A Phase II Multi-center, Single Arm, Safety and Efficacy Study of MBG453 in Combination With Azacitidine and Venetoclax for the Treatment of Acute Myeloid Leukemia (AML) in Adult Patients Unfit for Chemotherapy
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
MBG453
Clinical Trial Protocol CMBG453C12201 / NCT04150029
A phase II multi-center, single arm, safety and efficacy 
study of MBG453 in combination with azacitidine and 
venetoclax for the treatment of Acute Myeloid Leukemia 
(AML) in adult patients unfit for chemotherapy
Document type:
Amended Protocol Version
EUDRACT number:
2019-000439-14
Version number:
05 (Clean)
Clinical Trial Phase:
II
Release date:
08-Dec-2022
Property of Novartis AG
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0 (01-Aug-2018)

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Protocol No. CMBG453C12201
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Amendment 5 (08-Dec-2022)............................................................................................13
Amendment 4 (22-Dec-2021)............................................................................................17
Amendment 3 (08-Apr-2021)............................................................................................20
Amendment 2 (19-May-2020)...........................................................................................23
Amendment 1 (10-Feb-2020)............................................................................................25
Protocol summary..............................................................................................................30
1
Introduction .......................................................................................................................34
1.1
Background............................................................................................................34
1.2
Purpose ..................................................................................................................35
2
Objectives and endpoints...................................................................................................36
3
Study design ......................................................................................................................38
4
Rationale............................................................................................................................41
4.1
Rationale for study design .....................................................................................41
4.2
Rationale for dose/regimen and duration of treatment ..........................................41
4.3
Rationale for choice of combination drugs............................................................43
4.4
Rationale for MRD assessment 
................................44
4.4.1
Rationale for MRD assessments ...........................................................44
45
4.5
Purpose and timing of interim analyses/design adaptations..................................46
4.6
Risks and benefits..................................................................................................46
4.7
Rationale for Public Health Emergency mitigation procedures ............................47
5
Population..........................................................................................................................47
5.1
Inclusion criteria ....................................................................................................48
5.2
Exclusion criteria...................................................................................................48
6
Treatment...........................................................................................................................51
6.1
Study treatment......................................................................................................51
6.1.1
Investigational and control drugs..........................................................51
6.1.2
Additional study treatments ..................................................................53
6.1.3
Treatment arms/group ...........................................................................53
6.1.4
Guidelines for continuation of treatment ..............................................53

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6.1.5
Treatment duration................................................................................53
6.2
Other treatment(s)..................................................................................................54
6.2.1
Concomitant therapy.............................................................................54
6.2.2
Prohibited medication ...........................................................................56
6.3
Subject numbering, treatment assignment, randomization....................................56
6.3.1
Subject numbering ................................................................................56
6.3.2
Treatment assignment, randomization ..................................................57
6.4
Treatment blinding.................................................................................................57
6.5
Dose escalation and dose modification..................................................................57
6.5.1
Guidelines for assessing the risk of overdosing for the regimen in 
the safety run-in.....................................................................................57
6.5.2
Definitions of dose limiting toxicities (DLTs)......................................58
6.5.3
Dose modifications................................................................................60
6.5.4
Follow-up for toxicities.........................................................................64
6.6
Additional treatment guidance...............................................................................69
6.6.1
Treatment compliance...........................................................................69
6.6.2
Emergency breaking of assigned treatment code..................................69
6.7
Preparation and dispensation.................................................................................69
6.7.1
Handling of study treatment and additional treatment..........................70
6.7.2
Instruction for prescribing and taking study treatment .........................71
7
Informed consent procedures ............................................................................................71
8
Visit schedule and assessments .........................................................................................72
8.1
Screening ...............................................................................................................81
8.1.1
Eligibility screening ..............................................................................81
8.1.2
Information to be collected on screening failures.................................81
8.2
Subject demographics/other baseline characteristics.............................................81
8.3
Efficacy..................................................................................................................82
8.3.1
Efficacy assessments.............................................................................82
8.3.2
Efficacy assessment: MRD by MFC.....................................................86
8.3.3
Appropriateness of efficacy assessments..............................................87
8.4
Safety.....................................................................................................................87
8.4.1
Laboratory evaluations..........................................................................88
8.4.2
Electrocardiogram (ECG) .....................................................................89
8.4.3
Pregnancy and assessments of fertility .................................................89
8.4.4
Additional safety monitoring and considerations during venetoclax 
ramp-up .................................................................................................90
8.5
Additional assessments..........................................................................................91

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8.5.1
Clinical Outcome Assessments (COAs) ...............................................91
8.5.2
Pharmacokinetics ..................................................................................92
94
9
Study discontinuation and completion ..............................................................................96
9.1
Discontinuation......................................................................................................96
9.1.1
Discontinuation of study treatment .......................................................96
9.1.2
Withdrawal of informed consent / Opposition to use data/biological 
samples..................................................................................................98
9.1.3
Lost to follow-up...................................................................................99
9.1.4
Early study termination by the sponsor.................................................99
9.2
Study completion and post-study treatment ..........................................................99
10 Safety monitoring and reporting......................................................................................100
10.1
Definition of adverse events and reporting requirements....................................100
10.1.1
Adverse events ....................................................................................100
10.1.2
Serious adverse events ........................................................................102
10.1.3
SAE reporting......................................................................................103
10.1.4
Pregnancy reporting ............................................................................104
10.1.5
Reporting of study treatment errors including misuse/abuse..............104
10.2
Additional Safety Monitoring..............................................................................105
10.2.1
Data Monitoring Committee ...............................................................105
10.2.2
Steering Committee.............................................................................105
11 Data Collection and Database management....................................................................106
11.1
Data collection.....................................................................................................106
11.2
Database management and quality control..........................................................106
11.3
Site monitoring ....................................................................................................107
12 Data analysis and statistical methods ..............................................................................107
12.1
Analysis sets ........................................................................................................108
12.2
Subject demographics and other baseline characteristics....................................108
12.3
Treatments ...........................................................................................................108
12.4
Analysis of the primary endpoint(s) ....................................................................109
12.4.1
Definition of primary endpoint(s).......................................................109
12.4.2
Statistical model, hypothesis, and method of analysis........................109
12.4.3
Handling of missing values/censoring/discontinuations.....................110
12.4.4
Sensitivity and Supportive analyses....................................................110
12.5
Analysis of secondary endpoints .........................................................................110
12.5.1
Efficacy endpoint(s)............................................................................111

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12.5.2
Safety endpoints..................................................................................112
12.5.3
Pharmacokinetics ................................................................................114
115
115
115
115
116
116
117
117
12.7
Interim analyses...................................................................................................117
12.8
Sample size calculation........................................................................................117
12.8.1
Primary endpoint(s).............................................................................117
13 Ethical considerations and administrative procedures ....................................................119
13.1
Regulatory and ethical compliance......................................................................119
13.2
Responsibilities of the investigator and IRB/IEC................................................119
13.3
Publication of study protocol and results.............................................................120
13.4
Quality Control and Quality Assurance...............................................................120
14 Protocol adherence ..........................................................................................................120
14.1
Protocol amendments...........................................................................................121
15 References .......................................................................................................................122
16 Appendices ......................................................................................................................127
16.1
Appendix 1: Statistical Details for Safety Run-in Part: Bayesian model: prior 
and design properties for hypothetical data scenarios .........................................127
16.1.1
Statistical Models................................................................................127
16.1.2
Hypothetical on-study scenarios .........................................................130
16.1.3
Operating characteristics.....................................................................132
16.1.4
References...........................................................................................133
16.2
Appendix 2: Concomitant medications to be used with caution and/or 
requiring action....................................................................................................134

