBG453+azacitidine combination from study [CPDR001X2105], 
MBG453 + HMA combination was safe and well tolerated. No Maximum Tolerated Dose 
(MTD) was reached and no new significant safety issues were observed. Most commonly 
reported treatment emergent adverse events were consistent with those for HMA alone. The 
majority (92%) of possible immune mediated adverse events (imAEs) related to study treatment 
were grade 1/2. No treatment related deaths were reported. 
Predicted target engagement: A population pharmacokinetic model of MBG453 concentration 
was fit to all subjects from both studies to the predicted TIM-3 occupancy in the bone marrow 
by making assumptions about MBG453 biodistribution to the bone marrow and binding to 
TIM-3. Using trial simulation, this model predicted that the 800 mg Q4W dose would give at 
least 95% receptor occupancy in at least 95% of subjects at steady state Ctrough. This high 
degree of target engagement is also supported by a plateau in the accumulated soluble TIM-3 
that is observed at doses of 240 mg Q2W and above, and at 800 mg Q4W and above.
In summary, given the excellent safety and tolerability seen across all doses and schedules 
in [CMBG453X2101] and [CPDR001X2105], the activity seen at all 3 doses tested in 
study [CPDR001X2105]; the predicted saturation of TIM-3 from the soluble TIM-3 data and 

Novartis
Confidential
Page 35 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
the receptor occupancy model; and the lack of a clear dose-response or exposure-response 
relationship for MBG453, 800 mg Q4W was selected as the dose regimen for this study.
4.3
Rationale for choice of combination drugs
4.3.1
Rationale for azacitidine
In MDS and CMML patients, allo HSCT is the only curative option. However, only a minority 
of MDS or CMML patients are candidates for allo HSCT and intensive chemotherapy, which 
may be used prior to transplant (Steensma 2018, Platzbecker 2019, Itzykson et al 2018).
Treatment strategies for MDS are generally non-intensive and risk-adapted (by IPSS-R), 
ranging from watchful surveillance, iron chelation and growth factors to lenalidomide and 
HMA including azacitidine. Also, EHA recommends recently to treat myelodysplastic 
CMML-2 ineligible for allo HSCT with azacitidine (Itzykson et al 2018), see Section 1.1.
Higher risk MDS patients who are not transplant candidates are commonly treated with HMA 
therapy. HMAs 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.
Azacitidine is approved in the USA and in Europe for treating MDS and CMML. Azacitidine 
is the sole HMA which demonstrated a survival advantage over other treatment options in a 
randomized trial. 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. 
In this pivotal study a few CMML patients have been enrolled and a clinical benefit has been 
seen also in this patient population. Other clinical studies reported median OS ranging from 19 
to 20 months in MDS patients (Garcia-Manero et al 2017, Silverman et al 2002).
Azacitidine is generally well tolerated and has a manageable toxicity profile 
(Derissen et al 2013). The most frequent 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. In clinical trials, hematologic adverse events were more frequently observed during 
the first two treatment cycles, and 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 antidiarrheals.
Azacitidine regimens used in this trial are the most studied regimens and recommended by 
international treatment guidelines (National Comprehensive Cancer Network (NCCN), 
European Society for Medical Oncology (ESMO), Steensma 2018). Azacitidine should be 
administered as per local standard practice (see Section 6.1.1).

Novartis
Confidential
Page 36 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
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 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, humanized anti-TIM-3 IgG4 
monoclonal 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.
MBG453 as a single agent or in combination with decitabine or azacitidine was very well 
tolerated. Early data of MBG453 when combined with HMA indicate that most of the treatment-
related AEs are anticipated in the context of MDS subjects receiving HMA (cytopenias, 
gastro-intestinal toxicities). Potential Immune-mediated AEs were generally low grades (grade 
1/2) and manageable. For more details please refer to Section 4.2 and the [MBG453 
Investigator's Brochure].
Preliminary efficacy data reported in study [CPDR001X2105] with higher-risk MDS subjects 
are showing high response rates. At the time of the latest analysis (cut-off: 10-Apr-2020), in the 
MBG453 + decitabine arm, 11 of 18 (61.1%) evaluable high risk and very high risk MDS 
patients have achieved a response (6 complete remissions [33.3%], 3 marrow complete 
remissions [16.7%], 2 stable diseases with hematologic improvement [11.1%]). Median of 

Novartis
Confidential
Page 37 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
exposure in this arm is approximately 8 months. Durability of response and clinical benefit is 
being observed with the longest responding higher-risk MDS subjects continuing on study for 
more than 30 months. In the MBG453 + azacitidine arm, 11 of 19 (57.9%) evaluable
higher-risk MDS patients have achieved a response (2 complete remissions [10.5%], 7 marrow 
complete remissions [36.8%], 2 stable diseases with hematologic improvement [10.5%]). Of 
note, data from this arm is less mature with duration of follow-up of approximately 3 months. 
4.3.3
Rationale for combining MBG453 with azacitidine
Despite the fact that single-agent HMAs are available for the treatment of patients with higher 
risk MDS and CMML2, 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 rate of patients who could receive allo HSCT or as alternative 
treatment of cytarabine have been disappointing. In addition, many higher risk MDS and 
CMML2 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 monoclonal antibody MBG453 combined with HMAs in myeloid neoplasms.
Preclinical data suggest that HMAs enhance checkpoint expression and that a synergistic 
response may be produced by using a checkpoint inhibitor and a hypomethylating agent; 
priming with HMA before giving MBG453.
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 checkpoint 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 higher-risk 
MDS subjects indicate that MBG453 plus decitabine combination is feasible, well tolerated and 
produces durable clinical responses (see Section 4.2 and Section 4.3.2). In [CPDR001X2105] 
study, a signal of a relevant clinical activity is being reported with high response rate, durable 
response and stable disease including in higher-risk MDS subjects who were treated (see above 
in Section 4.3.2).
Regarding safety data of MBG453, please refer to the [MBG453 Investigator's Brochure] for 
more details.
4.4
Purpose and timing of interim analyses
The statistical basis for claim of efficacy in favor of the MBG453 arm is based on statistical 
significance for OS as detailed in Section 12.4.2.

Novartis
Confidential
Page 38 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
There will be two interim analysis:

A futility interim analysis will be performed after approximately 72 OS events (40% 
information fraction out of 180 events as per protocol version 00) have been documented, 
with an option to stop for futility.

An efficacy interim analysis will be performed after approximately 135 OS events (48%
information fraction out of 282 events as per protocol version 03) have been documented 
and all patients randomized, with an option to stop for efficacy.
The primary OS analysis will be performed after approximately 282 OS events have been 
documented. The final analysis will occur at the end of study.
The timing of the interim, primary, and final OS analyses are detailed in Section 12.7. 
Figure 12-1 describes 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 [CPDR001X2105], which showed achievement of durable complete 
remission or bone marrow CR in higher-risk MDS patients 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 decitabine 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 for that trial, dose modifications must be applied per protocol based 
on clinical or laboratory findings, and a close safety monitoring will be performed during the 
study.
Occurrence of an immune-related event is an anticipated risk in subjects treated with 
immunologic agents, 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 guidelines for non-hematologic non-immune-related toxicities that are clinically 
significant per investigator judgement and that are possibly attributable to the investigational 
drug are also provided (see Section 6.5.1).
Based on currently available data, there are no known significant overlapping toxicities between 
azacitidine and MBG453. However, there may be unforeseen risks from combining 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 antitumor immune response, there is the 
potential for increased toxicity secondary to increased release of cytokines which could result 
in cytokine release syndrome due to activation of T cells and macrophages. There may also be 
changes in the 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 

Novartis
Confidential
Page 41 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
following Prognostic Risk Categories, based on the revised International Prognostic Scoring 
System (IPSS-R) as per Greenberg et al 2012:

Very high (> 6 points)

High (> 4.5 - ≤6 points)

Intermediate (> 3 - ≤4.5 points)
OR
Morphologically confirmed diagnosis of Chronic Myelomonocytic Leukemia -2 based on 
WHO 2016 classification (Arber et al 2016 - persistent PB monocytosis ≥ 1 x109/L and 
monocytes accounting for ≥ 10% of the WBC differential count) by local investigator 
assessment with WBC < 13 x 109/L at time of initial diagnosis
4. Indication for azacitidine treatment according to the investigator, based on local standard 
medical practice and institutional guidelines for treatment decisions
5. Not eligible at time of screening for intensive chemotherapy according to the investigator, 
based on local standard medical practice and institutional guidelines for treatment decisions, 
including assessment of individual clinical factors such as age, comorbidities and 
performance status (de Witte et al 2017)
6. Not eligible at 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, including assessment of individual clinical factors such 
as age, comorbidities, performance status, and donor availability (de Witte et al 2017)
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
8. Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73m2 (estimation based on 
Modification of Diet in Renal Disease (MDRD) formula, by local laboratory)
9. AST and ALT ≤ 3 × upper limit of normal (ULN)
10. Total bilirubin ≤ 1.5 × ULN (except in the setting of isolated Gilbert syndrome, where 
subjects may only be included with direct bilirubin ≤ 1.5 x ULN)
11. 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 checkpoint 
inhibitors (e.g, anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines is 
allowed except if the drug was administered within 4 months prior to randomization
2. Previous first-line treatment for intermediate, high, very high risk myelodysplastic 
syndromes (based on IPSS-R) or CMML with any antineoplastic agents including for 
example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as 
decitabine or azacitidine. However, previous treatment with hydroxyurea or leukapheresis 
to reduce WBC count is allowed prior to randomization.
3. Investigational treatment received within 4 weeks or 5 half-lives of this investigational 
treatment, whatever is longer, prior to randomization
In case of a checkpoint inhibitor: a minimal interval of 4 months prior to randomization is 
necessary to allow randomization

Novartis
Confidential
Page 42 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
4. Current use or use 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. Live vaccine administered within 30 days prior to randomization
6. History of severe hypersensitivity reaction to any ingredients of the study treatments 
(azacitidine or MBG453) or their excipients, or to monoclonal antibodies
7. Subjects with Myelodysplastic syndrome (MDS) based on 2016 WHO classification 
(Arber et al 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 3
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 primary or secondary myelofibrosis grade 2 or higher based on WHO 2016 
classification (Arber et al 2016). Patients with myelofibrosis grade 1 must not be enrolled 
if they have symptoms of concurrent myeloproliferative neoplasm (e.g. splenomegaly, 
constitutional symptoms, proliferative features and WBC not increased)
10. Diagnosis of therapy related myeloid neoplasms based on WHO 2016 classification 
(Arber et al 2016)
11. History of organ transplant or allogeneic hematopoietic stem cell transplant
12. 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 with lenalidomide 
and then failed are eligible
c) subjects with history of adequately treated malignancy for whom no anticancer systemic 
therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during 
the course of the study. Subjects who are receiving adjuvant therapy such as hormone 
therapy are eligible. However, subjects who developed therapy related neoplasm are 
not eligible (see exclusion 10).
13. Active autoimmune disease requiring systemic therapy (e.g. 10 mg/day prednisone or 
equivalent or any immunosuppressive therapy)
14. Any concurrent severe and/or uncontrolled medical condition including significant cardiac 
or cardiac repolarization abnormalities, history of QT prolongation or QTcF > 470 ms at 
screening. Subjects with active infection requiring parenteral antibacterial, antiviral or 
antifungal therapy which are controlled by adequate treatment are eligible.
15. 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 
serology for Hepatitis B, please refer to Section 16.2 (Appendix 2).
16. HIV infection not controlled by standard therapy and/or with known history of opportunistic 
infection.
17. Any other co-morbidity that, in the opinion of the investigator, predisposes the subject to 
high risk of noncompliance with the protocol

Novartis
Confidential
Page 43 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
18. Sexually active males unwilling to use a condom during intercourse while taking azacitidine 
and for 3 months after stopping this treatment. 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 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 while 
taking study treatment and for 3 months after the last dose of azacitidine (or as per the 
respective local label, 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 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 
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 six 
weeks before taking study treatment. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment.
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 azacitidine.
The term “investigational drug” refers to the Novartis study drug, MBG453 or placebo.

Novartis
Confidential
Page 44 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
A dose of 800 mg/8 ml MBG453 or placebo will be provided by Novartis and administered 
every 4 weeks (Q4W). Azacitidine will be administered in a standard dose of 75 mg/m2 as per 
local clinical practice and locally available dose strengths.
For any component of the study treatment, all dosages prescribed and administered to the 
subject and all dose changes during the study (including the reason for change) must be recorded 
on the appropriate electronic Case Report Form (eCRF).
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global or 
local)
MBG453 400 mg/4 
ml/Placebo
Concentrate for 
solution for infusion
Intravenous use
Double Blind; vial
Sponsor (global)
Azacitidine 100 mg 
(or other locally 
available dose 
strengths)
Lyophilized powder
Intravenous or 
subcutaneous
Open label; vial
Provided Locally
Azacitidine is considered as a Standard of Care in the population enrolled in this study and it 
should be administered according to standard local clinical practice. For further instructions, 
refer to Section 6.7.2. Azacitidine regimens used in this protocol were selected because these 
are the most studied regimen and recommended by international treatment guidelines (NCCN, 
ESMO, Steensma 2018).
MBG453 or placebo will be administered via i.v. infusion preferably over 30 minutes, with a 
maximum administration time of 2 hours. Further instructions for the preparation and 
administration of MBG453 or placebo are described in Section 6.7.2
and in the 
[CMBG453B12301 Pharmacy Manual].
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
Subjects will be randomized in a 1:1 ratio to:

MBG453 + azacitidine or

Placebo + azacitidine
The randomization will be stratified into 4 groups:

Intermediate risk MDS,

High risk MDS,

Very high risk MDS,

CMML-2

Novartis
Confidential
Page 45 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
6.1.4
Guidelines for continuation of treatment
The study treatment consists of azacitidine plus MBG453 or azacitidine plus placebo 
(Section 6.1.1).
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).
6.1.5
Treatment duration
Subjects will be treated until they experience progression of disease (including transformation 
to acute leukemia per WHO 2016 classification), experience unacceptable toxicity or 
discontinue the study treatment for other reasons (see Section 9.1.1 and Section 9.2). 
Continuation of study treatment beyond progression (excluding transformation to acute 
leukemia: continuation in this case is not possible) may be possible in selected subjects 
(Section 6.1.5.1).
Subjects may continue study treatment (azacitidine plus MBG453/placebo), azacitidine alone 
or MBG453/placebo alone if the investigator considers this is in the best interest for the subject. 
In this case, the subjects should continue to conduct the assessments outlined for treatment 
phase in Table 8-1. 
Patients who complete participation in this trial and continue to derive clinical benefit from the 
treatment based on the investigator’s evaluation may receive post-trial access. Post Trial Access 
(PTA) means the provision of investigational treatment to trial participants following their 
completion of trial participation. PTA will be provided until one of the following is met: 
participant no longer derives clinical benefit, investigator discontinues treatment, launch or 
reimbursement (where applicable), treatment fails to achieve registration in the trial 
participant’s country, or the clinical program is discontinued for any other reason.
Mechanisms for provision of PTA may include an extension phase to this study, a separate 
extension protocol, a rollover protocol, provision of the Novartis investigational product in a 
non-trial setting (known as post-study drug supply [PSDS]) when no further safety or efficacy 
data are required, or any other mechanism appropriate for the country.
The PTA mechanism must comply with local laws and regulations in the participating trial 
countries. If Novartis discontinues the PTA for this trial, Novartis will work with investigators 
to transition patients onto locally available alternative treatment, or standard of care.
6.1.5.1
Treatment beyond disease progression
Subjects receiving study treatment may enjoy clinical benefit despite initial evidence of disease
progression. Subjects will be allowed to continue study treatment (azacitidine and 
MBG453/placebo), azacitidine alone, or MBG453/ placebo alone, beyond disease progression 
for up to the end of the study if all following criteria are met:

Absence of acute leukemia per WHO 2016 classification (as defined as ≥20% of blasts in 
bone marrow and/or peripheral blood) (Arber et al 2016) 

There is a clinical benefit observed per investigator assessment. The clinical benefit at the 
time of disease progression should consist of:

Novartis
Confidential
Page 46 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Improved or stable ECOG performance status and no cell lineage (neutrophils count, platelets 
count, hemoglobin) have worsened by >25% as compared to baseline status
And, at least one of the two following criteria:

Improvement or stabilization of cytopenia in at least one cell lineage (neutrophils count, 
platelets count, hemoglobin) as compared to baseline values, or

Reduction of RBC/platelet transfusion needs within the 8 weeks prior to evidence of 
disease progression as compared to transfusion needs reported prior to randomization

No unacceptable toxicity is reported

The subject continues to follow all protocol requirements
In addition, treatment beyond disease progression should not jeopardize critical interventions 
to treat/prevent severe complications or prevent subjects from receiving adequate care.
If the study treatment continues, the subjects should continue to perform all assessments for 
treatment phase as per Table 8-1.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
In general, the use of any concomitant medication/therapy deemed necessary for the care of the 
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.
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.
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 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 readily 
available.
Subjects should receive appropriate prophylaxis (e.g. antiemetics) for azacitidine as per local 
practice.
Relevant prior and all concomitant medication and non-drug therapies (including vitamin C 
intake for example) will be collected. Blood transfusions taken within 16 weeks before 
randomization and during the course of the study (including post-treatment/survival follow-up) 
should be recorded in the appropriate case report form (CRF). Information about antineoplastic 
therapies and HSCT after the end of study treatment should be collected during post-treatment 
and survival follow-up. 