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List of tables
Table 2-1
Objectives and related endpoints ..........................................................36
Table 6-1
Study Treatment....................................................................................51
Table 6-2
Dosing schedule for ramp-up of venetoclax in Cycle 1........................52
Table 6-3
Management of potential interactions of CYP3A and P-gp 
inhibitors with venetoclax.....................................................................55
Table 6-4
Criteria for defining dose-limiting toxicities during the safety run-
in............................................................................................................59
Table 6-5
Criteria for dose interruption and re-initiation of study drug 
MBG453 for adverse drug reactions.....................................................61
Table 6-6
Dose modifications for venetoclax........................................................63
Table 6-7
Follow-up of abnormal liver chemistry results .....................................66
Table 6-8
Action required for isolated total bilirubin elevation............................68
Table 8-1
Assessment Schedule ............................................................................74
Table 8-2
Response classification in AML at a given evaluation time (based 
on IWG Cheson et al 2003, ELN 2017 Döhner et al 2017)..................83
Table 8-3
Collection of BMA for MRD by flow cytometry .................................86
Table 8-4
Assessments & Specifications...............................................................87
Table 8-5
ECOG performance status.....................................................................87
Table 8-6
Local clinical laboratory parameters collection plan ............................88
Table 8-7
Central clinical laboratory parameters collection plan..........................88
Table 8-8
ECG collection plan..............................................................................89
Table 8-9
MBG453 PK, IG and 
 blood collection log ..............................93
Table 8-10
Venetoclax PK blood collection log .....................................................94
95
95
Table 10-1
Guidance for capturing the study treatment errors including misuse .105
Table 12-1
Data scenarios, inferential results and decisions (n=80).....................118
Table 12-2
Operating characteristics for various true CR rate (n=80)..................118
Table 16-1
Prior distributions for the parameters of the MAP model used to 
derive the prior for the logistic model parameters ..............................128
Table 16-2
Historical data from [MBG453X2105] for MBG453 administered 
every 2 weeks in combination with decitabine or azacitidine.............129
Table 16-3
Historical data from [MBG453X2105] for MBG453 administered 
every 4 weeks in combination with decitabine or azacitidine.............129
Table 16-4
Prior distribution (BVN Mixture (log(α, β)).......................................129
Table 16-5
Summary of prior distribution of DLT rates.......................................130

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Table 16-6
Probability of excessive toxicity estimated by the Bayesian model 
after the first cohort.............................................................................130
Table 16-7
Probability of excessive toxicity estimated by the Bayesian model 
after the second cohort ........................................................................131
Table 16-8
Operating characteristics for different true values of DLT rate..........132
Table 16-9
List of medications to be used with caution and/or requiring action 
during study drug treatment ................................................................134
List of figures
Figure 3-1
Study Design .........................................................................................39
Figure 3-2
Study Flow ............................................................................................40

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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
BMA
Bone marrow aspirate
BSA
Body Surface Area
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CMV
Cytomegalovirus
CNS
Central Nervous System
COVID-19
Coronavirus Disease 2019
COA
Clinical Outcome Assessment
CR
Complete Remission
CRF
Case Report/Record Form (paper or electronic)
CRi
Complete Remission with incomplete hematologic recovery
CRh
Complete Remission with partial hematologic recovery
CRO
Contract Research Organization
CSR
Clinical Study Report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTIS
Clinical Trials Information System
CV
coefficient of variation
CYP
Cytochrome P450
DILI
Drug Induced Liver Injury
DLCO
Diffusing Capacity for Carbon Monoxide
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
EBV
Epstein-Barr virus
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EFS
Event-free Survival
eGFR
Estimated Glomerular Filtration Rate
ELISA
Enzyme-linked immunosorbent assay
ELN
European Leukemia Network
EMA
European Medicines Agency
EMD
Extramedullary disease
EORTC QLQ-
C30
European Organisation for Research and Treatment of Cancer - Quality of Life 
Questionnaire
EOT
End of treatment

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ePRO
Electronic Patient Reported Outcome
EQ-5D-5L
EuroQol Group - standardized measure of health status questionnaire
ESA
Erythropoiesis Stimulating Agent
eSAE
Electronic Serious Adverse Event
ESMO
European Society for Medical Oncology
FAS
Full Analysis Set
FDA
Food and Drug Administration
FEV 1
Force Expiratory Volume Force 1
GCP
Good Clinical Practice
GCSF
Granulocyte-Colony Stimulating Factor
GLDH
Glutamate dehydrogenase
HbcAb
Hepatitis B core antibody
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HMA
Hypomethylating agent
HR
Hazard Ratio
HSCT
Hemopoietic Stem Cell Transplant
HSV
Herpes-simplex virus
i.v.
intravenous
ICF
Informed consent form
ICH
International Council forHarmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IG
Immunogenicity
irAE
Immune related adverse event
IRB
Institutional Review Board
IRT
Interactive Response Technology
IWG
International Working Group
LDH
lactate dehydrogenase
LFT
Liver function test
MDRD
Modification of Diet in Renal Disease
MDS
Myelodysplastic syndromes
MedDRA
Medical dictionary for regulatory activities
MFC
Multiparameter Flow Cytometry
MFC-MRD
Multiparameter Flow Cytometry-Measurable Residual Disease
Mg
milligram(s)
mL
milliliter(s)
MLFS
Morphologic Leukemia-Free State
MRD
Measurable residual disease
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NGS
Next Generation Sequencing
NK
Natural killer
OS
Overall Survival

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PAS
Pharmacokinetic Analysis Set
PCR
Polymerase Chain Reaction
PD
Progressive Disease
PD-1
Programmed cell death protein 1
PGIS
Patient Global Impression of Severity
PGITS
Patient Global Impression of Treatment Satisfaction
PK
pharmacokinetic(s)
PR
Partial remission
PRO
Patient Reported Outcome
PS
Performance status
Q4W
Every 4 weeks
RBC
red blood cell(s)
RFS
Relapse Free Survival
RNA
Ribonucleic acid
SC
Steering Committee
SAE
serious adverse event
SCT
Stem cell transplant
SD
Stable Disease
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
TFQ
Trial Feedback Questionnaire
TIM-3
T-cell immunoglobulin domain and mucin domain-3
TLS
Tumor lysis syndrome
TSH
Thyroid-Stimulating Hormone
ULN
upper limit of normal
USPI
United States Prescribing Information
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of consent

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Personal data
Participant information collected by the Investigator that is coded and transferred to 
Novartis/Sponsor for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
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
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned completion of all 
study drug administration and assessments; at this time all study drug administration 
is discontinued and no further assessments are planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a specific 
treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Re-screening
If a participant fails the initial screening and is considered as a Screen Failure, he/she 
can be invited once for a new Screening visit after medical judgment and as specified 
by the protocol.
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.
Source 
Data/Document
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet or even hard-
coded data, such as paper or eSource
Stage
A major subdivision of the study timeline; begins and ends with major study milestones 
such as enrollment, randomization, completion of treatment, etc.
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 drug/treatment
Any drug (or combination of drugs) administered to the subject as part of the required 
study procedures; includes investigational drug, active drug run-ins or background 
therapy.
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 
Treatment arm/group
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts.
Variable (or endpoint)
The variable (or endpoint) to be obtained for each participant that is required to address 
the clinical question. The specification of the variable might include whether the 
participant experiences an intercurrent event.
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study occurs when the participant explicitly requests to 
stop use of their data and/or 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. This request should be distinguished from a request to discontinue the 
study. Other study participant's privacy rights are described in the corresponding 
informed consent form.