Novartis
Confidential
Page 47 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Concomitant medications/therapy do not need to be recorded after a patient started post-
treatment antineoplastic medication. However, a concomitant medication/therapy given for an 
adverse event suspected to be related to study treatment will be recorded even if the patient has 
started the antineoplastic medication, for up to 150 days after discontinuation of 
MBG453/placebo.
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 
participation in the study.
Supportive therapy including prophylactic antibiotic and antifungal treatments, transfusions, or 
any other supportive care 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 prophylaxis, infection or 
septicemia. Please adhere to Table 8-2 that no growth factors should be given prophylactically 
within 2 weeks before response assessments. Erythropoietin stimulating agents and 
thrombopoietic agents are prohibited during the course of the study (see Section 6.2.2).
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
on the appropriate Case Report Forms.
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. 
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, 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, since 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.
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 in the context of blood transfusion or replacement-dose 

Novartis
Confidential
Page 48 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
steroids in the setting of adrenal insufficiency or any transient exacerbation of other underlying 
diseases, as an example 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 start of the cycle. If more than 10 mg/day prednisone is used, study treatment 
(Azacitidine + MBG453/placebo) 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, unless these are attenuated vaccines, but 
should not be administered on the same day of study treatment administration to avoid potential 
overlapping adverse events. 
Erythropoietin stimulating agents and thrombopoeitic 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 prophylaxis, infection or septicemia. Please 
adhere to Table 8-2 that no growth factors should be given prophylactically within 2 weeks 
before response assessments.
In addition, prohibited medication related to azacitidine will apply according to the locally 
approved product information.
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 for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject’s participation is numbered uniquely across the entire 
database. Upon signing the informed consent form, the site will use the electronic data capture 
system to assign the subject the next sequential Subject No.
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 the Interactive Response Technology (IRT) system should be notified as soon 
as possible. Re-screening is allowed once for subjects that were initially screen failures for any 
reason. All eligibility criteria must be re-checked and met prior to enrollment of the subject into 
the study. A new ICF will need to be signed if the investigator chooses to re-screen the subject. 
A new Subject No. should be assigned for all re-screened subjects.
6.3.2
Treatment assignment, randomization
In this randomized, placebo-controlled trial, subjects will be randomized in a 1:1 ratio to one of 
the two treatment arms (MBG453 + azacitidine or placebo + azacitidine) (Section 6.1).

Novartis
Confidential
Page 49 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
At visit C1D1, following completion of screening procedure, all eligible subjects will be 
randomized via IRT to one of the treatment arms. The investigator or his/her delegate will 
contact the IRT after confirming that the subject fulfills all the inclusion/exclusion criteria. The 
IRT will assign a randomization number to the subject, which will be used to link the subject 
to a treatment arm. The randomization number will not be communicated to the investigator or 
his/her delegate.
MBG453/placebo will not be dispensed at this visit, the IRT will specify at C1D8 a unique 
medication number for the first package of MBG453 or placebo to be administered to the 
subject.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. Random permuted 
blocks scheme will be used for this study.
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. A separate medication list will be produced under the 
responsibility of Novartis Global Clinical Supply (GCS) using a validated system that 
automates the random assignment of medication numbers to packs containing the study 
treatment.
Randomization will be stratified into 4 groups: intermediate risk MDS, high risk MDS, very 
high risk MDS and CMML-2 (for rationale for stratification, please refer to Section 4.1).
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
OS futility and all safety/efficacy interim analyses will be performed by an independent 
statistician and reviewed by a Data Monitoring Committee (DMC). Novartis clinical team, 
subjects, investigators and persons performing the assessments will remain blinded to the results 
of the analysis and the identity of the treatment from the time of randomization until primary 
analysis unless the DMC has determined that the study needs to be terminated due to any cause 
including safety reasons.
At the time of the efficacy interim analysis, if the OS is statistically significant, the Novartis 
clinical team will be unblinded. Subjects, investigators, site personnel, persons performing the 
assessments, will remain blinded to the results of the analysis and the identity of the treatment 
until the primary analysis.
Blinding will be ensured using the following methods: (1) Randomization data are kept strictly 
confidential until the time of unblinding and will not be accessible by anyone else involved in 
the study with the following exceptions: Global Clinical Supply and PK analysts team (2) the 
identity of the treatments will be concealed by the use of study treatment that are all identical 
in packaging, labeling, schedule of administration, appearance, taste, and odor.

Novartis
Confidential
Page 50 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
The randomization codes associated with subjects from whom PK samples are taken will be 
disclosed to the PK analysts to facilitate the analysis of the PK samples. The PK analysts will 
keep the PK results confidential until the final database lock.
To limit the impact of unblinding on the scientific validity of the study results, individual subject 
unblinding is prohibited. Unblinding will only be permitted in the case of subject emergencies 
(Section 6.6.2), at the conclusion of the study and for regulatory reporting purposes.
6.5
Dose escalation and dose modification
Dose escalation is not applicable.
6.5.1
Dose modifications
For subjects who do not tolerate the protocol-specified dosing schedule, dose interruptions, 
and/or reductions are either recommended or mandated in order to allow subjects to continue 
the study treatment.
Dose modifications for azacitidine 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 on the 
management of immune-related AEs (Brahmer et al 2018). Additionally, a guidance indicated 
in Table 6-2 below provides instructions for infusion reactions, immune-related AEs not 
covered by ASCO guidelines and a general guideline for non-hematologic non-immune-related 
toxicities that are clinically significant per investigator judgment 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 dose interruptions, reductions and/or permanent discontinuations outlined in 
Table 6-2 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 14 days. If a dose cannot be administered within the planned 
window within the cycle, then the dose should be skipped. Next scheduled dosing may resume 
once the adverse event has resolved to ≤ Grade 1 or baseline by the next planned treatment 
cycle. Dose reductions for MBG453 or placebo are not allowed; however, longer intervals for 
administration (Q8W instead of Q4W) are permitted in some clinical situations, as described in 
Table 6-2.
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.

Novartis
Confidential
Page 51 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Dose modifications for azacitidine
If azacitidine treatment is deemed by the investigator to possibly have contributed to an 
observed adverse event, the dose or schedule of azacitidine treatment may be modified within 
a cycle and/or for subsequent cycles or temporary/permanent interruptions of azacitidine 
treatment may be decided by the investigator according to local practice and/or the country-
specific label guiding azacitidine use.
Permanent discontinuation of MBG453 or placebo and azacitidine
If the study treatment (i.e. MBG453 + azacitidine or placebo + azacitidine) 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, azacitidine and 
MBG453/placebo), the subject should be discontinued from study treatment. In exceptional 
cases this may be longer; please consult with the Novartis study team.
Permanent discontinuation of only one component MBG453/placebo or 
azacitidine
If one component only of the study treatment (azacitidine 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 azacitidine alone) as long as the subject benefits per 
investigator's judgment.
These dose changes must be recorded on the appropriate CRF.
Table 6-2
Criteria for dose interruption and re-initiation of MBG453 or placebo 
for adverse drug reactions
Worst toxicity CTCAE 
Grade V5.0
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
Adverse events thought to be immune-related AEs 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 (800 mg) and 
schedule (Q4W)
Grade 2, or Grade 3 ≤ 7 
days
Delay MBG453/placebo until toxicity resolved to ≤ Grade 1 or baseline. Then 
resume at the same dose (800 mg) and schedule (Q4W)
Grade 3 lasting > 7 days but 
< 21 days
Delay MBG453/placebo until toxicity resolved to ≤ Grade 1 or baseline. Then 
resume at the same dose (800 mg) but with a longer treatment interval (Q8W). 
Return to the initial treatment interval (Q4W) may be possible but only after 
discussion and agreement with Novartis Medical Lead.

Novartis
Confidential
Page 52 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Worst toxicity CTCAE 
Grade V5.0
Dose Modifications
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 at 
least possibly attributable to the investigational drug.
This guideline does not apply for toxicities attributable to azacitidine or the underlying MDS including its 
complications.
Grade 1
No change. Continue MBG453/placebo at the same dose (800 mg) and 
schedule (Q4W)
Grade 2, or Grade 3 ≤ 7 
days
Delay MBG453/placebo until toxicity resolved to ≤ Grade 1 or baseline. Then 
resume at the same dose (800 mg) and schedule (Q4W)
Grade 3 > 7 days
Delay MBG453/placebo until toxicity resolved to ≤ Grade 1 or baseline. Then 
resume at the same dose (800 mg) but with a longer treatment interval (Q8W). 
Return to the initial treatment interval (Q4W) may be possible but only after 
discussion and agreement with Novartis Medical Lead.
Grade 4
Discontinue MBG453/placebo
All dose modifications should be based on the worst preceding toxicity.
* Infusion related reaction or allergic reaction/anaphylaxis. See Section 6.2.1 for instructions regarding 
prophylaxis.
** Per investigator judgment
6.5.2
Follow-up for toxicities
Subjects, whose treatment is interrupted or permanently discontinued due to an adverse event 
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. 
If subjects experience a SAE or an AE leading to discontinuation of the study treatment, an 
unscheduled PK blood sample should be obtained as close as possible to the event occurrence.
For guidance on renal alert criteria, actions and events follow up, please refer to Section 16.1
(Appendix 1).
Immune-related AEs
The emergence of immune-related AE (irAE) may be anticipated based on general experience 
in clinical studies with a similar class of compounds that block the negative immune regulators.
An irAE is any clinically significant AE affecting any organ that is associated with study drug 
exposure, is consistent with an immune-mediated mechanism, and where alternative 
explanations have been investigated and ruled out or are considered to be unlikely. Serologic, 
histologic and immunological assessments should be performed as deemed appropriate by the 
Investigator, to verify the immune related nature of the AE. An empiric trial of corticosteroids 
may also contribute to understanding the etiology of a potential irAE. All 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). For irAEs not covered by ASCO guidelines, please refer 
to Table 6-2.

Novartis
Confidential
Page 53 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
In case of a suspected irAE, the relevant immunological assessments (e.g. rheumatoid factor, 
anti-DNA Ab, etc.) should be performed. In case of toxicity suspected to be a cytokine release 
syndrome, the assessments outlined in Table 8-5 must be performed.
Please follow Section 8.5.2 for additional instructions regarding PK.
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 rare in MDS and no cases of TLS have 
been reported in the ongoing [CPDR001X2105] for MDS subjects receiving MBG453 in 
combination with HMA.
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.
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 (eg, 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 three days before or in the days 
following initiation of a treatment cycle:

Uric acid ≥ 8 mg/dL or 25% increase from baseline

Potassium ≥ 6 mEq/L or 25% increase from baseline

Phosphorus ≥ 4.5 mg/dL or 25% increase from baseline

Calcium ≤ 7 mg/dL or 25% decrease from baseline

Novartis
Confidential
Page 54 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301

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

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
Guidelines for follow-up on potential DILI cases are described in Table 6-3 and Table 6-4.
Table 6-3
Follow-up of abnormal liver chemistry results
ALT
TBL
Liver Symptoms
Action
ALT increase without bilirubin increase:
If normal at baseline:
ALT > 3 x ULN
Normal
For subjects with 
Gilbert’s syndrome: No
change in baseline TBL
None
- No change to study treatment
- Measure ALT, AST, ALP, 
GGT, TBL, INR, albumin and 
CK in 48-72 hours (GLDH is 
recommended as well)
- Follow-up for symptoms
If elevated at baseline:
ALT > 2 x baseline or > 
200 U/L (whichever 
occurs first)
If normal at baseline:
ALT > 5 x ULN for more 
than two weeks
Normal
For subjects with 
Gilbert’s syndrome: No 
change in baseline TBL
None 
- Interrupt investigational drug
- Measure ALT, AST, ALP, 
GGT, TBL, INR, albumin and 
CK in 48-72 hours (GLDH is 
recommended as well).
- Follow-up for symptoms.
- Initiate close monitoring and 
workup for competing 
etiologies.
- Investigational drug can be 
restarted only if another etiology 
is identified and liver enzymes 
return to baseline.
If elevated at baseline:
ALT > 3 x baseline or > 
300 U/L (whichever 
occurs first) for more than 
two weeks
If normal at baseline:
ALT > 8 x ULN
Normal 
None
ALT increase with bilirubin increase:
If normal at baseline:
ALT > 3 x ULN
TBL > 2 x ULN (or INR > 
1.5)
None

Novartis
Confidential
Page 55 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
ALT
TBL
Liver Symptoms
Action
If elevated at baseline:
ALT > 2 x baseline or > 
200 U/L (whichever 
occurs first)
For subjects with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin
If normal at baseline:
ALT > 3 x ULN
Normal or elevated
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain
If elevated at baseline:
ALT > 2 x baseline or > 
200 U/L (whichever 
occurs first)
Table 6-4
Action required for isolated total bilirubin elevation
Abnormality
Action required
Any elevation > ULN
Fractionate bilirubin, evaluate for cholestatic liver injury (ALP) or alternative 
causes of bilirubin elevation. Treat alternative causes according to local 
institutional guidelines
Grade 2 (>1.5 - 3.0 ULN)
Maintain treatment. Repeat Liver Function Tests (LFTs) within 48-72 hours, 
then monitor LFTs weekly until resolution to ≤ Grade 1 or to baseline
Grade 3 (>3.0 – 10 ULN)
Interrupt treatment. Repeat LFTs within 48-72 hours, then monitor LFTs 
weekly until resolution to ≤ Grade 1 or to baseline
Grade 4 (> 10 x ULN)
Discontinue study treatment
If abnormalities are confirmed, close observation and follow-up are required:
1. A detailed history, including relevant information, such as cardiac disease, history of any 
pre-existing liver conditions or risk factors, blood transfusions, i.v. drug abuse, travel, work, 
alcohol intake, and full clinical examination for evidence of acute or chronic liver disease, 
cardiac disease and infection etc. should be performed.
2. Review of concomitant medications, including nonprescription medications and herbal and 
dietary supplement preparations, alcohol use, recreational drug use, special diets, and 
chemicals exposed to within one month of the onset of the liver injury.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary tract) 
may be warranted.
4. Obtain PK sample, as close as possible to last dose of MBG453/placebo, if PK analysis is 
performed in the study.
5. Additional testing for other hepatotropic viral infection (Cytomegalovirus, Epstein–Barr 
virus or Herpes-simplex virus), autoimmune hepatitis or liver biopsy may be considered as 
clinically indicated or after consultation with specialist/hepatologist.
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.