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Amended Protocol Version 05 (Clean)
Protocol No. CMBG453C12201

Updated to clarify the safety monitoring for patients continuing on MBG453 through 
an alternative setting after the end of the study

Section 9.1.2 - Withdrawal of informed consent/opposition to use data/biological samples

Section language updated as per latest Novartis protocol template language for further 
clarification

Section 9.1.3 -Lost to follow up

Language updated as per latest Novartis protocol template language for further 
clarification

Section 9.2 – Study completion and post-study treatment

Updated to reflect the revised timing of primary analysis (CR analysis)

Section 10.1.1 – Adverse Events

Updated to clarify the safety monitoring for patients continuing on MBG453 through 
an alternative setting after the end of the study

Section 10.1.3 – SAE reporting

Updated to clarify the safety reporting for patients continuing on MBG453 through an 
alternative setting after the end of the study

Section 11.2 - Database management and quality control

Paragraph added to state minimal required retention period for study records and 
documents

Section 12 – Data analysis and statistical methods

Updated to reflect the revised timing of primary analysis (CR analysis)

Section 12.4.2 – Statistical model, hypothesis, and method of analysis

CR analysis (safety run-in and expansion parts) paragraph, updated to reflect the 
revised timing of primary analysis (CR analysis)

Section 12.5 – Analysis of secondary endpoints

CR/CRh rate was added as a secondary endpoint

Duration of response (CR, CR/CRi, CR/CRh) was used to replace RFS

Section 12.5.1 – Efficacy endpoint(s)

Updated to clarify that all response assessments used for efficacy analysis will be based 
on investigator assessment, unless otherwise stated

Duration of response paragraph, updated to use duration of CR and duration of CR/CRi 
instead of the terminologies of “RFS in CR patients” and “RFS in CR/CRi patients”, 
respectively 

Duration of CR/CRh was added as secondary endpoint

Added criteria for derivation of CRh

CR/CRh rate was added as a secondary endpoint

MRD negativity rate in subjects in CR/CRh was added as secondary endpoint



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Amended Protocol Version 05 (Clean)
Protocol No. CMBG453C12201
Amendment 4 (22-Dec-2021)
Amendment rationale
At the time of release of this amendment, 29 subjects have been enrolled to this trial. Part 1 
(safety run-in) has been completed, and following investigator’s recommendation from the 
Safety Review Meeting held on 26-Oct-2021, the expansion phase has opened to enrollment. 
The main purpose of this amendment is to modify the guidance on permanent discontinuation 
of treatment for patients experiencing prolonged cytopenias. Cytopenia is a common adverse 
event with the triplet combination of MBG453, venetoclax, and azacitidine and may take longer 
than 28 days to recover. For patients experiencing prolonged cytopenias, the study treatment 
may be interrupted for up to 42 days. This change will allow patients the opportunity to stay on 
study treatment while their blood counts recover.
In addition, the DLT criteria related to prolonged hematologic toxicities, applicable during the 
safety run-in phase, were modified. A CTCAE Grade 4 neutropenia, thrombopenia or 
pancytopenia, not related to leukemic infiltration, persisting beyond 42 days (instead of 56 days 
previously) from start of treatment cycle constitutes a DLT. This change was implemented 
consistently for pertinent combination studies within the MBG453 program. Furthermore, the 
following changes were made to the protocol:
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Section 3 – Study Design

Updated to clarify subjects’ hospitalization is recommended during venetoclax rampup
period and anytime at investigator’s discretion.

Section 4.2 – Rationale for dose/regimen and duration of treatment

Updated to implement latest MBG453 Investigator Brochure (v.7 dated 26-Nov-2021) 
updates

Section 4.6 – Risks and Benefits 

Reference to ASCO Guidelines updated to 2021 version

Section 6.1.5 – Treatment duration

Permanent discontinuation criterion for subjects experiencing prolonged cytopenias 
updated to indicate that in absence of clinical benefit for the patient per investigator 
assessment subjects without recovery within 42 days should be discontinued

Section 6.2.1.1 - Permitted concomitant therapy requiring caution and/or action

Table 6-3 – Management of potential interactions of CYP3A and P-gp inhibitors with 
venetoclax

Dosing schedule of the ramp-up period, for subjects on moderate CYP3A4 or P-
gp inhibitor, was updated to reflect USPI for venetoclax

Section 6.2.2 - Prohibited medication

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
Updated to note that vaccination against COVID-19, unless these are live vaccines, is 
allowed during the study. However, it was clarified that SARS-CoV-2 vaccines should 
not be administered the same day as study treatment as recommended by the ASCO 
guidelines 2021 version

Section 6.5.2 – Definitions of dose limiting toxicities (DLTs) 

Table 6-4 - Criteria for defining dose-limiting toxicities during the safety run-in updated

DLT for hematologic toxicities shortened to 42 days

Minor edit was performed for DLT for liver toxicities 

Section 6.5.3 – Dose modifications

Paragraph - Dose interruption at the start of a new treatment cycle and Table 6-6 - Dose 
modification for venetoclax, updated to include reference to the local label for dose 
modifications for venetoclax, 

Permanent discontinuation criterion for subjects experiencing prolonged cytopenias 
updated to indicate that - in absence of clinical benefit for the patient per investigator 
assessment - subjects without recovery within 42 days should be discontinued

Reference to ASCO Guidelines updated to 2021 version in Table 6-5 and within 
paragraph of dose modifications for MBG453

Section 6.5.4.1 – Follow-up for immune related AEs

Reference to ASCO Guidelines updated to 2021 version

Section 8 – Visit Schedule and Assessments

The allowed visit window for BMA procedures was updated to +/- 8 days from the 
planned visit date. Further the maximum days allowed between BMA efficacy, 
extramedullary disease assessment and hematology assessments of the same visits was 
updated to 8 days.

Table 8-1 – Assessment Schedule - footnote 21 was added to clarify that the Trial 
Feedback Questionnaire (TFQ) is not considered study data and will be received 
electronically outside the clinical database

Section 8.3.1 – Efficacy assessment

Updated to provide clarification on how hematology assessments should be performed 
in the absence of count recovery at C2D1 and beyond

Table 8-2 – Response classification in AML at a given evaluation time (based on IWG 
Cheson et al 2003, ELN 2017 Döhner et al 2017)

CRi definition was edited to reflect accurately ELN 2017 guidelines 

Section 8.5.1.2 Trial Feedback Questionnaire (TFQ)

Updated to clarify that the Trial Feedback Questionnaire (TFQ) is not considered study 
data and will be received electronically outside the clinical database

Section 10.1.3 – SAE reporting

Updated to note if more stringent, local regulations regarding reporting timelines for 
initial or follow-up AEs prevail

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
Updated to note that initial and follow-up SAEs, must be reported, without undue delay 
and under no circumstances later than within 24 hours of obtaining knowledge of the 
initial event or receiving the follow up information.