Determine the serum electrolyte levels (in particular potassium and magnesium levels for 
detecting hypokalemia, hypomagnesemia). If abnormal, correct abnormalities.

Review concomitant medication use for possible causes for QT prolongation (refer to 
Crediblemeds). Record all concomitant medications in the appropriate eCRF page.

Monitor ECG per the institutional standards.

Novartis
Confidential
Page 56 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
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 accessed to assign a medication (kit) number to the subjects every time MBG453 
or placebo is to be administered. The date and time of all study treatment administrations 
(azacitidine and MBG453/placebo) during the study and any deviations from the protocol 
treatment schedule will be captured by the investigator staff and reviewed by field monitor on 
the appropriate study treatment dispensing form. Compliance with the study treatment will be 
assessed by the field monitor at each visit and information provided by the pharmacist or by the 
investigator. All study treatment dispensed, returned or destroyed as per local regulation must 
be recorded in the Drug Accountability Log.
Pharmacokinetic samples will be taken in all subjects as detailed in the pharmacokinetic 
Section 8.5.2.
All dosages for MBG453 or placebo as well as azacitidine prescribed to the subject and all dose 
changes during the study must be recorded on the corresponding Dosage Administration Record 
eCRF.
6.6.2
Emergency breaking of assigned treatment code
Emergency unblinding should only be undertaken for safety reasons essential for effective 
treatment of the patient. Blinding codes may also be broken after a patient discontinues 
treatment due to disease progression if deemed essential to allow the investigator to select the 
patient’s next treatment regimen, and after discussion and agreement with the sponsor.
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

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.

Novartis
Confidential
Page 57 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
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 as 
specified in the protocol (Section 9.1.5 and Section 9.1.6).
6.7
Preparation and dispensation
Each study site will be supplied by Novartis with investigational drug (MBG453 or placebo) in 
packaging of identical appearance per product volume. A unique medication number is printed 
on the label of the investigational drug.
Investigator staff will identify the investigational drug kits to administer to the subject by 
contacting the IRT and obtaining the medication number(s). The investigational drug has a 
2-part label (base plus tear-off label), immediately before administering 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 will be administered i.v. Further instructions for the preparation and 
dispensation of MBG453 or placebo are described in the [CMBG453B12301 Pharmacy 
Manual].
Azacitidine will be sourced locally. For details on preparation, refer to the country-specific label 
instructions and/or azacitidine package insert.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure, or the locally approved 
product information. Clinical supplies are to be administered only in accordance with the 
protocol. Technical complaints are to be reported to the Quality Assurance at Novartis or the 
respective manufacturing company.
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.
Study drug MBG453/placebo will be administered to the patient by the study site staff. 
Azacitidine will be administered per local country and site regulations. This may include 
administration by study site staff, or local administration at another hospital or through home 
administration by qualified site staff, or by trained non-study personnel. Compliance will be 
assured by administration of the study treatment under the supervision of investigator or his/her 
designee. Administration of azacitidine at C1D1 must be done at the investigational site. 
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.

Novartis
Confidential
Page 58 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
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
Dose and treatment schedule of MBG453 or placebo as well as azacitidine is described in 
Table 6-5. 
Table 6-5
Dose and treatment schedule
Investigational / Control Drug
Dose
Frequency and/or Regimen
MBG453 or placebo
800 mg
i.v. infusion over 30 minutes on Day 8
Azacitidine
75 mg/m2
i.v. or subcutaneously on Day 1-7
or on Day 1-5, 8 and 9
Azacitidine should be administered according to local standard clinical practice. A standard 
dose of azacitidine (75mg/m2) will be given subcutaneously or intravenously (see local 
azacitidine package insert) every day for seven consecutive days on days 1 to 7 out of a 28 day 
cycle, followed by MBG453 or placebo. In keeping with standard clinical practice, the 
alternative schedule of 75 mg/m2 for five consecutive days on days 1 to 5, followed by a two 
day break, then two consecutive days on days 8 and 9 will alternatively be permitted (alternative 
schedule).
MBG453 or placebo infusions will be administered on day 8 out of a 28 day cycle. Refer 
to Table 6-1.
If the alternative schedule is selected for azacitadine 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 [CMBG453B12301 
Pharmacy Manual].
MBG453 or placebo will be administered via i.v. infusion preferably over 30 minutes, with a 
maximum administration time of 2 hours. Further instructions for the preparation and 
dispensation of MBG453 or placebo are described in the [CMBG453B12301 Pharmacy 
Manual].
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation) informed consent approved by
Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC).
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 

Novartis
Confidential
Page 59 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
his/her 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.
Information about common side effects already known about the study drug can be found in the 
Investigator's Brochure (IB) for MBG453 and/or in the latest locally approved product 
information for azacitidine. 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.
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 may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Health Authority. Remote ICF process may also be used (if allowed by 
local Health Authority) for re-consenting subjects who are in the follow-up phase of the study. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.).
The study includes the option for the subjects to continue MBG453 or placebo alone. The study 
also includes the option for the subjects to continue treatment with MBG453/placebo and 
azacitidine, azacitidine alone, MBG453/placebo alone beyond progression in selected subjects 
without acute leukemia (see Section 6.1.5.1). 
In both options (continuation of MBG453/placebo alone, or continuation of treatment beyond 
progression), this will require informed consent before treatment continuation 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.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
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 

Novartis
Confidential
Page 60 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
cryopreservation. Female partners of male subjects will be instructed to use highly effective 
contraception methods.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
8
Visit schedule and assessments
Assessment schedule (Table 8-1) lists all of the assessments when they are performed. All data 
obtained from these assessments must be supported in the subject’s source documentation.
Screening evaluations should be performed within ≤ 28 days of Cycle 1 Day 1 (except for the 
pregnancy test which has to be performed within 72 hours before the first dose). For screening 
assessments, please refer to Section 8.2.
If the hematology, chemistry and coagulation laboratory tests are performed within 7 days 
before randomization, it is not required to perform them again on C1D1.
During the course of the study, test and/or procedures should occur on schedule whenever 
possible. During the treatment phase a visit window of +/- 3 days is allowed (however the time 
window for bone marrow aspirate/biopsy and ePRO is - 7 days), during the post-treatment 
follow up phase and the survival follow-up a visit window of +/-14 days is allowed. In case the 
infusion of MBG453 or placebo or azacitidine cannot be administered at the scheduled visit, it 
has to be administered as soon as possible. Every effort should be made on C1D1 for the 
azacitidine to be administered on the same day as randomization. After C1D1, a window of 
+/- 3 days is allowed for treatment administration for reason other than toxicities. For 
adjustment of study treatment for toxicities, please refer to Section 6.5.1. For PK collection 
days, the windows for the PK sampling time are provided in Section 8.5.2.1.
Each treatment cycle is 28 days. Each cycle’s Day 1 visit and corresponding assessments are 
determined by the first dose of Azacitidine for the cycle.
If administration of study treatment is delayed within the allowed window for reasons other 
than toxicities, the investigator should preferably shorten the current cycle to bring the next 
back to schedule if allowed by local standard practice.
Subjects who discontinue the study treatment for any reason should be scheduled for an end of 
treatment (EOT) visit as soon as possible (up to 7 days after discontinuation), 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). 
At this visit, all administered investigational product should be reconciled, and the adverse 
event and concomitant medications recorded on the CRF.
All subjects receiving the study treatment must have safety evaluations for 30 days after the last 
dose of azacitidine, and 150 days after the last dose of MBG453 or placebo. In addition, a 
pregnancy test should be performed for women of child-bearing potential at timepoints 
described in Section 8.4.3. After the safety follow-up onsite visit on Day 30 (to allow for PK 
and IG sampling), subjects will be followed via telephone call or onsite visits for the Day 90 
and Day 150. For the safety follow-up visits a visit window of +/- 3 days is allowed.

Novartis
Confidential
Page 61 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Post-treatment follow-up or survival follow-up start from end of treatment visit. For details, 
please refer to Section 8.3.1, Section 9.1.5 and Section 9.1.6.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
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 
participant´s home, can replace on-site study visits, for the duration of the disruption until it is 
safe for the participant to visit the site again. Screening, C1D1, efficacy/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. 

Novartis
Confidential
Page 62 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Table 8-1
Assessment Schedule
Period
Screening Treatment
EOT
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7
(28d)
Cycle 8 (and beyond) 
(28d)
Visit Name
Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
EOT
Days
-28 to -1
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
-
Informed 
consent
X
IRT Screening 
X
IRT 
Randomizatio
n
X
Demography
X
Inclusion / 
Exclusion 
criteria
X
Medical 
history/current 
medical 
conditions
X
Disease 
History
X
Prior 
antineoplastic 
therapies
X
Prior 
medications, 
surgery and 
medical 
procedures 
(including 
blood 
transfusions 
requirement)
X

Novartis
Confidential
Page 63 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Period
Screening Treatment
EOT
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7
(28d)
Cycle 8 (and beyond) 
(28d)
Visit Name
Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
EOT
Days
-28 to -1
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
-
Physical 
Examination
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body Height
X
BSA (use
height from 
screening)
X
X
X
X
X
X
X
X
Body Weight
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
12-Lead ECG 
(triplicates)
S
If clinically indicated
S
Hematology
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
On cycle 9 
and every 2 
cycles 
thereafter
X
Coagulation
X
X
X
X
X
X
X
X
On cycle 9 
and every 2 
cycles 
thereafter
X
Thyroid 
function
X
X
X
On cycle 8 
and every 3 
cycles 
thereafter
X
Ferritin, iron, 
erythrocyte 
and serum 
folates, 
vitamin B12
X
If clinically indicated

Novartis
Confidential
Page 64 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Period
Screening Treatment
EOT
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7
(28d)
Cycle 8 (and beyond) 
(28d)
Visit Name
Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
EOT
Days
-28 to -1
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
-
Vitamin C
X
hs-CRP
X
Cytokines
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 (only 
women with 
child-bearing 
potential)
S
S
S
Urine 
Pregnancy 
Test OR 
Serum 
Pregnancy 
Test (only 
women with 
child-bearing 
potential)
S
S
S
S
S
S
S
Urinalysis 
dipstick and 
sediment
S
If clinically indicated

Novartis
Confidential
Page 65 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Period
Screening Treatment
EOT
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7
(28d)
Cycle 8 (and beyond) 
(28d)
Visit Name
Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
EOT
Days
-28 to -1
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
-
Efficacy -
Bone marrow 
aspirate 
and/or biopsy
X
X
On cycle 13 
and every 
12 cycles 
thereafter, 
and if 
clinically 
indicated
If 
clinically 
indicate
d
Efficacy -
Peripheral 
blood 
collection and 
pathology
X
X
On cycle 13 
and every 
12 cycles 
thereafter, 
and if 
clinically 
indicated
If 
clinically 
indicate
d
Cytogenetics 
X
Response 
assessment
X
On cycle 13 
and every 
12 cycles 
thereafter, 
and if 
clinically 
indicated
X
FACIT-
Fatigue
X
At Cycle 3 Day 1, then every 2 cycles thereafter, and at time of EOT
EORTC QLQ-
C30 
X
At Cycle 12 
Day 1

Novartis
Confidential
Page 66 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Period
Screening Treatment
EOT
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7
(28d)
Cycle 8 (and beyond) 
(28d)
Visit Name
Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
EOT
Days
-28 to -1
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
-
EORTC QLQ-
C30 (only 
emotional and 
physical 
functioning 
domain items)
At Cycles 3 - 6 - 9 Day 1, then from cycle 15 every 3 cycles thereafter, and at time of EOT
EQ5D-5L 
(including 
VAS)
X
At Cycle 3 Day 1, then every 3 cycles thereafter, and at time of EOT

Novartis
Confidential
Page 67 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Period
Screening Treatment
EOT
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7
(28d)
Cycle 8 (and beyond) 
(28d)
Visit Name
Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
EOT
Days
-28 to -1
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
-
Blood sample 
for PK 
analysis
X
X
X
X
X
On cycles 9, 
12 and every 
6 cycles 
thereafter
X
Blood sample 
for IG analysis
X
X
X
X
X
On cycles 9, 
12 and every 
6 cycles 
thereafter
X

Novartis
Confidential
Page 68 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Period
Screening Treatment
EOT
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7
(28d)
Cycle 8 (and beyond) 
(28d)
Visit Name
Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
EOT
Days
-28 to -1
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
-
Azacitidine 
infusion
on Days 1- 7 of each cycle OR on Days 1-5 and then on Day 8 and Day 9: IV or SC75mg/m2
MBG453/Plac
e-bo infusion
on Day 8 of each cycle: 800 mg IV Q4W
IRT - Drug 
Dispensation 
MBG453/Plac
e-bo
X
X
X
X
X
X
X
X
Adverse 
Events
X
Continuous

Novartis
Confidential
Page 69 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Period
Screening Treatment
EOT
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7
(28d)
Cycle 8 (and beyond) 
(28d)
Visit Name
Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
EOT
Days
-28 to -1
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
D1
D8
-
Concomitant 
medications 
and medical 
procedures 
(including 
blood 
transfusions 
requirement)
Continuous
Antineoplastic 
therapies, 
HSCT and 
transfusions 
since 
discontinuatio
n of study 
treatment 
Disposition
X
X
IRT 
Discontinuatio
n
X
Survival 
Follow up

Novartis
Confidential
Page 70 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Period
Safety FU
Post- treatment FU
Survival
Cycle
Visit Name
D30
D90
D150
Post Treatment Follow 
Up
Survival
Days
-
-
-
-
-
Informed consent
IRT Screening 
IRT Randomization
Demography
Inclusion / Exclusion criteria
Medical history/current medical conditions
Disease History
Prior antineoplastic therapies
Prior medications, surgery and medical 
procedures (including blood transfusions 
requirement)
Physical Examination
Vital Signs
Body Height
BSA (use height from screening)
Body Weight
ECOG PS
12-Lead ECG (triplicates)
Hematology
Every 12 weeks and if 
clinically indicated
Chemistry
Coagulation
Thyroid function
Ferritin, iron, erythrocyte and serum folates, 
vitamin B12

Novartis
Confidential
Page 71 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Period
Safety FU
Post- treatment FU
Survival
Cycle
Visit Name
D30
D90
D150
Post Treatment Follow 
Up
Survival
Days
-
-
-
-
-
Vitamin C
hs-CRP
Cytokines
Virology hepatitis B and C
HIV serology (only if required per local 
regulation)
Serum Pregnancy Test (only women with 
child-bearing potential)
S
Urine Pregnancy Test OR Serum Pregnancy 
Test (only women with child-bearing 
potential)
D30, D60, D90, D120 after the last dose of 
MBG453/placebo 
Urinalysis dipstick and sediment
Efficacy - Bone marrow aspirate and/or 
biopsy
If clinically indicated (for 
example if progression or 
relapse is suspected)
Efficacy - Peripheral blood collection and 
pathology
If clinically indicated (for 
example if progression or 
relapse is suspected)
Cytogenetics 
Response assessment
If clinically indicated (for 
example if progression or 
relapse is suspected)
FACIT-Fatigue
Every 12 weeks
EORTC QLQ-C30 
EORTC QLQ-C30 (only emotional and 
physical functioning domain items)
Every 12 weeks
EQ5D-5L (including VAS)
Every 12 weeks

Novartis
Confidential
Page 72 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Period
Safety FU
Post- treatment FU
Survival
Cycle
Visit Name
D30
D90
D150
Post Treatment Follow 
Up
Survival
Days
-
-
-
-
-
Blood sample for PK analysis
X
If visit is done at 
site
Blood sample for IG analysis
X
If visit is done at 
site
Azacitidine infusion
MBG453/Placebo infusion
IRT - Drug Dispensation MBG453/Placebo

Novartis
Confidential
Page 73 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Period
Safety FU
Post- treatment FU
Survival
Cycle
Visit Name
D30
D90
D150
Post Treatment Follow 
Up
Survival
Days
-
-
-
-
-
Adverse Events
Continuous
Concomitant medications and medical 
procedures (including blood transfusions 
requirement)
Continuous
Antineoplastic therapies, HSCT and 
transfusions since discontinuation of study 
treatment 
Continuous
Disposition
X
IRT Discontinuation
Survival Follow up
Every 12 weeks
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only

Novartis
Confidential
Page 77 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Response category
Definition#
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: 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**

Novartis
Confidential
Page 78 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Response category
Definition#
Occurrence of acute leukemia, or extramedullary leukemia per investigator's 
judgement
Modified Hematologic Improvement per IWG-MDS criteria (Cheson et al 2006)
HI category
Definition# (HI must last at least 8 weeks)
Erythroid response 
(HI-E) 
(pretreatment*, <11 
g/dL)
1. Hgb increase from baseline by ≥ 1.5 g/dL, in at least 2 consecutive Hgb 
measurements and maintained over at least 8 weeks
2. Relevant reduction from baseline of units of RBC transfusions by an absolute 
number of at least 4 RBC transfusions/8 weeks compared with the pre-treatment 
transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hgb 
of < 9 g/dL pre-treatment will count in the RBC transfusion response evaluation.
Platelet response 
(HI-P) 
(pretreatment*, <100 
x 109/L)
3. Absolute increase from baseline of ≥ 30 x 109/L for subjects starting with > 20 x 109/L 
platelets
4. Increase from baseline from < 20 x109/L to > 20 x109/L and by at least 100% for 
subjects starting with < 20 x 109/L platelets
Neutrophil response 
(HI-N)
(pretreatment*, <1.0 
x 109/L)
At least 100% increase and an absolute increase from baseline of > 0.5 x 109/L
#If not defined otherwise, all of the criteria apply. Words that are written in italics highlights the 
modifications from the IWG criteria described in the reference publications.
*Pretreatment counts correspond to the baseline (not influenced by transfusions)
**Definition of transfusion dependence and independence for red blood cells (RBC) and/or platelets are 
described below.
***maximum remission/response levels correspond to the best values reported in post baseline.
Transfusions Status Definitions for RBC/platelets
Transfusions for intercurrent diseases not due to study indication (e.g. bleeding, surgical procedure, 
hemolysis, infections) should not be taken into account for the following:
Transfusion dependence
1. At baseline: subjects having received ≥ 3 units of transfusion within the 8 consecutive weeks prior to baseline.
2. Post-baseline: subjects having received ≥ 3 units of transfusion within any 8 consecutive weeks during the 
course of the study
Transfusion independence:
1. At baseline: subjects having received 0 units of transfusion within the 8 consecutive weeks prior to baseline.
2. Post-baseline: subjects having received 0 units of transfusion within any 8 consecutive weeks during the 
course of the study
Response assessment will be performed by investigator according to the assessment schedule 
depicted in Table 8-1. Moreover, subjects can be assessed for disease response (bone marrow 
assessment, hematology, transfusion) at any time if clinically indicated as an example if there 
is a clinical suspicion of progression/relapse, in particular after a subject has achieved a CR. 
Bone marrow assessments will be performed at screening and pre-dose on C7D1 and C13D1. 
After C13D1, bone marrow assessments will be performed every 12 cycles (C25D1, C37D1, 
etc.) until end of treatment. Hematology assessments will be performed at screening, and 
pre-dose on D1 and D8 of each cycle until cycle 7 included; and thereafter on D1 of each cycle 
until end of treatment.
Bone marrow and peripheral blood pathology specimens (i.e. bone marrow aspirate slides, bone 
marrow biopsy block if applicable, peripheral blood smears) prepared locally for the disease 
response assessment, should be sent to the Novartis designated central laboratory for storage. 
This includes specimens taken during the regular work-up of the subject and used as baseline 

Novartis
Confidential
Page 79 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
assessment for the study as mentioned in Section 8-2. A copy of the corresponding pathology 
reports should be collected and sent to the Novartis designated central laboratory for storage. 
Central morphology review of the pathology specimens may be performed, if deemed necessary. 
For China only: Storage of the above pathology specimens and reports in a Novartis designated 
laboratory will be performed, if adequate approval has been obtained from all relevant Chinese 
authorities.
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. Hematology assessments must continue to be 
performed every 12 weeks, and bone marrow assessments should be done if clinically indicated 
(for example if progression or relapse is suspected) per Table 8-1. Transfusion information will 
be collected during post-treatment follow-up phase.
The post-treatment follow-up period will last until subject's documented disease progression 
(per IWG criteria Table 8-2), death, lost to follow-up, or withdrawal of consent/opposition to 
use data/biological samples, or the end of the study whichever comes first.
All randomized subjects have to be followed for efficacy, regardless whether treatment 
received or not.
8.3.2
Appropriateness of efficacy assessments
Overall Survival is the primary endpoint of the study and will be assessed according to a 
standard methodology. Hematological responses based on assessment of bone marrow, 
peripheral blood and history of blood transfusions are standard for the indications (MDS, 
CMML-2) investigated in this study and recommended by international treatment guidelines 
(IWG-MDS).
8.4
Safety
Safety assessments are specified below (Table 8-3) with the assessment schedule detailing 
when each assessment is to be performed.
For safety evaluations, baseline is defined as assessments done on C1D1 prior to the first dose 
of study treatment. For assessment which are not done at C1D1 as per Table 8-1, baseline is 
defined as the last available assessment prior to C1D1.
The investigator will report any vital signs considered clinically significant in the eCRF. For 
details on AE collection and reporting, refer to AE Section 10.1.1.

Novartis
Confidential
Page 80 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Table 8-3
Assessments & Specifications
Assessment
Specification
Physical 
examination
A complete physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular, and neurological. If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be 
performed.
A complete physical examination is required at D1 of each cycle. At D8, an abbreviated 
examination can be done at investigator's discretion.
Information for all physical examinations must be included in the source documentation at 
the study site. Clinically relevant findings that are present prior to signing informed 
consent must be recorded on the appropriate eCRF 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 at screening and at 
subsequent time points as specified in Table 8-1.
Performance status:
The Eastern Cooperative Oncology Group/World Health Organization Performance Status 
(ECOG/WHO PS) scale will be used as described in Table 8-4.
Table 8-4
ECOG performance status
Grade
ECOG Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light house work, office work)
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Death
8.4.1
Laboratory evaluations
Local clinical laboratory parameters will be used for the analysis of scheduled hematology, 
chemistry and other blood specimens collected as part of safety monitoring (as detailed in
Table 8-1 and Table 8-5) and the results will be collected in the eCRF, except for specific 
parameters which will be performed centrally by a Novartis designated laboratory (as detailed 
in Table 8-5).
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.
If participants cannot visit the site for protocol specified safety lab assessments due to public 
health emergency, an alternative lab (local) collection site may be used. The local lab must 

Novartis
Confidential
Page 81 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
provide Novartis with a copy of the certification and a tabulation of the normal ranges and units 
for all local laboratories used in the trial.
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 
There are no specific notable range criteria for this study; however, the local and central 
laboratory will flag laboratory values falling outside of the normal range, on the local and 
central laboratory report (as applicable) (which the investigator should sign off) as per local 
practice, and the investigator will report any values considered clinically significant in the eCRF.
Table 8-5
Clinical laboratory parameters collection plan
Test 
Category
Local/Central
Test Name
Hematology1
Local
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cells, 
White blood cells, RBC Morphology, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Bands), Blasts7, Other (absolute 
value preferred, percentages are acceptable)
Chemistry
Local
Albumin, ALP, 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 T3
Virology2
Local
HBsAg, HBcAb, HBV DNA (in subjects positive for HBcAb), HCV RNA 
(Polymerase chain reaction)
HIV (Only if required by local regulation)
Coagulation
Local
International normalized ratio (INR), Activated partial thromboplastin time 
(aPTT)
Cytokines
Central
IFN-γ, IL-6, IL-1 β, TNF-α, IL-10, IL-2, IL-4, IL12-p70, IL-13, IL-8
Urinalysis 
dipstick and 
sediment2
Local
Dipstick examination includes specific gravity, pH, glucose, protein, blood, 
bilirubin, ketones and WBC as clinically indicated
Pregnancy 
Test2
Local
Serum / Urine pregnancy test (refer to Section 8.4.3)
Additional 
tests
Local
Ferritin, iron, vitamin B12, erythrocyte and serum folates4, TSH5, Free T3 
and/or Free T4
Central
hs-CRP (high-sensitivity C-reactive protein), vitamin C, glutamate 
dehydrogenase6
1 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 12 weeks and if clinically indicated 
at any time during the study
2 Virology, urinalysis and pregnancy test will only be reported in the source documentation.
3 If Troponin T is not available, Troponin I may be performed. Troponin T can be assessed centrally in China, if not 
feasible locally.
4 Preferred method is erythrocyte folate but in case it is not available, then serum should be performed. However, 
every effort should be made to perform both tests.
5 During treatment: TSH at timepoints indicated in Table 8-1 and as clinically indicated. If TSH is abnormal, then 
test free-T3 and/or free-T4
6 Test to be done in case of a suspicion of DILI, please refer to Table 6-3.
7 As blasts in MDS/CMML-2 are counted: myeloblasts, monoblasts and promonocytes
8.4.2
Local Electrocardiogram (ECG)
Three sequential (triplicate) 12 lead ECGs are to be collected with ECG machines available at 
the site at Screening and at End of Treatment. Additional, unscheduled, safety ECGs may be 

Novartis
Confidential
Page 82 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
repeated at the discretion of the investigator at any time during the study as clinically indicated 
(Table 8-6). Unscheduled ECGs with clinically significant findings should be collected in 
triplicate. Interpretation of the tracing must be made by a qualified physician and documented 
in the source documents at site. Each ECG tracing should be labeled with the study number, 
subject initials (where regulations permit), date, and kept in the source documents at the study 
site. Local cardiologist ECG assessment may also be performed at any time during the study at 
the discretion of the investigator. Clinically significant abnormalities present at screening 
should be reported on the appropriate CRF. Clinically significant findings 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.
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position to 
ensure a stable baseline. The individual ECGs should be recorded approximately 3 minutes 
apart. The preferred sequence of cardiovascular data collection during study visits is ECG 
collection first, followed by vital signs, and blood sampling. The Fridericia QT correction 
formula (QTcF) should be used for clinical decisions.
ECGs should always be performed in triplicate to confirm a safety finding.
Clinically significant abnormalities (including clinically significant ECG findings) must be 
recorded on the CRF as either medical history/current medical conditions or adverse events as 
appropriate. Follow-up in case of QT prolongation should be performed as per Section 6.5.2.2.
Table 8-6
Local ECG collection plan
Visit
Day
Time
ECG Type
Screening
-28 to -1
Anytime
12 Lead
End of Treatment
-
Anytime
12 Lead
Unscheduled or Unplanned sample
-
Anytime
12 Lead
8.4.3
Pregnancy and assessments of fertility
Female subjects
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
A serum pregnancy test (serum ß-HCG) must be performed at screening and at EOT visit. The 
test needs to be repeated at C1D1 before start of study treatment unless a serum pregnancy test 
had been performed within 72 hours before 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).
Additionally, during the safety follow up, women of child-bearing potential will be tested 
monthly with urine or serum pregnancy tests up to D90 after the last dose of azacitidine. They 
will also be tested monthly with urine or serum pregnancy tests up to D120 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 or during a Public 
Health emergency as declared by Local or Regional authorities i.e. pandemic, epidemic or 

Novartis
Confidential
Page 83 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
natural disaster, that limits or prevents on-site study visits, the urine 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.
Serum and/or urine pregnancy test will be performed only for women of child-bearing potential.
Women of child-bearing potential should employ the use of highly effective contraception 
during study treatment, for 3 months after the last dose of azacitidine (or as per their respective 
local labels, whichever is longer) and for 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.
Male subjects
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner while taking 
azacitidine and for 3 months after stopping these drugs. In addition, male participants should 
not donate sperm for the time period specified above, and female partners will be instructed to 
use highly effective contraception.
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.
8.4.4
Additional safety monitoring and considerations
Due to the known risk of TLS with azacitidine treatment, during this study, subjects should be 
closely monitored (including relevant laboratory tests) for signs and symptoms of TLS. High 
risk patients may need additional measures like i.v. hydration and hospitalization; events should 
be managed per local guidelines. Refer to Section 6.5.2 for guidance on minimizing the risk 
of TLS and procedures to be followed before initiation of a treatment cycle and during the 
treatment cycle.
8.4.5
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population.

Novartis
Confidential
Page 87 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
PK, IG and sTIM-3 samples will be analyzed only in subjects receiving MBG453.
Table 8-7
Blood (serum) collection schedule for PK, IG 
Cycle
Day
Scheduled Time Point (h)*
PK 
sample
IG 
sample
1
1
Pre-Azacitidine infusion
X
1
8
Pre-MBG453/placebo infusion
X
X
X
1
8
End of MBG453/placebo infusion 
(within 2 hours)
X
2
8
Pre-MBG453/placebo infusion
X
X
3
8
Pre-MBG453/placebo infusion
X
X
X
3
8
End of MBG453/placebo infusion 
(within 2 hours)
X
X
4
8
Pre-MBG453/placebo infusion
X
X
6
8
Pre-MBG453/placebo infusion
X
X
X
9
8
Pre-MBG453/placebo infusion
X
X
Cycle 12 and every 6 
cycles thereafter
8
Pre-MBG453/placebo infusion
X
X
EOT
-
Anytime
X
X
30 Day Follow up
-
Anytime
X
X
150 Day Follow up**
-
Anytime
X
X
Unscheduled***
-
Anytime
X
X
*All predose samples should be collected within 30 min before the infusion begins. If Azacitidine and 
MBG453/placebo are administered on the same day, a time window of up to 2 hours before the infusion begins 
is acceptable for the pre-dose sample.
**150 Day Follow up samples can be collected at the investigator's discretion, if follow up visit is done at the site.
***Unscheduled PK and IG samples may be collected at any time if clinically indicated or at the Investigator’s 
discretion. An unscheduled PK sample and IG sample should be collected upon confirmed disease progression.