Section 15 – References 

Reference Brahmer et al 2018 deleted

Reference for 2021 ASCO Guideline update added 

Reference for Version 3.2021 NCCN Acute Myeloid Leukemia Clinical Practice 
Guidelines added
This amendment also includes minor editorial changes and additional clarifications
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.

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Amendment 3 (08-Apr-2021)
Amendment rationale
At the time of release of this amendment, 5 subjects have been enrolled to this trial.
The main purpose of this amendment is to modify the exclusion criteria to permit enrollment of 
patients with therapy-related AML. This change will align eligibility criteria with VIALE-A, 
the Phase III study that demonstrated the efficacy of venetoclax and azacitidine in patients with 
AML not suitable for intensive chemotherapy.
In addition, the following notable changes were made:

Exclusion criterion #6 was modified to allow enrollment of patients who have been treated 
for a malignancy and have been disease free (absence of residual disease) for at least 1 year; 
previously a disease free period of 2 years was required.

Requirements for evaluation of extramedullary disease were modified to allow imaging 
modalities and techniques to be selected based on institutional standard of care. The 
previous specifications for use of CT scan or MRI have been removed.

Venetoclax ramp-up dosing was updated based on Venclexta® (Venetoclax) USPI 2018 
(Section 2.1). The 4-day ramp-up dosing was amended to 100 mg (D1), 200 mg (D2), 400 
mg (D3), 400 mg (D4) compared to the original protocol which noted 4-day ramp-up dosing 
as 100 mg (D1), 200 mg (D2), 300 mg (D3), 400 mg (D4).

New, Novartis standard language, referred to as disruption proofing language, has been 
added to address trial conduct during public health emergencies. The added language 
addresses study participant safety and trial integrity. In addition, updates to the new version 
of Novartis protocol CTP template were made.

This amendment also includes minor editorial changes and additional clarifications
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 abbreviation further to protocol version 4.0 template

Section 4.6 Evaluation of risk due to COVID-19 pandemic added

Section 4.7- Rationale for Public Health Emergency mitigation procedures was added
Section 5.0 - Population

Clarified that therapy-related AML patients may be included
Section 5.2 - Exclusion criteria

Exclusion criterion # 3 was removed

Exclusion criterion #6 was amended to specify subject with history of adequately treated 
malignancy for which the subject has been disease free (absence of residual disease) for at 
least 1 year can enter the study if all other criteria are met.

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Section 6.1 - Study treatment

Table 6-2 Dosing schedule for ramp-up of venetoclax in Cycle 1was updated to note 
ramp-up period and dosing schedule per USPI

Updated to move the dosing interval recommendations for days of coadminstration of 
venetoclax with other study treatment to the venetoclax section, and to add reference to 
the pharmacy manual for detailed instructions on drug administration on coadministration 
days with MBG453
Section 6.2.1 - Concomitant therapy

Updated to provide a window of when concomitant medications should be collected

Updated to allow the use of cytarabine as a standard of care
Section 6.2.2 - Prohibited medication

Updated to allow prophylactic intrathecal chemotherapy
Section 6.6.1 - Treatment Compliance

Added the possibility of an off-site healthcare personnel to confirm compliance of 
administration of azacitidine, where applicable
Section 6.7 - Preparation and Administration

Added the possibility to administer azacitidine off-site if requested by an Investigator
Section 8 - Visit schedule and assessments

Added the option of a contingency plan if the patient cannot come onsite (phone calls)

Added Patient Reported Outcomes must be completed before any clinical assessments are 
performed at any given visit
Table 8.1 - Assessment schedule

CT scan/MRI replaced with Imaging assessment for extramedullary disease

Footnote #4: Updated to specify suspected to be related to treatment AEs and SAEs and 
concomitant medication collection window

Footnote #7: Updated to allow the use of preexisting cytogenetics results for the screening
Section 8.2 - Subject demographics/other baseline characteristics

Modified language regarding race/ethnicity baseline characteristics to match CTP template 
v4.0

CT scan/MRI removed to allow for appropriate imaging determined by the investigator
Section 8.3.1 - Efficacy assessments

CT scan/MRI removed to allow for appropriate imaging of extramedullary disease to be 
determined by the investigator as clinically indicated and per standard of care
Table 8-6 Local clinical laboratory parameters collection plan

Updated to allow the assessment of Troponin-I, if Troponin-T is not available
Section 8.4.2 Electrocardiogram (ECG)

Providing clarification on how many minutes apart triplicate ECGs should be performed

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Section 8.4.4 - Additional safety monitoring and considerations during venetoclax ramp-up

Ramp-up period for venetoclax updated as lasting 3 or 4 days per USPI
Section 9.1.2, Section 10.1.3, Section 10.1.4 - Updated relevant sections to match new Novartis 
protocol standard language (CTP template v4.0)
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.

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Amendment 2 (19-May-2020)
Amendment rationale
As the release of this amendment, no sites have been initiated, and no subject has been screened 
or has received study treatment in this trial.
The main purpose of this amendment is to allow enrollment of patients receiving moderate or 
strong CYP3A4 inhibitors or Pg-p inhibitors, in order to allow use of prophylactic antifungal 
medications (e.g. posaconazole, fluconazole or other azoles) commonly used in this patient 
population. This amendment expands the pool of eligible subjects, allowing enrollment of 
subjects more representative of the overall population with AML not suitable for intensive 
chemotherapy. Venetoclax is metabolized via the CYP3A4 system. Inhibitors of CYP3A4 
administered concurrently with venetoclax result in higher, potentially toxic plasma levels of 
venetoclax. This has been studied extensively and is reflected in the prescribing information for 
venetoclax. It is allowed to co-administer venetoclax with strong CYP3A inhibitors, but 
venetoclax doses need to be reduced. As many antifungal drugs commonly used for prophylaxis 
or treatment of fungal infections in AML are strong CYP3A inhibitors, this amendment 
removes the strict ban of co-administration in lieu of dose-reduction rules for venetoclax.
In addition, the following updates have been implemented:

Extend the restrictions on the use of live vaccines until the end of the follow-up period 
after the last dose of MBG453.

Guidance has been added on the criteria for MBG453 dose management for 
dermatological adverse drug reactions (ADRs) and non-immune related toxicities to align 
with the MBG453 Investigator’s Brochure.

Guidance has been added that subjects should be monitored carefully for any skin toxicity 
or mucositis, and that study treatment should be discontinued for any suspected case of 
Stevens-Johnson syndrome (SJS), or Lyell syndrome/toxic epidermal necrolysis (TEN) to 
align with the MBG453 Investigator’s Brochure.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Section 5.2 - Exclusion criteria

Exclusion criterion # 10 removed to allow enrollment of subjects receiving CYP3A4 
inhibitors or Pg-p inhibitors
Section 6.1 - Study treatment

Updated to refer to the latest Pharmacy Manual for detailed administration instructions to 
ensure consistency between documents and compliance with compounding standards and 
internal guidance.
Section 6.2 - Other treatment(s)- Updated to clarify that subjects who received a reduced dose 
of venetoclax due to co-administration of moderate or strong CYP3A or P-gp inhibitors, as per 

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Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Protocol summary

Primary objectives updated to reflect the addition of one safety cohort (400 mg Q4W)

Secondary objectives: EFS definition updated

Study design updated to reflect the addition of one safety cohort (400 mg Q4W)

Key inclusion criteria updated to add a definition of the criteria for patients to be assessed 
as unfit for intensive chemotherapy based on age and pre-existing comorbidities and to 
include subjects with ECOG performance status of 3 to align with the respective 
comorbidity criteria in other inclusion criterion.

Language added for primary CR analysis that will be done on patients treated with 
MBG453 at 800 mg Q4W.
Section 2 - Objectives and endpoints

Primary objectives: language added to specify that CR rate will be assessed on patients 
receiving MBG453 at 800 mg Q4W only. Incidence of DLTs will be assessed at the two 
tested dose levels.

Secondary objectives: EFS definition updated.

Section 3- Study Design

Updated with the addition of one safety cohort.

Figure 3-1 updated
Section 4.1 - Rationale for study design

Language updated to include a safety review meeting at each dose level.
Section 4.2 - Rationale for dose/regimen and duration of treatment

Language updated to reflect the addition of a safety cohort

Clinical safety data updated based on most recent safety data.
Section 4.4.1 - Definition of MRD was updated.
Section 4.5 - Purpose and timing of interim analyses/design adaptations

Updated with the addition of one safety cohort.

Updated timing of interim analysis to be performed after all subjects have completed 7 
months (previously 6 months) to align with the definition of treatment failure and 
assessment schedule for CR.
Section 4.6 - Risks and benefits

Updated with the addition of one safety cohort.
Section 5 - Population

Updated with the addition of one safety cohort

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Section 5.1 - Inclusion criteria

Inclusion criterion # 3 updated with addition of a definition of the criteria for patients to 
be assessed as unfit for intensive chemotherapy based on age and pre-existing 
comorbidities

Inclusion criterion # 5 updated to include subjects with ECOG performance status of 3 to 
align with the respective comorbidity criteria in inclusion criterion # 2

Inclusion criterion # 7 updated to include subjects with total bilirubin up to 3 x ULN 
(Grade 2) (except in the setting of isolated Gilbert syndrome, in which case higher total 
bilirubin is allowed provided that conjugated bilirubin is ≤ 3.0 x ULN) to align with the 
respective comorbidity criteria in inclusion criterion # 2
Section 6.1.1 - Investigational and control drugs

Table 6-1 updated wording for dose strength used for MBG453 for better illustration of 
formulations used

Language updated to reflect the addition of a safety cohort

Added formula for body surface area (BSA) calculation
Section 6.5 - Dose escalation and dose modification

Language updated to reflect the addition of a safety cohort and a safety review meeting.

Table 6-4: Immune toxicity: Language updated for better clarity. Footer added to the table 
regarding organ specific immune toxicity.
Section 6.5.4.2 - Follow-up for TLS: updated instruction for maintaining adequate hydration
Section 6.5.3 - Dose modification

Correction to add condition of subjects with CR requiring dose interruption at the start of a 
treatment cycle in case of Grade 4 neutropenia and /or Grade 4 thrombocytopenia
Section 8 - Visit schedule and assessments

Language added to specify that a maximum of 7 days is allowed between BMA efficacy, 
extramedullary disease assessment (if applicable) and hematology assessments of the 
same visit.

Table 8-1 updated the description urinalysis to align with updated table 8-6 and typos 
corrected related to PK sample collection not done at Cycles 4 and 5 and to efficacy 
response assessment not done at screening.
Section 8.2 - Language updated to clarify that racial and ethnic information will be collected in 
this study in order to allow for signal detection for differences and to allow for racial/ethnic 
sensitivity reports required for registration in multiple countries· Table 8-6 updated to clarify 
that detailed urinalysis as per local practice is required only for patient with abnormalities 
during the dipstick analysis, if clinically indicated.

Table 8-7 updated to specify IL1 subunit

Section 8.5.2.1- language added to clarify that PK sample collection for pre-MBG453 
infusion is no longer needed after permanent discontinuation of MBG453.

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Section 16.1 - Appendix 1: Statistical Details for Safety Run-in Part: Bayesian model: prior and 
design properties for hypothetical data scenarios
Sections 16.1.1 to 16.1.3 updated to consider the new Bayesian model including the two doses 
tested of MBG453 in the safety run-in part: 400 mg Q4W and 800 mg Q4W.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.

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Protocol summary
Protocol number
CMBG453C12201
Full Title
A phase II multi-center, single arm, safety and efficacy study of MBG453 in 
combination with azacitidine and venetoclax for the treatment of Acute Myeloid 
Leukemia (AML) in adult patients unfit for chemotherapy
Brief title
A study of MBG453 in combination with azacitidine and venetoclax in AML patients 
unfit for chemotherapy
Sponsor and
Clinical Phase
Novartis
Phase II
Study Indication
Acute Myeloid Leukemia (AML)
Investigation/Treatment
type
Drug; Biological
Study type
Interventional
Purpose and rationale
MBG453, a novel monoclonal antibody inhibitor of TIM-3, has shown preliminary 
evidence of clinical activity as a single-agent in patients with relapsed/refractory 
AML. The study will be conducted in two parts. The primary purpose of Part 1 (Safety 
Run-in) is to rule out excessive toxicity of MBG453, when administered in 
combination with azacitidine and venetoclax. The primary purpose of the combined 
Part 1 and Part 2 (Safety run-in and Expansion Part) is to evaluate efficacy of 
MBG453, when administered in combination with azacitidine and venetoclax in adult 
patients with newly diagnosed AML, who are not suitable for treatment with intensive 
chemotherapy.
The current trial will seek to extend the preliminary findings of efficacy of MBG453 
in combination with hypomethylating agents (HMA) by evaluating MBG453 in 
combination with the HMA azacitidine and the Bcl-2 inhibitor venetoclax. The doublet 
of venetoclax and azacitidine has demonstrated improved efficacy relative to 
azacitidine alone in early phase Ib and phase III trials (DiNardo et al 2019, DiNardo 
et al 2020), and recently has received approval by the FDA for treatment of unfit 
AML. Despite the improved efficacy demonstrated by the venetoclax-azacitidine, a 
significant unmet medical need remains as a substantial number of patients do not 
achieve CR (complete remission), the CRs which are observed are only of limited 
duration and MRD negativity is achieved by a minority of patients.
Primary Objective(s) 
The primary objective for the safety run-in part is to determine whether MBG453 
at the two tested dose levels (400 mg and 800 mg Q4W) is not meeting the 
overdose criteria when added to azacitidine + venetoclax in subjects with AML 
not suitable for chemotherapy by measuring the incidence of dose-limiting 
toxicities (DLTs) between Cycle 1 Day 8 and the end of Cycle 2 of treatment.
The primary objective for the overall study (safety-run-in + expansion) is to assess 
the complete remission rate (CR) of MBG453, administered at 800 mg Q4W, in 
combination with azacitidine and venetoclax in subjects with AML not suitable for 
chemotherapy by determining the proportion of subjects achieving a complete 
remission (CR) as per investigator assessment.