Novartis
Confidential
Page 88 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Table 8-8
Blood (serum) collection schedule for PK subgroup (in China only)
Cycle
Day
Scheduled Time Point (h)*
PK 
sample
IG 
sample
1
1
Pre-Azacitidine infusion
X
1
8
Pre-MBG453/placebo infusion
X
X
X
1
8
End of MBG453/placebo infusion (within 2 
hours)
X
1
9
24 h after start of MBG453/placebo infusion 
(+/- 2h)
X
1
15
168 h after start of MBG453/placebo infusion 
(+/- 8h)
X
1
22
336 h after start of MBG453/placebo infusion 
(+/- 24h)
X
2
8
Pre-MBG453/placebo infusion
X
X
3
8
Pre-MBG453/placebo infusion
X
X
X
3
8
End of MBG453/placebo infusion (within 2 
hours)
X
X
3
9
24 h after start of MBG453/placebo infusion 
(+/- 2h)
X
3
15
168 h after start of MBG453/placebo infusion 
(+/- 8h)
X
3
22
336 h after start of MBG453/placebo infusion 
(+/- 24h)
X
4
8
Pre-MBG453/placebo infusion
X
X
6
8
Pre-MBG453/placebo infusion
X
X
X
9
8
Pre-MBG453/placebo infusion
X
X
Cycle 12 and every 6 
cycles thereafter
8
Pre-MBG453/placebo infusion
X
X
EOT
-
Anytime
X
X
30 Day Follow up
-
Anytime
X
X
150 Day Follow up**
-
Anytime
X
X
Unscheduled***
-
Anytime
X
X
*All predose samples should be collected within 30 min before the infusion begins. If Azacitidine and 
MBG453/placebo are administered on the same day, a time window of up to 2 hours before the infusion begins 
is acceptable for the pre-dose sample.
**150 Day Follow up samples can be collected at the investigator's discretion, if follow up visit is done at the site.
***Unscheduled PK and IG samples may be collected at any time if clinically indicated or at the Investigator’s 
discretion. An unscheduled PK sample and IG sample should be collected upon confirmed disease 
progression.
8.5.2.2
Analytical method
Bioanalysis for pharmacokinetic studies will employ several validated assays:

The assay to quantify MBG453 will be a validated liquid chromatography mass 
spectrometry (LC-MS) assay.

Immunogenicity testing will consist a multi-tiered ADA testing. A screening assay will be 
used to assess clinical samples. Samples testing positive in the screening assay will then be 
subjected to a confirmatory assay to demonstrate that ADAs are specific for the therapeutic 
protein product. Samples identified as positive in the confirmatory assay will be further 
characterized in titration and neutralization assays. 

Novartis
Confidential
Page 89 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301

Novartis
Confidential
Page 92 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Bone marrow aspirate/biopsy will be done as clinically indicated but every effort should be 
made to obtain a bone marrow sample at time of progression.
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.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data
should be collected at clinic visits or via telephone/email contact:

New / concomitant treatments

Adverse Events / Serious Adverse Events
For details on AE/SAE reporting, please refer to Section 10.1. 
In addition, for women with child-bearing potential, a serum or urine pregnancy test must be 
performed as indicated in Section 8.4.3.
The investigator must also contact the IRT to register the 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.
All subjects who discontinued both study treatments will enter a long-term post-treatment
and/or survival follow-up every 12 weeks after the end of treatment visit. Subjects who 
discontinued both study treatments due to reasons other than progression will have to perform 
hematology 
assessments 
every 
12 
weeks, and 
follow-up 
visits with PRO 
and 
response assessments as indicated in Table 8-1 until documented disease progression, death, 
lost to follow-up, withdrawal of consent/opposition to use data/biological samples. Survival and 
efficacy/PRO follow-up data will be collected for up to 5 years after the last subject was 
randomized.
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 
assessments as outlined in the assessments section (Section 8) and will complete the EOT visit 
only after permanent discontinuation of both study treatments.
9.1.2
Withdrawal of informed consent/Opposition to use data/biological 
samples
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent/opposition to use data/biological samples occurs 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)

Novartis
Confidential
Page 93 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
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 participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the 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 the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition.
9.1.3
Lost to follow-up
For 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. At least the information 
about the subject’s survival status should be collected at the frequency described in Table 8-1. A 
subject should not be considered as lost to follow-up until due diligence has been completed 
(at least 3 failed documented attempts of contact), or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen or notified as soon as possible (before next scheduled study 
drug administration) and treated as a prematurely withdrawn subject. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the subject’s interests. The investigator or sponsor depending on 
the local regulation will be responsible for informing IRBs/IECs of the early termination of the 
trial.

Novartis
Confidential
Page 94 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
9.1.5
Post treatment follow-up
Subjects who discontinue study treatment for reasons other than disease progression, death, lost 
to follow-up, or withdrawal of consent/opposition to use data/biological samples should 
continue the efficacy and PRO assessments as well as 
 as 
per Table 8-1 until progressive disease, withdrawal of consent/opposition to use data/biological 
samples, lost to follow-up, or death.
9.1.6
Survival follow-up
Subjects will be followed up for survival once study treatment is discontinued after disease 
progression, or once disease progression occurred in the post-treatment follow-up phase. 
Subjects will be contacted every 12 weeks to follow-up on their survival status and to complete 
PRO assessments. Any new anti-neoplastic therapies and transfusions that have been started 
since the previous contact will be collected. HSCT information will also be collected.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their End of Treatment or Follow-
up visits and any repeat assessments associated with these visits have been documented and 
followed-up appropriately by the Investigator or, in the event of an early study termination 
decision, the date of that decision.
All treated subjects should have a safety follow-up for 30 days following the last dose of 
azacitidine and 150 days following the last dose of MBG453 or placebo. The safety follow-up 
can be done by telephone call or visit. The information collected is kept as source 
documentation. All AEs/SAEs reported during this time period must be reported as described 
in Section 10.1.1 and Section 10.1.3. Documentation of attempts to contact the subject should 
be recorded in the source documentation.
The OS futility analysis will be performed when approximately 72 OS events have occurred. 
The study may be terminated if the futility boundary is crossed following an assessment by the 
independent Data Monitoring Committee.
The OS primary analysis will be conducted when approximately 282 OS events have occurred. 
At this time, the primary clinical study report (CSR) will be produced. After the primary 
analysis, the study will remain open provided the OS demonstrates treatment benefit. Subjects 
still being followed on the study after the primary analysis time point will continue as per the 
schedule of assessments.
The end of study (Last patient last visit) is defined as the earliest occurrence of one of the 
following:
1. at the futility interim analysis if the study was stopped for lack of efficacy and all subjects 
discontinued study treatment,
2. at the primary analysis if the study failed to reject any null hypothesis and all subjects 
discontinued study treatment,
3. all subjects have died or discontinued from the study treatment and ended survival 
follow-up,
4. once all subjects were transitioned to treatment outside the study which is targeted at the 
latest 5 years after the last subject was randomized

Novartis
Confidential
Page 95 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
At the end of the study, in alignment with local regulations, Post Trial Access (PTA) will be set 
up to provide MBG453 outside this study through an alternative setting to subjects who are 
receiving treatment with MBG453 and 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 volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. The Common Toxicity Criteria (CTC) AE grade (version 5.0). 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
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Novartis
Confidential
Page 96 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301

Dose not changed

Dose reduced/increased

Drug interrupted/permanently discontinued
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.
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
Adverse event monitoring should be continued for at least

150 days after the last administration of MBG453/placebo, or 30 days after the last 
administration of azacitidine, whichever is later
OR

until the start of a new post-treatment antineoplastic medication if sooner than the 150 days 
mentioned above. If a patient starts post-treatment antineoplastic medication, then only 
adverse events suspected to be related to study treatment should be collected, up to 150 days 
after discontinuation of MBG453/placebo.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Disease progression (including fatal outcomes), if documented by use of appropriate method 
(for example, as per response assessment), should not be reported as a serious adverse event, 
please refer to Section 10.1.3 for more details. 
Adverse events separate from the disease progression (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 
[MBG453 Investigator's Brochure].
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

Novartis
Confidential
Page 97 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
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.
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 judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the 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 new malignant neoplasms will be assessed as serious “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.

Novartis
Confidential
Page 98 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
All reports of intentional misuse and abuse of the product are also considered serious adverse 
events irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure subject safety, SAEs occurring after the subject has provided informed consent and 
until 30 days after the date of the last actual administration of azacitidine or 150 days after the 
last dose of MBG453 or placebo must be reported to Novartis safety immediately, without 
undue delay, but under no circumstances later than within 24 hours of obtaining knowledge of 
the events (Note: If more stringent, local regulations regarding reporting timelines prevail). 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. Information about all SAEs is collected and recorded 
on the Serious Adverse Event Report Form; all applicable sections of the form must be 
completed in order to provide a clinically thorough report.
The following SAE reporting timeframes apply:

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.

Subjects receiving study treatment: SAEs must be collected between time subject signs ICF 
until 30 days after the subject has discontinued or stopped azacitidine, or 150 days after the 
subject has discontinued or stopped MBG453 or placebo.

Subjects who were randomized but not treated with study treatment: SAEs must be collected 
between time subject signs ICF until discontinuation (no safety follow-up period required).
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, under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). 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), if documented by use of appropriate method 
(for example, as per response assessment), should be reported as a serious adverse event only 
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 
and 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.

Novartis
Confidential
Page 99 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
10.1.4
Pregnancy reporting
Pregnancies
If a female subject becomes pregnant, the study treatment should be stopped, and the pregnancy 
consent form should be presented to the subject. The subject must be given adequate time to 
read, review and sign the pregnancy consent form. This consent form is necessary to allow the 
investigator to collect and report information regarding the pregnancy. To ensure subject safety, 
each pregnancy occurring after signing the informed consent must be reported to Novartis 
within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence 
or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety. Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the study treatment any pregnancy outcome. 
Any SAE experienced during pregnancy must be reported.
For all pregnancies with live birth and/or unknown outcome the newborn has to be followed up 
to obtain infant health status and development up to twelve months after delivery.
Pregnancy data will not be collected from 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 (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.

Novartis
Confidential
Page 100 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in Dosing 
CRF (Yes/No)
Document in AE eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with an AE
Only if associated with an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not associated 
with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections (Section 10.1.1 and Section 10.1.2).
10.2
Additional Safety Monitoring
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, critical 
efficacy variables and recommend to the sponsor whether to continue, modify, or terminate a 
trial.
Details regarding composition, responsibilities, data monitoring, meeting frequency, DMC 
reports, minutes and recommendations will be described in a separate charter that is established 
between the sponsor and the DMC.
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 also be responsible to review overall survival and relevant efficacy data of subjects 
randomized into the study at the time of the futility interim analysis and efficacy interim 
analysis.
It is envisioned that the DMC may make recommendations with regards to efficacy, namely:

Recommendation to continue the study blinded as planned, no details about the efficacy 
results will be revealed

Novartis
Confidential
Page 101 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301

Recommendation to continue the study blinded as planned but proposing to the Sponsor to 
unblind the interim results, if OS is statistically significant

Recommendation to stop the study due to lack of efficacy, if OS cross the pre-specified 
futility boundary
DMC Meetings Frequency 
The DMC will be established prior to the randomization of the first subject.
There will be an initial meeting with the DMC describing their roles and responsibilities and 
discussing potential data format and process prior to finalization of the DMC charter and the 
study analysis plan.
Thereafter, DMC will meet on a regular basis as described in the DMC Charter to review safety 
data from subjects receiving study drug. The frequency of the DMC safety reviews may vary 
and depends on the recruitment rate, the number of subjects on-treatment and upon DMC's 
request. They may also be notified periodically if concerns develop.
More specific details will be described in the DMC charter.
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.

Novartis
Confidential
Page 102 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
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 entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. The Investigator must 
certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the 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.
Samples for some laboratory assessments, 
 and PK samples and/or data will be 
processed centrally and the results will be sent electronically to Novartis as described in the 
Data Transfer Specifications.
11.2
Database management and quality control
Novartis personnel (or designated Contract Research Organization) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Dates of screenings, randomizations, screen failures, as well as randomization codes and data 
about investigational drug 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.
At time of final analysis at study end, once all the necessary actions have been completed and 
the database has been declared to be 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.

Novartis
Confidential
Page 103 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
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. 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 
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
There will be two interim analyses for the primary endpoint OS, following a group sequential 
design:

A futility interim analysis will be performed after approximately 72 OS events 
(40% information fraction of 180 events as per protocol version 00) have been documented.

An efficacy interim analysis will be conducted when approximately 135 OS events
(48% information fraction of 282 events as per protocol version 03) have been documented 
and when all subjects have been randomized.
In the absence of early stopping, a primary analysis will be performed after approximately 282 
OS events have been documented. The final analysis will occur at the end of study.
All data will be summarized by treatment arm: 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.

Novartis
Confidential
Page 104 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
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 one dose of any component of the 
study treatment (MBG453+azacitidine or placebo+azacitidine). Subjects will be analyzed 
according to the treatment they received, either MBG453+azacitidine or placebo+azacitidine. 
If the subjects never received the investigational drug (i.e. MBG453 or placebo) and took at 
least one dose of azacitidine, subjects will be analyzed in the placebo+azacitidine arm.
Pharmacokinetic Analysis Set: PAS
The Pharmacokinetic Analysis Set (PAS) includes all subjects in the Safety Set, who had at 
least one evaluable PK concentration.
For a concentration to be evaluable:

Dosing information must be properly documented (data and time of administration)

For pre-dose samples: the sample is collected before the next dose administration

For post-dose samples: planned dose of MBG453 must be taken prior to sampling
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 azacitidine). 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 azacitidine 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.

Novartis
Confidential
Page 105 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
12.4
Analysis of the primary endpoint(s)
12.4.1
Definition of primary endpoint(s)
The primary endpoint is Overall Survival defined as time from randomization until death due 
to any cause, regardless of start of new therapies, HSCT, or discontinuation of treatment. If a 
subject is not known to have died, then OS will be censored at the latest date the subject was 
known to be alive (on or before the cut-off date).
The primary estimand is described by the following four attributes:

A. The population is defined as higher-risk MDS/CMML-2 subjects as defined by selection 
criteria.

B. The primary variable is OS.

C. The treatment is the intended study treatment of azacitidine+MBG/placebo, followed 
by any standard of care therapy including HSCT and new antineoplastic therapies.

D. Intercurrent events may affect the interpretation of the variable. Based on the treatment 
attribute definition, OS will be analyzed regardless of treatment discontinuation, start of 
further anti-neoplastic therapy or HSCT.