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Secondary Objectives
To assess the CR/CRi rate and the duration of CR/CRi by measuring the 
proportion of subjects achieving a complete remission (CR) or complete 
remission with incomplete hematologic recovery (CRi) and the time from the date 
of the first documented CR/CRi to the date of first documented relapse or 
progressive disease or death due to any cause, whichever occurs first, as per 
investigator assessment
To assess the duration of complete remission (CR) by measuring the time from 
the date of the first documented CR to the date of first documented relapse or 
progressive disease or death due to any cause, whichever occurs first, as per 
investigator assessment
To assess the CR/CRh rate and the duration of CR/CRh by measuring the 
proportion of subjects achieving a complete remission (CR) or complete 
remission with partial hematologic recovery (CRh) and the time from the date of 
the first CR/CRh to the date of first relapse or progressive disease or death due 
to any cause, whichever occurs first, as per derivation

To assess the Event-free Survival (EFS) by measuring the time from start of 
treatment until date of death due to any cause, relapse from CR, or treatment 
failure, whichever comes first. 

To assess Overall Survival (OS) by measuring the time from start of treatment to 
death due to any cause
To determine safety and tolerability of MBG453 when administered in 
combination with azacitidine and venetoclax by evaluating the incidence and 
severity of AEs and SAEs, changes in laboratory values and vital signs, incidence 
of notable ECG abnormalities
To characterize the pharmacokinetics (PK) of MBG453 when administered in 
combination with azacitidine and venetoclax by determining the serum 
concentrations for MBG453 and plasma concentrations for venetoclax
To evaluate immunogenicity of MBG453 when given in combination of azacitidine 
and venetoclax by measuring Anti-drug Antibody (ADA) prevalence at baseline 
and ADA incidence on-treatment
To assess the MRD negativity rate by determining the proportion of subjects with 
MRD negativity (a MRD negative sample determined by Multiparameter Flow 
Cytometry-Measurable Residual Disease (MFC-MRD) and a bone marrow 
remission) in the full study population and/or any subgroup of interest (CR, 
CR/CRi, CR/CRh, etc...)
To assess the effect of MBG453 in combination of venetoclax + azacitidine on 
transfusion independence by measuring the number and percent of all subjects 
who achieve transfusion independence on 
treatment, 
and 
from 
baseline 
respectively
Study design
This phase II, open-label, single-arm, multi-center study of MBG453 in combination 
with azacitidine and venetoclax in adult subjects with AML will be conducted in two 
parts. Part 1 is a Safety Run-in of approximately 18 subjects, to assess whether 
MBG453 at the two tested dose levels (400 mg and 800 mg Q4W) is safe when 
given in combination with azacitidine and venetoclax. Following the observation 
period a Safety Review Meeting will be conducted. If no safety concerns are 
identified with the tested combination of MBG453, azacitidine and venetoclax, 
Novartis will provide notification to the investigational sites that Part 2 (expansion) is 
open to enrollment. Enrollment to Part 2 will continue until a total enrolment of 
approximately 80 subjects treated with MBG453 at 800 mg Q4W (including those in 
the safety run-in) has been achieved.
Population
The study population will include approximately 86, adult subjects with newly 
diagnosed AML, who are not suitable for intensive chemotherapy and not eligible for 
HSCT, based on the medical judgment of 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)Newly 
diagnosed with AML (based on WHO 2016 classification (Arber et al 2016), who 

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are not suitable for intensive chemotherapy based on one or more of the 
following criteria:

age ≥75 years

ECOG performance status of 2 or 3

or at least one of the following comorbidities:

severe cardiac comorbidity (including congestive heart failure 
requiring treatment, left ventricular ejection fraction ≤ 50%, or chronic 
stable angina)

pulmonary comorbidity (including DLCO ≤ 65% or FEV1 ≤ 65%)

moderate hepatic impairment with total bilirubin > 1.5 to 3 times the 
upper limit of normal

eGFR ≥ 30 mL/min/1.73 m2 to < 45 mL/min/1.73 m2 (estimation 
based on Modification of Diet in Renal Disease (MDRD) formula, by 
local laboratory)

any other comorbidity (to be documented in the CRF) that the 
physician judges to be incompatible with intensive chemotherapy 
must be reviewed and approved by the Novartis Medical Monitor 
before study enrollment.

Patients with antecedent MDS, myelofibrosis, essential thrombocythemia, or 
polycythemia vera are eligible, provided no prior therapy, as specified in the 
exclusion criterion #1.

No planned hematopoietic stem-cell transplantation (HSCT).

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2 or 
3.WBC < 25x10^9/L (may be reduced with leukopheresis or hydroxyurea)
Key Exclusion criteria

Previous treatment with any of the following antineoplastic agents, approved or 
investigational; checkpoint inhibitors, venetoclax and hypomethylating agents 
(HMAs) such as decitabine or azacitidine. Previous treatment for AML, MDS, 
myelofibrosis, essential thrombocythemia, or polycythemia vera is permitted 
with hydroxyurea, growth factors or ruxolitinib

Prior exposure to TIM-3 directed therapy at anytime

Subjects with AML-M3 / APL (Acute promyelocytic leukemia) with PML-RARA 
and patients with AML secondary to Down's syndrome

Subjects with CNS leukemia or neurologic symptoms suggestive of CNS 
leukemia (unless CNS leukemia has been excluded by a lumbar puncture)

Subjects with concurrent or prior malignancy, except:
a) subject with history of MDS, myelofibrosis, essential thrombocythemia, or 
polycythemia vera
b) subject with history of adequately treated malignancy for which the subject 
has been disease free (absence of residual disease) for at least 1 year and if 
no anticancer systemic therapy (namely chemotherapy, radiotherapy or 
surgery) is ongoing or required during the course of the study. Patients who 
are receiving adjuvant therapy such as hormonotherapy are eligible
Study treatment
MBG453 + azacitidine + venetoclax
Efficacy assessments
Bone marrow aspirate and peripheral blood will be collected at screening and at 
regular intervals during treatment for assessment of disease.
Response evaluation will be per Investigator’s assessment, based on standardized 
criteria as proposed by the European Leukemia Network (ELN) and International 
Working Group (IWG) for AML (Cheson et al 2003; Döhner et al 2017). Disease 
classification at baseline and evaluation of response during study treatment will rely 
on bone marrow or peripheral blood assessment, as well as on the presence or 
absence of extramedullary disease, and status of transfusion dependence.
Pharmacokinetic 
assessments 
Pharmacokinetic (PK) samples will be obtained and evaluated in all subjects.