E. The summary measure is the hazard ratio (HR) for OS between two treatment arms. It 
will be estimated using Cox proportional hazard model stratified by randomization 
stratification factors. The primary comparison will be performed using log-rank test 
stratified by randomization stratification factors.
12.4.2
Statistical model, hypothesis, and method of analysis
Assuming proportional hazards model for OS, the following statistical hypotheses will be tested 
to address the primary efficacy objective for OS:
H01 : θ1 ≥ 1 vs. Ha1 : θ1 < 1
where θ1 is the OS hazard ratio (MBG453+azacitidine versus placebo+azacitidine).
The analysis to test these hypotheses and compare the two treatment groups will consist of a 
stratified log-rank test at an overall one-sided 2.5% level of significance. The stratification will 
be based on the randomization stratification factors in 4 groups: i.e. Intermediate risk MDS, 
High risk MDS, Very high risk MDS, CMML-2. 
OS analysis will be made as a part of a three-look group sequential design using a Lan-DeMets 
(O’Brien-Fleming) alpha spending function.
Analyses will be based on the Full analysis set according to the randomized treatment group 
and strata assigned at randomization. The OS distribution will be estimated using the Kaplan-
Meier method, and Kaplan-Meier curves, quartiles and associated 95% confidence intervals 
will be presented for each treatment group. The hazard ratio for OS will be calculated, along 
with its 95% confidence interval, from a stratified Cox model using the same randomization 
stratification factors as for the log-rank test.

Novartis
Confidential
Page 106 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
12.4.3
Handling of missing values/censoring/discontinuations
OS will be censored at the date of the last contact date if a subject is not known to have died at 
or prior to the analysis cut-off date. All deaths at or prior to cut-off date will be taken into 
account whenever the death occurred, i.e. even after new anti-neoplastic therapy, SCT, 
interruptions, or discontinuation of study treatment due to any reason.
12.4.4
Supportive analyses
Subgroup analyses for OS
If the primary endpoint analyses for OS are statistically significant at the efficacy IA or primary 
analysis, subgroup analyses to assess the homogeneity of the treatment effect will be performed 
for the subgroups as shown below:

Intermediate risk MDS, High risk MDS, Very high risk MDS, CMML-2 as per 
randomization.
Additional subgroup analyses may be conducted for OS. Details will be specified in the SAP.
The number of subjects censored and reasons for OS censoring will be summarized by treatment 
arm.
12.5
Analysis of secondary endpoints
12.5.1
Key secondary objectives
The first two key secondary objectives of the study are to compare time to definitive 
deterioration (TTDD) of fatigue and RBC transfusion-free intervals (TFI) between the two 
treatment arms. Additional three key secondary objectives will be tested in a hierarchical 
approach described in Section 12.5.1.3.
The type I error control for this key secondary endpoint family is described in Section 12.5.1.4.
12.5.1.1 Time to definitive deterioration (TTDD) of fatigue
Time to definitive deterioration (TTDD) of fatigue is defined as time from randomization to

at least 3 points worsening from baseline in FACIT-fatigue scores with no subsequently 
observed improvement above this threshold, or

death due to any cause,
whichever occurs first. Subjects without TTDD event will have their TTDD censored at the 
time of the last adequate assessment performed on or before cut-off date. 
A threshold of at least 3 points worsening from baseline in the FACIT fatigue score is based on 
Cella et al 2002.
The primary estimand is described by the following attributes:

A. The population is defined as higher-risk MDS/CMML-2 subjects as defined by selection 
criteria.

B. The primary variable is TTDD. 

Novartis
Confidential
Page 107 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301

C. The treatment is the intended study treatment of azacitidine+MBG/placebo, followed 
by any standard of care therapy including HSCT and new antineoplastic therapies.

D. Intercurrent events: Based on the treatment attribute definition, TTDD will be analyzed 
regardless of treatment discontinuation, start of further anti-neoplastic therapy or HSCT.

E. The summary measure is the hazard ratio (HR) for TTDD between two treatment arms. 
It will be estimated using Cox proportional hazard model stratified by randomization 
stratification factors. The primary comparison will be performed using log-rank test 
stratified by randomization stratification factors.
For subjects without TTDD event, TTDD is censored at last adequate assessment. This is the 
last FACIT-Fatigue assessment conducted that is not missing. 
For TTDD, a death event occurring after two or more consecutive missing assessments 
(not done or unknown) is censored in the analysis at the last adequate FACIT-Fatigue 
assessment before the event date and reason for censoring then summarized as ‘Death 
documented after two or more missing assessments’. 
For those subjects who cannot deteriorate (i.e. patients with a baseline score < 3), TTDD will 
be censored at randomization date unless deteriorate due to death (i.e. if death occurring after 
two or more consecutive missing assessments, then TTDD will be censored at the 
randomization date).
Assuming proportional hazards model for TTDD of fatigue, the following statistical hypotheses 
will be tested at the 1-sided alpha-TTDD level of significance:
H02 (null hypothesis): θ2 ≥ 1 vs Ha2 (alternative hypothesis): θ2 < 1
where θ2 is the TTDD hazard ratio (MBG453+azacitidine versus placebo+azacitidine).
The analysis to test this hypothesis will consist of a stratified log-rank test at the alpha-TTDD 
level of significance (see Section 12.5.1.4 for definitions). The same randomization 
stratification factors as for the OS analysis will be used.
12.5.1.2 RBC transfusion-free intervals (TFI)
RBC transfusion-free intervals (TFI) correspond to cumulative times of intervals with no 
evidence of RBC transfusion for at least 8 weeks at any point after randomization until death 
due to any cause.
Only RBC transfusions due to MDS or CMML-2 will be considered for this analysis. If the 
RBC transfusion-free interval is terminated by the resumption of RBC transfusion, the subjects 
remains "at risk", i.e. for such a subject, there can be another RBC transfusion-free interval later 
in time. As per the definition above, this analysis will label days where no transfusion was given 
as "transfusion-free" only if they fall into a transfusion-free interval lasting at least 8 weeks.
The primary outcome is the annualized RBC transfusion-free rate (TFR), which is defined as 
the average number of days in RBC transfusion-free intervals in a year (i.e., the total number 
of days in RBC transfusion-free intervals divided by the total days in the study multiplied by 
365.25). The annualized RBC transfusion-free rate is estimated in a negative binomial (NB) 
model by using the number of days in RBC transfusion-free intervals as the response variable 
with natural log of time in study as an offset variable.

Novartis
Confidential
Page 108 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Under the Negative binomial (NB) model, the following statistical hypotheses will be tested at 
the 1-sided alpha-TF level of significance:

H03 (null hypothesis): μMBG453+azacitidine ≤ μplacebo+azacitidine

Ha3 (alternative hypothesis): μMBG453+azacitidine > μplacebo+azacitidine
where μMBG453+azacitidine and μplacebo+azacitidine are the annualized RBC transfusion-free rates under 
the two treatments, respectively. 
The hypotheses will be tested using a negative binomial regression model with log link, using 
treatment as covariates. Randomization stratification factors and baseline transfusion status 
(see Table 8-2) will be used as stratification factors in this analysis.
12.5.1.3 Hypothesis testing strategy
If OS is statistically significant at the efficacy interim or at the primary analysis, the key 
secondary endpoints will be tested according to the testing strategy as described in Figure 12-1:

Time to definitive deterioration (TTDD) of fatigue

RBC transfusion-free intervals

Fatigue improvement rate

Physical functioning improvement rate

Emotional functioning improvement rate

Novartis
Confidential
Page 114 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
confidence intervals (Clopper CJ and Pearson 1934). Subgroup analyses of response rate by 
blasts percentage at baseline (≤ 5% or > 5%) will be performed. 
In order to be classified as CR, no progression or relapse from CR should be reported within 
the following 4 weeks.
Stable Disease (SD) rate is defined as the proportion of subjects with best overall response of 
SD per investigator assessment at any time during the study (on or before cut-off date). Any 
hematologic improvement with exact 95% confidence intervals will be reported separately.
Improvement in 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. The number and percentage of subjects will be shown for the overall FAS and 
then also in only those with transfusion dependence at baseline (for definitions, see Table 8-2). 
Percentages 
will 
be 
provided 
with
exact 
95% 
confidence 
intervals 
(Clopper CJ and Pearson 1934).
12.5.3
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:

Pre-treatment period: from day of subject’s informed consent to the day before first dose 
of study treatment

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 azacitidine)

Post-treatment period: starting at day 30+1 after date of last administration of study 
treatment (MBG453, placebo or azacitidine).
Overall safety period: from date of first administration of study treatment to 30 days after the 
date of the last administration of azacitidine 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.

Novartis
Confidential
Page 115 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
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.
In addition, selected summaries of adverse events will be produced for the overall safety period.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths, and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment, post-treatment period and 
overall safety period will be flagged.
Vital signs
All vital signs abnormalities will be summarized by treatment arm.
Clinical laboratory evaluations
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher.
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low/normal/high based on laboratory normal ranges.
For laboratory tests where grades are defined by CTCAE v5.0:

Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value
For laboratory tests where grades are not defined by CTCAE v5.0:

Shift tables using the low/normal/high/ (low and high) classification to compare baseline to 
the worst on-treatment value.
Other safety evaluations
ECOG
ECOG PS will be summarized at each timepoint during the study.
12.5.4
Pharmacokinetics
When feasible, the pharmacokinetic parameters in Table 12-1 will be determined by profiles 
using noncompartmental method(s) for MBG453 in Chinese patients in PK subgroup.

Novartis
Confidential
Page 116 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Table 12-1
Noncompartmental pharmacokinetic parameters
Parameter
Definition
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x 
time x volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x 
volume-1)
Cmax
The maximum (peak) observed drug concentration after single dose administration (mass x 
volume-1)
Tmax
The time to reach maximum (peak) drug concentration after single dose administration (time)
T1/2
The terminal half-life associated with the terminal slope ((z) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives
CL
The total body clearance of drug from the blood circulation (volume x time-1)
Vz
The apparent volume of distribution during terminal phase (associated with (z) (volume)
PAS will be used in all pharmacokinetic data analyses. Descriptive statistics of all 
pharmacokinetic parameters, including arithmetic and geometric mean, median, SD, and CV, 
geometric CV, minimum and maximum, will be presented by cycle. 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 
concentration will be presented at each scheduled timepoint. Below the limit of quantitation 
(BLQ) values will be set to zero by the Bioanalyst and will be displayed in the listings as zero 
and flagged. However, BLQ values will be treated as missing for the calculation of the 
geometric means and geometric CV%. 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.
MBG453 serum concentration data will be listed by treatment, subject, and visit/sampling time 
point. The concentrations collected before dose administration on Day 8 of Cycle 3 and beyond 
are Ctrough for MBG453.
Population pharmacokinetic analysis
If data permit, 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. If there is sufficient data for analysis, the details of the 
population pharmacokinetic analyses may be provided in a separate reporting and analysis plan, 
and the results may be reported in a separate population pharmacokinetic report.
12.5.4.1 Immunogenicity
Immunogenicity will be characterized descriptively by tabulating ADA prevalence at baseline 
and ADA incidence on-treatment.

Novartis
Confidential
Page 119 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
12.7
Interim analyses
The primary efficacy analyses on overall survival will be based on the full analysis set and are 
event driven.

primary analysis will be performed when approximately 282 OS events have been 
documented.

futility interim analysis (IA) will be performed when approximately 40% of 180 OS events 
as per protocol version 00 have occurred.

efficacy IA will be performed when approximately 48% of 282 OS events have occurred 
and all subjects have been randomized.
Futility IA 
The futility IA will be performed when there are approximately 72 OS events. Probability of 
Success (PoS) will be used to determine futility boundary at the futility IA. Details are specified 
in the statistical appendix.
At the time of the futility IA, the OS data available from the parallel ongoing Phase II study 
[CMBG453B12201] will be used to construct a prior to calculate the probability of success 
(PoS). PoS is defined as the marginal conditional probability of achieving statistical 
significance of the primary OS endpoint at either the efficacy interim or the primary analysis, 
given the Phase II and Phase III data available at the time of the Phase III futility interim. It is 
calculated by averaging the conditional Phase III power function over the posterior distribution 
for the log hazard ratio given the available Phase II and Phase III OS data. The study will be
terminated for lack of efficacy after the futility IA if the PoS is less than 15%.

If the futility IA occurs before CR rate analysis of [CMBG453B12201] study, no phase II 
study data will be used.

If the futility IA occurs after CR rate analysis and before the PFS IA of [CMBG453B12201]
study, OS data collected until CR rate analysis in Phase II will be used.

If the futility IA occurs after PFS IA of [CMBG453B12201] study, OS data collected until 
PFS IA in Phase II will be used.
Efficacy IA 
The efficacy IA will be performed when there are approximately 135 OS events and when all 
subjects have been randomized. Group sequential plan using Lan and DeMets α-spending 
approach with O’Brien-Fleming type boundary (Lan and DeMets 1983) as implemented in the 
software East 6.4 will be applied. The study will conclude for efficacy at the efficacy IA if the 
null hypothesis is rejected at one-sided significance 0.0012 (corresponding hazard ratio (HR)
threshold assuming proportional hazards: HR < 0.593).

Novartis
Confidential
Page 120 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
If OS is significant at the efficacy interim, it will not be tested again at the primary analysis, but 
the OS analysis will be updated at the primary analysis.
No external data will be used for the efficacy IA and primary analysis.
Primary Analysis
The primary analysis will be performed when there are approximately 282 OS events. The 
projected timing of interim and primary analysis is summarized in Table 12-2.
A simulation in East 6.4 of 10000 trials of the described setup of protocol version 03 (simulating 
for each trial the individual outcomes for the fully recruited 530 patients, using actual 
recruitment distribution and following group-sequential design with an interim at 135 events) 
was conducted and the percentage of significant trial analysis results recorded. A piecewise 
exponential model was used which assumed a constant hazard rate of 0.035 in both treatment 
arms in the first 5 months after treatment start (piece 1) and 0.021 and 0.035, respectively, 
(HR=0.6) subsequently (piece 2). Based on total 282 OS events at primary analysis, the 
cumulative probability to detect an efficacious treatment by the primary analysis is 85%, while 
the cumulative probability of erroneously detecting a non-efficacious treatment by the primary 
analysis is 2.4%. 
Since the futility analysis was already conducted under protocol version 00 (40% information 
fraction out of the planned 180 events per protocol version 00), no changes were made to the 
thresholds for declaring futility or their calculation. If the primary null hypothesis as per 
protocol version 00 was true, then the probability to stop the trial at the futility analysis was 
73%. 
The futility and efficacy interim analyses for OS will be performed by an independent 
statistician. Results from OS interim analyses will not be communicated to clinical team or any 
party involved in the study conduct (apart from the independent statistician and IDMC 
members) or external parties including Health Authority and investigators, until OS is found to 
be significant or study needs to be terminated due to safety or lack of efficacy.