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1
Introduction
1.1
Background
Acute myeloid leukemia (AML) is a malignant disease characterized by the clonal expansion 
of myeloid blasts in the bone marrow, peripheral blood and extramedullary tissues. AML is the 
most common form of acute leukemia in adults; an estimated 21,450 new cases of AML and 
10,920 
deaths from the disease will 
occur in 
the United 
States, in 
2019 
(American Cancer Society 2019). AML is primarily a disease of older patients, with 
approximately two-thirds of patients above the age of 60, and a median age at presentation of 
68 years (Noone et al 2018). Patients aged 65 and older typically have AML associated with 
adverse cytogenetic characteristics, inferior performance status, and lower complete response 
(CR) rates, in addition to higher treatment-related mortality and shorter overall survival (OS).
Intensive chemotherapy, which is standard of care for first line treatment, is not considered 
suitable for many elderly AML patients due to higher toxicity, especially in patients with 
significant comorbidities and adverse cytogenetic risk AML. The subpopulation of patients with 
AML not considered suitable for intensive chemotherapy or HSCT, are often referred to as unfit 
AML, a term that will be used in this protocol.
Low dose cytarabine was the first agent reported to prolong survival and improve the quality of 
life of these unfit AML patients (Burnett et al 2007). More recently, decitabine (Dacogen®) and 
azacitidine (Vidaza®) have been approved in the EU for patients aged 65 years and above with 
newly-diagnosed leukemia who are not candidates for standard induction chemotherapy (or 
HSCT in the case of azacitidine) based upon phase 3 clinical trial results showing clinically 
meaningful improvements in OS (Kantarjian et al 2012, Dombret et al 2015). In addition, the 
use of azacitidine for elderly or unfit AML patients is included in the NCCN AML treatment 
guidelines version 3.2017 (O'Donnell et al 2017).
In 2018, venetoclax, a small molecule inhibitor of BCL-2, the over-expression of which has 
been implicated in the maintenance and survival of AML cells and has been associated with 
resistance to chemotherapeutics (Konopleva et al 2006), has received accelerated approval by 
the FDA in combination with azacitidine or decitabine or low-dose cytarabine for the treatment 
of newly-diagnosed AML in adults who are age 75 years or older, or who are unfit for intensive 
induction chemotherapy. Approval was based on two open-label, non-randomized trials, and 
efficacy was established based on the rate of complete remission (CR) and CR duration. In a 
most recent data update (DiNardo et al 2019), it is reported that the CR and CRi rates were 
37% and 30% respectively, for patients treated with venetoclax in combination with azacitidine 
or decitabine, with a median observed time in remission (CR or CRi) of 11.3 months (95% CI, 
8.9 months-not reached). Furthermore, only 29% of patients in remission achieved levels of 
MRD below 0.1%, suggesting that deep leukemic clearance (< 0.1%) remains a challenge for a 
majority of the patients. In the randomized, placebo-controlled Phase III study comparing 
venetoclax plus azacitidine to azacitidine plus placebo (control group) in previously untreated 
and ineligible to standard induction patients with AML (DiNardo et al 2020) overall survival 
was significantly longer with median survival of 14.7 months in the azacitidine+ venetoclax 
group versus 9.6 months in the control group with HR= 0.66 (95% CI, 0.52 to 0.85; P<0.001). 
Although the incidence of complete remission was higher (36.7% vs. 17.9%; P<0.001) among 
patients who received azacitidine plus venetoclax than among those who received azacitidine 

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alone, significant number of patients still did not achieve a complete remission. Furthermore, 
MRD negativity rate occurred only in 23.4% of the patients receiving azacitidine plus 
venetoclax (DiNardo et al 2020). Thus, although these results represent an advance in treatment 
of the unfit AML population, complete remission achievement, remission duration and 
leukemic clearance to MRD levels below 0.1% are still modest, and an unmet need remains for 
new therapy options for this patient population.
Inhibition of immune checkpoints, including PD-(L)1 and CTLA4, have demonstrated durable 
objective responses in multiple tumor types, and 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 are used 
in daily clinical practice. However, the optimal immunotherapy for AML has not yet been 
identified.
T-cell immunoglobulin and mucin domain-containing 3 (TIM-3; also known as hepatitis A 
virus cellular receptor 2) is a negative regulator of T cells. TIM-3 was initially described as an 
inhibitory protein expressed on activated T helper (Th) 1 CD4+ and cytotoxic CD8+ T cells 
that secrete interferon-gamma (IFN-γ) (Monney et al 2002, Sánchez-Fueyo et al 2003 ). TIM-3 
is enriched on FoxP3+ Tregs and constitutively expressed on DCs, monocytes/macrophages, 
and NK cells (Anderson et al 2007, Ndhlovu et al 2012). Further, TIM-3 has also been 
identified as an acute myeloid leukemia (AML) stem cell antigen that is present in leukemic 
blasts but not normal hematopoietic stem cells, and anti-TIM-3 antibody treatment has shown 
efficacy in blocking engraftment of AML in a mouse xenotransplantation model 
(Kikushige et al 2010). Promising preclinical and clinical anti-cancer activity has been reported 
for 
TIM-3 
blockade (Kikushige et al 2010, 
Sakuishi et al 2010, 
Ngiow et al 2011, 
Sakuishi et al 2011, Jing et al 2015, Asayama et al 2017).
MBG453 is a high-affinity, ligand-blocking, humanized anti-TIM-3 IgG4 antibody which 
blocks the binding of TIM-3 to phosphatidylserine (PtdSer). First-in-human trials have shown 
that 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 in AML and in high and very high risk MDS 
subjects (see clinical responses in Section 4.3).
For further details about MBG453, refer to the IB [MBG453 Investigator's Brochure].
1.2
Purpose
The current study will be conducted in two parts. The primary purpose of Part 1 (Safety Run-
in) is to rule out excessive toxicity of MBG453 when administered in combination with 
azacitidine and venetoclax. The primary purpose of the combined Part 1 and Part 2 (Expansion 
Part) is to evaluate the efficacy of MBG453 at 800 mg Q4W when administered in combination 
with azacitidine and venetoclax in adult patients with newly diagnosed AML who are not 
suitable for treatment with intensive chemotherapy or HSCT. In addition, Part 2 will evaluate 
safety and tolerability and characterize the pharmacokinetics of MBG453 when administered 
in combination with azacitidine and venetoclax.
MBG453, a novel monoclonal antibody inhibitor of TIM-3, has shown preliminary evidence of 
clinical activity as a single-agent in patients with relapsed/refractory AML. More importantly, 

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in study [CPDR001X2105] MBG453 has shown promising evidence of efficacy, including 
durable CRs of up to15 months in ongoing patients, when administered in combination with the 
HMA decitabine to patients with newly diagnosed AML and high-risk MDS.
The current trial will seek to extend these preliminary findings of efficacy by evaluating 
MBG453 in combination with the HMA azacitidine and the Bcl-2 inhibitor venetoclax. The 
doublet of venetoclax and azacitidine has demonstrated improved efficacy relative to 
azacitidine alone in early phase Ib and phase III trials (DiNardo et al 2019, DiNardo et al 2020), 
and recently has received approval by the FDA for treatment of unfit AML. Despite the 
improved efficacy demonstrated by the addition of venetoclax to HMA, a significant unmet 
medical need remains as a substantial number of patients do not achieve CR (complete 
response), the majority patients in remission still retain leukemic burden (detection of 
MRD >0.1%), and the CRs which are observed are only of limited duration.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

Safety run in + Expansion:
To assess the complete remission (CR) rate of 
MBG453, administered at 800 mg Q4W, in 
combination with azacitidine and venetoclax in 
subjects 
with 
AML 
not 
suitable 
for 
chemotherapy
Proportion of subjects achieving a complete remission (CR) 
as 
per 
investigator 
assessment 
(Cheson et al 2003, 
Döhner et al 2017) will be determined when all subjects 
have completed at least 12 cycles of treatment with 
MBG453 + azacitidine + venetoclax or discontinued earlier.

Safety run-in:
To determine whether MBG453 at the two 
tested dose levels is not meeting overdose 
criteria when added to azacitidine + 
venetoclax in subjects with AML not suitable 
for chemotherapy.