Novartis
Confidential
Page 121 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Table 12-2
Estimated timelines for interim and primary analysis assuming 5 
months delayed effects
Months after 
randomization of 
the first subject 
(approximation)
Intent of 
Analysis
# OS events (Information 
Fraction)
Decision threshold
(PoS for futility or 
alpha-threshold and 
corresponding HR
for efficacy)
Boundary 
Crossing 
Probability
17
IA for 
Futility
72 (40% of 180 events as 
per protocol version 00)
15%
73%b
22e
IA for 
Efficacy
135 (48% of 282 events as 
per protocol version 03)a
α<0.0012 (HR 
<0.593)d
3%c
44e
primary
282 (100% of 282 events as 
per protocol version 03)a
α<0.0246 (HR 
<0.791)d
85%c
a Efficacy interim and primary analysis using O'Brien-Fleming boundaries in Group Sequential Design
b The futility boundary crossing probability was calculated under null hypothesis in Phase III and under null 
hypothesis in Phase II, based on the assumption that OS data from CR analysis of [CMBG453B12201] was
available at the time of futility interim analysis
c The efficacy boundary crossing probability is calculated under alternative hypothesis (HR=1 for the first 5 months 
followed by HR=0.6) using East 6.4
dAlpha-thresholds and corresponding HR thresholds (assuming proportional hazards) are calculated using East 
6.4
e timeline estimated based on actual recruitment distribution
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
The sample size calculation is based on the primary variable OS. The hypotheses to be tested 
and details of the testing strategy are described in Section 12.4.2.
With 282 OS events and assuming a delayed onset of effect of 5 months followed by HR=0.6, 
the cumulative probability to detect an efficacious treatment by the primary analysis is 85% 
based on 10000 simulations in East 6.4 using the piecewise exponential model described in 
Section 12.7. The median OS for Placebo+HMA is assumed to be 20 months and actual 
recruitment pattern at time of protocol version 03 was used.
This calculation assumes analysis by a one-sided log-rank test at the overall 2.5% level of 
significance where subjects are randomized to the two treatments in a 1:1 ratio. Assuming that 
total enrollment time will be 20 months (based on the observed recruitment rate), and losses to 
follow-up of 10% per treatment arm per year, a total of 500 subjects will need to be randomized 
to observe the targeted 282 OS events at about 44 months after the randomization date of the 
first subject. These calculations were made using the software package East 6.4 and R 3.4.3.

Novartis
Confidential
Page 122 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
The efficacy analyses on overall survival will be based on full analysis set and are event driven. 
Primary analysis will be performed when there are approximately 282 OS events. A futility 
interim analysis will be performed when approximately 40% of the 180 OS events as per 
protocol version 00 have occurred. A efficacy interim analysis will be performed when 
approximately 48% of the 282 OS events have occurred and all subjects have been randomized.
12.8.2
Secondary endpoint(s)
The hypotheses to be tested and details of the testing strategy for the two key secondary 
endpoints are provided in Section 12.5.1.
Time to definitive deterioration (TTDD) of fatigue
Based on available data from previous study [CETB115D2301], out of the subjects remaining 
on study, the median of FACIT fatigue showed a worsening of 3 point from baseline by Cycle 
14. Taking into account that the Kaplan-Meier first quartile estimate of OS in the 
azacitidine+placebo was 273 days (about 9 months), we assume the median TTDD of fatigue 
as 9 months for azacitidine+placebo arm in this study. It is hypothesized that treatment with 
MBG453+ azacitidine will result in a 40% reduction in the hazard ratio for TTDD, i.e. an 
expected hazard ratio of 0.6 which corresponds to a median TTDD of fatigue of 15 months in 
MBG453+ azacitidine arm under the exponential model assumption.
If OS is significant at the primary analysis, and assuming an HR of 0.6 for TTDD, it is calculated 
that approximately 180 TTDD events are observed which ensures 90% power at the primary 
analysis with an alpha-TTDD level of 1.6%.
RBC Transfusion-free intervals
Based on available data from previous study [CETB115D2301], out of 164 subjects randomized 
in azacitidine+placebo arm, from Cycle 1 to Cycle 4, 123 (75%) subjects needed RBC 
transfusions, with a median of 5 RBC transfusions and standard deviation of 5.06. 
We assume the over-dispersion parameter (k=0.5) and the annualized RBC transfusion-free rate 
for subjects treated with azacitidine+placebo is µplacebo+azacitidine = 0.25, the annualized RBC 
transfusion-free rate for those treated with MBG453+ azacitidine is µMBG453+azacitidine = 0.385. 
Therefore, the estimated annualized transfusion-free rate increase for MBG453+azacitidine 
versus azacitidine+placebo is 35%. A total number of 500 subjects will give overall 91% 
statistical power at a 1-sided significance level of 0.016 given OS is significant.
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.

Novartis
Confidential
Page 123 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
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 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis/ immediately that 
this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. clinicaltrials.gov, EudraCT etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal standard operating procedures (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
Confidential
Page 124 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.

Novartis
Confidential
Page 125 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
15
References
References are available upon request
Aaronson NK, Ahmedzai S, Bergman B, et al (1993) The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical 
trials in oncology. J. Natl. Cancer Inst.; 85(5): 365-76.
Arber DA, Orazi A, Hasserjian R, et al (2016) The 2016 revision to the World Health 
Organization classification of myeloid neoplasms and acute leukemia. Blood; 127(20): 2391-
405.
Asayama T, Tamura H, Ishibashi M, et al (2017) Functional expression of Tim-3 on blasts and 
clinical impact of its ligand galectin-9 in myelodysplastic syndromes. Oncotarget; 8(51): 
88904-17.
Bejar R, Stevenson K, Abdel-Wahab O, et al (2011) Clinical effect of point mutations in 
myelodysplastic syndromes. N Engl J Med; 364(26): 2496-506.
Bell JA, Galaznik A, Blazer M, et al (2019) Transfusion-free interval is associated with 
improved survival in patients with higher-risk myelodysplastic syndromes engaged in routine 
care. Leuk. Lymphoma; 60(1): 49-59.
Brahmer JR, Lacchetti C, Thompson JA (2018) Management of Immune-Related Adverse 
Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of 
Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract; 36(17): 1714-48.
Bretz F, Maurer W, Brannath W, et al (2009) A graphical approach to sequentially rejective 
multiple test procedures. Stat Med; 28(4): 586-604.
Bretz F, Posch M, Glimm E, et al (2011) Graphical approaches for multiple comparison 
procedures using weighted Bonferroni, Simes, or parametric tests. Biom J; 53(6): 894-913.
Cairo MS, Bishop M (2004) Tumour lysis syndrome: new therapeutic strategies and 
classification. Br. J. Haematol.; 127(1): 3-11.
Cella D, Eton DT, Lai JS, et al (2002) Combining anchor and distribution-based methods to 
derive minimal clinically important differences on the Functional Assessment of Cancer 
Therapy (FACT) anemia and fatigue scales. J Pain Symptom Manage; 24(1): 547-61.
Chen J, Kao YR, Sun D, et al (2019) Myelodysplastic syndrome progression to acute myeloid 
leukemia at the stem cell level. Nat Med; 25(1): 103-10.
Chen X, Liu S, Wang L, et al (2008) Clinical significance of B7-H1 (PD-L1) expression in 
human acute leukemia. Cancer Biol. Ther.; 7(5): 622-7.
Cheson BD, Bennett JM, Kantarjian H, et al (2000) Report of an international working group 
to standardize response criteria for myelodysplastic syndromes. Blood; 96(12): 3671-4.
Cheson BD, Greenberg PL, Bennett JM, et al (2006) Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood; 108(2): 419-25.

Novartis
Confidential
Page 126 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Chou FC, Kuo CC, Chen HY, et al (2016) DNA demethylation of the TIM-3 promoter is critical 
for its stable expression on T cells. Genes Immun; 17(3): 179-86.
Clopper CJ and Pearson ES (1934) The use of confidence or fiducial limites illustrated in the 
case of the binomial. Biometrika; 26(4): 404-413.
Coiffier B, Altman A, Pui CH, et al (2008) Guidelines for the management of pediatric and 
adult tumor lysis syndrome: an evidence-based review. J. Clin. Oncol.; 26(16): 2767-78.
Crediblemeds https://crediblemeds.org/.
de Witte T, Bowen D, Robin M et al (2017) Allogeneic Hematopoietic Stem Cell 
Transplantation for MDS and CMML: Recommendations From an International Expert Panel. 
Blood; Mar 30;129(13):1753-62.
Daver N, Garcia-Manero G, Basu S, et al (2019) Efficacy, Safety, and Biomarkers of Response 
to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A 
Nonrandomized, Open-Label, Phase II Study. Cancer Discov; 9(3): 370-83.
Derissen EJ, Beijnen JH, Schellens JH (2013) Concise drug review: azacitidine and decitabine. 
Oncologist; 18(5): 619-24.
Fayers PM (2001) Interpreting quality of life data: population-based reference data for the 
EORTC QLQ-C30. Eur. J. Cancer; 37(11): 1331-4.
Fenaux P, Haase D, Sanz GF, et al (2014) Myelodysplastic syndromes: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Ann. Oncol.; 25(supp_3): iii57-69.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al (2009) Efficacy of azacitidine compared with 
that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: 
a randomised, open-label, phase III study. Lancet Oncol.; 10(3): 223-32.
Freeman SD, Hills RK, Virgo P, et al (2018) Measurable Residual Disease at Induction 
Redefines Partial Response in Acute Myeloid Leukemia and Stratifies Outcomes in Patients at 
Standard Risk Without NPM1 Mutations. J Clin Oncol; 36(15): 1486-97.
Freeman SD, Virgo P, Couzens S, et al (2013) Prognostic relevance of treatment response 
measured by flow cytometric residual disease detection in older patients with acute myeloid 
leukemia. J Clin Oncol; 31(32): 4123-31.
Garcia-Manero G, Montalban-Bravo G, Berdeja JG, et al (2017) Phase 2, randomized, double-
blind study of pracinostat in combination with azacitidine in patients with untreated, higher-
risk myelodysplastic syndromes. Cancer; 123(6): 994-1002.
Garcia-Manero G, Sasaki K, Montalban-Bravo G (2018) A Phase II Study of Nivolumab or 
Ipilimumab with or without Azacitidine for Patients with Myelodysplastic Syndrome (MDS). 
Blood; 132(supp_1): 465
Glimm E, Maurer W, Bretz F (2010) Hierarchical testing of multiple endpoints in group-
sequential trials. Stat Med: 29(2): 219-28.

Novartis
Confidential
Page 127 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Gonçalves Silva I, Yasinska IM, Sakhnevych SS, et al (2017) The Tim-3-galectin-9 Secretory 
Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells. 
EBioMedicine; p. 44-57.
Greenberg PL, Tuechler H, Schanz J, et al (2012) Revised international prognostic scoring 
system for myelodysplastic syndromes. Blood; 120(12): 2454-65.
Heaney ML, Golde DW (1999) Myelodysplasia. N. Engl. J. Med.; 340(21): 1649-60.
Heptinstall K (2006) Quality of Life in Myelodysplastic Syndromes (MDS): Results from U.S. 
& European Patient Forums. Blood; 108(11): 2623.
Herdman M, Gudex C, Lloyd A, et al (2011) Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res; 20(10): 1727-36.
Itzykson R, Fenaux P, Bowen D, et al (2018) Diagnosis and Treatment of Chronic 
Myelomonocytic Leukemias in Adults; 2(6): 150.
Ivey A, Hills RK, Simpson MA, et al (2016) Assessment of Minimal Residual Disease in 
Standard-Risk AML. N Engl J Med; 374: 422-33.
Jan M, Chao MP, Cha AC, et al (2011) Prospective separation of normal and leukemic stem 
cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell 
marker. Proc Natl Acad Sci USA; 108(12): 5009-14.
Jing W, Gershan JA, Weber J, et al (2015) Combined immune checkpoint protein blockade and 
low dose whole body irradiation as immunotherapy for myeloma. J Immunother Cancer; 3(1): 
2.
Jongen-Lavrencic M, Grob T, Hanekamp D, et al (2018) Molecular Minimal Residual Disease 
in Acute Myeloid Leukemia. N Engl J Med; 378(13): 1189-99.
Kikushige Y, Miyamoto T, Yuda J, et al (2015) A TIM-3/Gal-9 Autocrine Stimulatory Loop 
Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression. Cell 
Stem Cell; 17(3): 341-52.
Kikushige Y, Shima T, Takayanagi S, et al (2010) TIM-3 is a promising target to selectively 
kill acute myeloid leukemia stem cells. Cell Stem Cell; 7(6): 708-17.
Klepin HD (2016) Myelodysplastic Syndromes and Acute Myeloid Leukemia in the Elderly. 
Clin. Geriatr. Med.; 32(1): 155-73.
Kong Y, Zhang J, Claxton DF, et al (2015) PD-1(hi)TIM-3(+) T cells associate with and predict 
leukemia relapse in AML patients post allogeneic stem cell transplantation. Blood Cancer J; 
5(7): e330.
Lan G, DeMets D (1983) Discrete sequential boundaries for clinical trials. Biometrika; 70(3): 
659–63.
Makishima H, Yoshizato T, Yoshida K, et al (2017) Dynamics of clonal evolution in 
myelodysplastic syndromes. Nat Genet; 49(2): 204-12.

Novartis
Confidential
Page 128 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Mo XD, Qin YZ, Zhang XH, et al (2016) Minimal residual disease monitoring and preemptive 
immunotherapy in myelodysplastic syndrome after allogeneic hematopoietic stem cell 
transplantation. Ann Hematol; 95(8): 1233-40.
Neuenschwander B, Roychoudhury S, Schmidli H (2016) On the Use of Co-Data in Clinical 
Trials. Stat Biopharm Res; 8(3): 345–54.
Ngiow SF, Teng MW, Smyth MJ (2011) Prospects for TIM3-Targeted Antitumor 
Immunotherapy. Cancer Res.; 71(21): 6567-71.
Papaemmanuil E, Gerstung M, Malcovati L, et al (2013) Clinical and biological implications 
of driver mutations in myelodysplastic syndromes. Blood; 122(22): 3616-27.
Passweg JR, Zhang MJ, Rocha V, et al (2011) Donor characteristics affecting graft failure, 
graft-versus-host disease, and survival after unrelated donor transplantation with reduced-
intensity conditioning for hematologic malignancies. Biol. Blood Marrow Transplant.; 17(12): 
1869-73.
Platzbecker U (2019) Treatment of MDS. Blood; 133(10): 1096-1107.
Platzbecker U, Fenaux P, Adès L, et al (2019) Proposals for revised IWG 2018 hematological 
response criteria in patients with MDS included in clinical trials. Blood; 133(10): 1020-30.
Ramos F, Robledo C, Izquierdo-Garcia FM, et al (2016) Bone marrow fibrosis in 
myelodysplastic syndromes: a prospective evaluation including mutational analysis. 
Oncotarget; 7(21): 30492-503.
Sakuishi K, Apetoh L, Sullivan JM, et al (2010) Targeting Tim-3 and PD-1 pathways to reverse 
T cell exhaustion and restore anti-tumor immunity. J. Exp. Med.; 207(10): 2187-94.
Sakuishi K, Jayaraman P, Behar SM, et al (2011) Emerging Tim-3 functions in antimicrobial 
and tumor immunity. Trends Immunol.; 32(8):345-9.
Silverman LR, Demakos EP, Peterson BL, et al (2002) Randomized controlled trial of 
azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia 
group B. J. Clin. Oncol.; 20(10): 2429-40.
Sohlberg E, Pfefferle A, Andersson S, et al (2015) Imprint of 5-azacytidine on the natural killer 
cell repertoire during systemic treatment for high-risk myelodysplastic syndrome. Oncotarget; 
6(33): 34178-90.
Steensma DP (2018) Myelodysplastic syndromes current treatment algorithm 2018. Blood 
Cancer J; 8(5): 47.
Steensma DP, Bennett JM (2006) The myelodysplastic syndromes: diagnosis and treatment. 
Mayo Clin. Proc.; 81(1): 104-30.
Tao JL, Li LJ, Fu R, et al (2014) Elevated TIM3+ hematopoietic stem cells in untreated 
myelodysplastic syndrome displayed aberrant differentiation, overproliferation and decreased 
apoptosis. Leuk Res; 38(6): 714-21.

Novartis
Confidential
Page 129 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Terwijn M, van Putten WL, Kelder A, et al (2013) High prognostic impact of flow cytometric 
minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK 
AML 42A study. J Clin Oncol; 31(31): 3889-97.
VanReenen M and Janssen B (2015) EQ-5D-5L User Guide: Basic information on how to use 
the EQ-5D-5L instrument.
Visser O, Trama A, Maynadié M, et al (2012) Incidence, survival and prevalence of myeloid 
malignancies in Europe. Eur. J. Cancer; 48(17): 3257-66.
Yang H, Bueso-Ramos C, DiNardo C, et al (2014) Expression of PD-L1, PD-L2, PD-1 and 
CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. 
Leukemia; 28(6): 1280-8.
Yellen SB, Cella DF, Webster K, et al (1997) Measuring fatigue and other anemia-related 
symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J 
Pain Symptom Manage; 13(2): 63-74.
Zeidan AM, Knaus HA, Robinson TM, et al (2018) A Multi-center Phase I Trial of Ipilimumab 
in Patients with Myelodysplastic Syndromes following Hypomethylating Agent Failure. Clin. 
Cancer Res.; 24(15): 3519-27.
Zhang L, Gajewski TF, Kline J (2009) PD-1/PD-L1 interactions inhibit antitumor immune 
responses in a murine acute myeloid leukemia model. Blood; 114(8): 1545-52.
clinicaltrials.gov https://clinicaltrials.gov/.
Ørskov AD, Treppendahl MB, Skovbo A, et al (2015) Hypomethylation and up-regulation of 
PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of 
PD-1 and DNA methylation. Oncotarget; 6(11): 9612-26.

Novartis
Confidential
Page 130 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
16
Appendices
16.1
Appendix 1: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-1
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Confirmed serum creatinine increase 
25 – 49%

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase 50 % +
OR if <18 years old, eGFR < 35 
mL/min/1.73 m2

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation unless other causes 
are diagnosed and corrected

Consider patient hospitalization and specialized treatment
New onset dipstick proteinuria ≥ 3+
OR
Protein-creatinine ratio (PCR) ≥ 1g/g 
Cr (or mg/mmol equivalent as 
converted by the measuring 
laboratory)

Consider causes and possible interventions

Assess serum albumin & serum total protein

Repeat assessment to confirm

Consider drug interruption or discontinuation unless other causes 
are diagnosed and corrected
New onset hematuria ≥ 3+ on urine 
dipstick
Assess & document

Repeat assessment to confirm

Distinguish hemoglobinuria from hematuria

Urine sediment microscopy

Assess sCr

Exclude infection, trauma, bleeding from the distal
urinary 
tract/bladder, menstruation

Consider bleeding disorder
+Corresponds to Kidney Disease Improving Global Outcomes (KDIGO) criteria for Acute Kidney Injury
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases, when a nephrologist considers a renal biopsy, it is recommended 
to make slide specimen available for evaluation by the RSG to potentially identify project-wide 
patterns of nephrotoxicity.)
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify and potentially eliminate risk factors that may have initiated or contributed to the event:

Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)

Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumorlysis

Novartis
Confidential
Page 131 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Table 16-2
Renal Event Follow Up
FOLLOW-UP OF RENAL EVENTS
Assess, document and record in CRF:

Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells (dysmorphic/glomerular vs. 
non-dysmorphic/non-glomerular), white blood cells, tubular epithelial cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid conditions) 
and additional diagnostic procedures (MRI etc.) in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until:

Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) or

Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio stabilization 
at a new level with ±50% variability over last 6 months.

Analysis of urine markers in samples collected over the course of the DIN event
16.2
Appendix 2: Guidance to support eligibility evaluation based on 
serologic markers for hepatitis B
Please consider the general guidelines below, investigators may consult specialists to decide 
subjects eligibility in case of borderline results 
Protocol exclusion criterion:

Positive serology for hepatitis B surface antigen (HBsAg)

Positive serology for hepatitis B core antibody (HBcAb), except if both criteria are met: 
1. HBV DNA negative
2. Hepatitis HBV monitoring is implemented: HBsAg or HBV DNA should be tested 
every 6 weeks for the first 6 months and every 12 weeks thereafter, until the end of 
study. Upon consultation with a specialist, if the management plan proposed differs 
from this, Novartis global team should be consulted.
Table 16-3
Eligibility based on serologic markers for hepatitis B
HBsAg
HBcAb
HBV DNA
Eligible
Comment
-
-
-
Yes
-
+
-
Yes
Prophylaxis + monitoring
-
+
+
No
Consider treatment
+
+
+
No
Consider treatment

Novartis
Confidential
Page 133 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
and phase III study [CMBG453B12301] data available at the time of the phase III study futility 
interim. It is calculated by averaging the conditional phase III power function (given the phase 
III data) over the posterior distribution for the log hazard ratio (log-HR) based on the available 
phase II and phase III data.
At the time of the futility IA, OS data available from the parallel ongoing phase II 
study [CMBG453B12201] will be used to formulate a robust meta-analytic-predictive (MAP) 
prior for the log-HR in phase III. If available, this prior will be used in the PoS calculation. The 
phase III study will be terminated for lack of efficacy at the futility IA if the PoS is less than 
15%. There are three scenarios for the phase II data that will be available to inform stopping 
decisions at the time of the phase III study futility IA:

If the futility IA occurs before CR rate analysis of [CMBG453B12201] study, no phase II 
study data will be used.

If the futility IA occurs after CR rate analysis and before the PFS IA 
of [CMBG453B12201] study, OS data collected until CR rate analysis in phase II will be 
used.

If the futility IA occurs after PFS IA of [CMBG453B12201] study, OS data collected until 
PFS IA in phase II will be used.
16.3.2
Statistical Models
16.3.2.1 Leveraging CMBG453B12201 data in robust MAP prior
Label the log-HRs underpinning [CMBG453B12201] and [CMBG453B12301] as θ2 and θ3, 
respectively. We will summarize the data accumulated by the time of the IA of the 
[CMBG453B12201] phase II study by the estimate of the log-HR and its standard error ( and 
se2). Similarly, we summarize the data accumulated by the time of the phase III futility IA by 
the estimate of the log-HR and its standard error ( and se3). Let di be the total number of OS 
events contributed from study i to the phase III futility analysis. Asymptotically,  ~ N(θi, 4/di) 
so that the standard error of  is sei = 	4/. Assuming the log-HRs underpinning the phase 
II and phase III studies are exchangeable, we can model the study-specific estimates using a 
Bayesian hierarchical random-effects model:
   ~ N(, 
),
i = 2,3
 | ,  ~ N(, ),
i = 2,3
 ~ HN()
We set z = 0.125, which is consistent with moderate between-study heterogeneity for a two-
group (comparative) parameter (Neuenschwander et al 2016)
Given the observed [CMBG453B12201] phase II log-HR estimate (), we will fit the Bayesian 
meta-analytic model above and derive a MAP prior for θ3, which we will approximate by a 
finite mixture of Gaussian distributions. To allow more rapid discounting of the phase II data 
in case of a prior-data conflict, we will use a robust version of the MAP prior. This will be a 
mixture of Gaussian distributions placing weight 0.9 on the MAP prior and weight 0.1 on a 
N(0, 22) distribution, which is a weakly informative prior centered at the null with unit 
information standard deviation. Then, at the phase III futility IA, we will update the robust MAP 

Novartis
Confidential
Page 134 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
prior with the phase III log-HR estimate (), to obtain a posterior distribution for the log-HR 
in phase III, θ3.
16.3.2.2 Simulating the phase II and phase III trials
Since the phase II data are not yet available, in order to evaluate the operating characteristics of 
the phase III study we simulate the [CMBG453B12301] and [CMBG453B12201] studies 
following the steps below. 
We simulate individual OS patient data (time to event) from the phase II study assuming OS 
follows a piecewise exponential distribution on each arm. We simulate individual accrual time 
from a piecewise Uniform distribution, with an accrual rate of an average of 4 subjects per 
month in the first month, 8 subjects per month in the second month, 12 subjects per month in 
the third month, 16 subjects per month in the fourth month, and 20 subjects per month thereafter. 
We assume losses to follow-up of 10% per treatment arm per year. We simulate under the 
assumption that the phase III futility IA will occur after the CR rate analysis and before the PFS 
IA in phase II, so that the OS data collected until the CR rate analysis in phase II will be used. 
We analyze the phase II dataset using a log-rank test, accounting for administrative censoring. 
We estimate the phase II log-HR by U2L/V2L, where U2L is the difference between the total 
number of observed and expected (under the null hypothesis) OS events in the MBG453 group 
in phase II and V2L is the variance of the U2L statistic. We approximate the standard error of the 
phase II log-HR estimate by 	4/. We use the estimate of the log-HR in phase II to create a 
robustified MAP prior for the log-HR in the phase III trial following the approach described in
Section 16.3.2.1. 
Similarly, we simulate individual patient data from the phase III study assuming OS times 
follow a piecewise exponential distribution on each arm. We deduce the dataset available at the 
time of the futility analysis taking into account administrative censoring. We estimate the phase 
III log-HR by U3L/V3L, where U3L is the difference between the total number of observed and 
expected (under the null hypothesis) OS events in the MBG453 group in phase III at the time 
of the futility analysis, and V3L is the variance of the U3L statistic. We estimate the standard 
error of the phase III log-HR estimate by 	4/. Using Bayes Theorem; we update the robust 
MAP prior distribution for the log-HR in phase III with the phase III log-HR estimate. We 
generate Monte Carlo samples from the posterior distribution for the phase III log-HR thus 
obtained. We stop the phase III trial for futility if the posterior predictive probability of success 
is less than the decision threshold of 15%, that is, if
∫
Pr(Reject !"in Ph3| , , ) #(|, )d
$
%$
< 0.15
where θ3 is the log HR in phase III; π(| , ) is the posterior density for the phase III log-
HR given the interim log-HR estimates from phase III and phase II (derived in Step 5). It is 
clear that given  and θ3, the outcome of the phase III trial is conditionally independent of . 
Therefore, the futility stopping rule can be written as: stop for futility if 
∫
Pr(Reject !"in Ph3| , ) #(|, )d
$
%$
< 0.15
Writing the standardized test statistic at the phase III futility interim as Z31 = 	/4, we 
know that Pr(Reject H0 in Ph3 | Z31=z31, θ3) = Pr(Z32 ≤ l2 | Z31 = z31, θ3) + Pr(Z32 > l2, Z33 ≤ l3 | 

Novartis
Confidential
Page 135 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Z31 = z31, θ3), where Z32 and Z33 denote the standardized test statistics at the efficacy IA and 
final analysis, respectively. Here Pr(Reject H0 in Ph3 | Z31=z31, θ3) is the conditional probability 
that the phase III trial will go on to reject H0 at either the efficacy IA or the final analysis given 
the phase III data available at the futility interim and given the true log-HR in phase III is θ3. 
We calculate PoS using Monte Carlo simulation. For i=1,..., N, we take the ith sample from the 
posterior distribution for θ3 (denoted by θ3(i)) and calculate Pr(Reject H0 in Ph3 | Z31=z31, θ3(i)). 
We then take the average of the N conditional powers. This average is the PoS which we 
compare with the PoS stopping threshold of 15%. In all of our evaluations, we have set N = 
40,000. 
16.3.3
Hypothetical scenarios
To illustrate the performance of the Bayesian model used to guide the futility decision making 
with PoS for MBG453 in combination with azacitidine, hypothetical data scenarios are 
displayed in the Table 16-4 below. In addition to the criteria based on PoS, the decision to stop 
the trial for lack of efficacy at the futility IA might be based on additional safety, PK or PD 
information.
Table 16-4
Futility interim decision recommended by PoS
PhII HR
PhIII HR
Posterior 
median
Conditional 
power under 
theta = delta
Effective 
sample 
size*
Critical 
HR**
PoS
Futility IA 
decision
Leverage PhII
0.60
0.60
0.60
0.97
100.32
0.95
90.3%
Go
1.00
0.60
0.69
0.97
97.77
0.86
79.0%
Go
0.60
0.90
0.81
0.66
98.83
0.95
21.6%
Go
0.80
0.90
0.87
0.66
101.69
0.89
14.3%
No-Go
1.00
0.90
0.93
0.66
100.07
0.86
10.0%
No-Go
0.40
1.00
0.80
0.52
82.56
1.01
16.5%
Go
0.60
1.00
0.88
0.52
96.87
0.95
9.4%
No-Go
1.00
1.00
1.00
0.52
100.30
0.86
3.5%
No-Go
No PhII data
-
0.60
0.60
NA
72
0.89
88.6%
Go
-
0.90
0.90
NA
72
0.89
14.4%
No-Go
-
1.00
1.00
NA
72
0.89
5.0%
No-Go
*Effective sample size means the number of OS events information
** Critical value for PoS=15% threshold
The decision rules at interim analysis based on the critical HR in phase III study as a function 
of the HR estimate in PhII are presented below in Figure 16-2.

Novartis
Confidential
Page 137 of 137
Amended Protocol Version 03 (Clean)
Protocol No. CMBG453B12301
Table 16-5
Operating characteristics
PhII
HR
PhIII
HR
(%)Trial 
stop at 
fut. IA
% Trial stop 
at fut. IA & 
success at 
eff. IA or 
primary
% Trial 
cont. at fut. 
IA & failed 
at eff. IA or 
primary
% trials cont. 
at fut. IA and
success at eff 
IA or primary 
(i.e. the 
power).
Effective SS 
median (min-
max)
# of PhII
OS events 
med (min-
max)
Leverage PhII
0.60
0.60
3.1%
1.7%
6.6%
90.3%
94 (82.7-100.4)
28 (19-38)
0.80
0.60
4.6%
2.8%
6.2%
89.2%
95.3 (69.7-102)
32 (22-41)
0.60
0.80
26.0%
2.1%
43.1%
30.9%
93.6 (72.4-100)
28 (19-38)
0.80
0.80
32.3%
3.0%
37.7%
30.0%
96 (81.5-102.3)
32 (22-41)
1.00
0.80
37.4%
3.6%
33.2%
29.4%
97.3 (71.4-
104.2)
35 (25-45)
0.80
1.00
67.2%
0.1%
30.5%
2.3%
95.7 (79-102)
32 (22-41)
1.00
1.00
73.4%
0.2%
24.4%
2.2%
97.9 (81.5-
104.5)
35 (25-45)
No PhII data
--
0.6
4.1%
2.2%
6.1%
89.8%
72
--
--
0.8
31.6%
2.4%
37.8%
30.6%
72
--
--
1.0
68.0%
0.1%
29.7%
2.3%
72
--