Incidence of DLTs between Cycle 1 Day 8 and end of 
cycle 2.
Secondary objective(s)
Endpoint(s) for secondary objective(s)
To assess the MRD negativity rate 
Proportion of subjects with MRD negativity (a MRD negative 
sample determined by MFC-MRD and a bone marrow 
remission) in the full study population and/or any subgroup 
of interest (CR, CR/CRi, CR/CRh, etc.)
To assess the CR/CRi rate and the duration 
of CR/CRi 

Proportion of subjects achieving a CR or CRi, as per 
investigator 
assessment
(Cheson et al 2003, 
Döhner et al 2017)

Time from the date of the first documented CR/CRi to the 
date of first documented relapse or progressive disease or
death due to any cause, whichever occurs first, as per 
investigator 
assessment 
(Cheson et al 2003, 
Döhner et al 2017),
To assess the duration of complete 
remission (CR) 
Time from the date of the first documented CR to the date 
of first documented relapse or progressive disease or death 
due to any cause, whichever occurs first, as per investigator 
assessment (Cheson et al 2003, Döhner et al 2017)

To assess the CR/CRh rate and the 
duration of CR/CRh

Proportion of subjects achieving a CR or CRh, as per 
derivation (Döhner et al 2022)

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Objective(s)
Endpoint(s)

Time from the date of the first CR/CRh to the date of first  
relapse or progressive disease or death due to any cause, 
whichever 
occurs 
first, 
as 
per 
derivation 
(Döhner et al 2022)
To assess the Event-free Survival (EFS)
The time from start of treatment until date of death due to 
any cause, relapse from CR, or treatment failure, whichever 
occurs first.

To assess Overall Survival (OS)

The time from start of treatment to death due to any cause
To determine safety and tolerability of 
MBG453 when administered in combination 
with azacitidine and venetoclax
Incidence and severity of AEs and SAEs, changes in 
laboratory values and vital signs, incidence of notable ECG 
abnormalities
Characterize the pharmacokinetics (PK) of 
MBG453 when administered in combination 
with azacitidine and venetoclax
Pharmacokinetic 
parameters 
(serum concentrations for 
MBG453 and plasma concentrations for venetoclax)
To evaluate immunogenicity of MBG453 
when given in combination of azacitidine 
and venetoclax
Anti-drug Antibody (ADA) prevalence at baseline and ADA 
incidence on-treatment
To assess the effect of MBG453 in 
combination of venetoclax + azacitidine on 
transfusion independence
Number and percent of all subjects who achieve transfusion 
independence on treatment, and from baseline respectively.

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3
Study design
This Phase II, open-label, single-arm, multi-center study of MBG453 in combination with 
azacitidine and venetoclax in adult subjects with AML not suitable for intensive chemotherapy 
is described in Figure 3-1 below. The study will enroll a total of approximately 86 subjects and 
will be conducted in two parts. Part 1 is a Safety Run-in to assess whether MBG453 is safe 
when given in combination with azacitidine and venetoclax. A total of approximately 18 
subjects will be enrolled to Part 1 across two dose levels. Approximately 6 subjects will be 
enrolled at the starting dose level, 400 mg Q4W, in order to obtain 3 to 6 evaluable subjects 
(see Section 6.5 for evaluability criteria). Provided the starting dose level is determined to be 
safe, approximately 12 subjects will be enrolled at the second dose level (800 mg Q4W), in 
order to obtain at least 9 evaluable subjects (see Section 6.5 for evaluability criteria). For each
dose level, once the required number of evaluable subjects has been confirmed, enrollment will 
be halted until subjects have completed the DLT observation period (see Section 6.5), and a 
Safety Review Meeting has been conducted (see Section 6.5.1). If no safety concerns are 
identified at either dose level, Novartis will provide notification to the investigational sites that 
Part 2 (expansion) is open to enrollment. Enrollment to Part 2 will continue until a total 
enrollment of approximately 80 subjects at the 800 mg Q4W dose level (including those in the 
safety run-in) has been achieved.

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Figure 3-1
Study Design
* The safety run-in cohort MBG453 400 mg Q4W requires 3 to 6 evaluable subjects (approximately 6 
enrolled subjects) to have been observed for at least 2 cycles
**The safety run-in cohort MBG453 800 mg Q4W requires at least 9 evaluable subjects (approximately 
12 enrolled subjects) to have been observed for at least 2 cycles
*** To achieve a total of 80 subjects at the 800 mg Q4W dose level
Study treatment will be administered in cycles with a planned duration of 28 days, and study 
treatment may continue until the subject experiences disease progression (as defined by ELN 
2017; Döhner et al 2017) or unacceptable toxicity.
In each cycle, azacitidine will be administered intravenous or subcutaneous at 75 mg/m2 on 
Days 1 to 5 and Days 8 and 9 (or, at discretion of the investigator on Days 1-7, or Days 1-6 and 
Day 8 respectively), and venetoclax will be administered orally at 400 mg daily (following 
ramp-up (see Table 6-2 and Section 6.1.1 for details), starting on Day 1). MBG453 will be 
administered intravenously at 400 mg (safety run-in cohort 1) or 800 mg (safety run-in cohort 
2 and expansion) on Day 8 (Q4W) of every 28-day cycle. Hospitalization during Cycle 1 from 
Day 1 to Day 3 is recommended at investigator’s discretion in order to monitor closely 
occurrence of TLS, (see Section 6.5.4.2), and thereafter is at the discretion of the investigator.
At any time during the study, patients unable to tolerate one or two of the study treatment drugs, 
may continue study treatment with only the tolerated drug(s). In addition, for patients who 
achieve a CR and have received at least 18 cycles of study treatment, treatment with venetoclax 
and azacitidine may be discontinued at the discretion of the investigator, and the patient 
continues on study receiving only single agent MBG453.

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After the end of study treatment, all patients must be followed for adverse events (AEs) for 30 
days; in addition, follow-up for AEs will be conducted for 150 days following the last dose of 
MBG453. All subjects who discontinued study treatment will enter a long-term follow-up (for 
efficacy and/or survival status) as described in the study flow diagram below (Figure 3-2) and 
outlined in Section 9.1.
Figure 3-2
Study Flow

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Study Flow
The study flow is comprised of 3 periods see (Figure 3-2): Pre-treatment (Screening), treatment 
and follow-up.
Patients will undergo safety and efficacy assessments during screening and periodically during 
treatment and follow-up as outlined in Table 8-1.
An end of treatment (EOT) visit will be performed when subjects permanently discontinue 
study treatment. Subjects will then enter safety/post-treatment follow-up as shown in Figure 3-2
(see also Section 9.1.1)
All subjects will be followed for survival as per Section 9.1.1.3.
4
Rationale
4.1
Rationale for study design
The overall study design, Phase II, single-arm, open-label, multi-center, is a design to evaluate 
safety, tolerability and efficacy of a novel combination. To avoid overdosing of MBG453 in 
combination with azacitidine and venetoclax, the study does employ a two-part design with a 
halt to enrolment between Part 1 (Safety Run-in) and Part 2 (Expansion part). This design 
element allows, in Part 1, a Safety Review Meeting at each dose level, with evaluation of DLTs, 
and review of available safety data to confirm that MBG453 in combination with azacitidine 
and venetoclax, which has not been evaluated clinically, is safe, prior to opening enrollment to 
a larger patient population. A Steering Committee (Section 10.2.2) will be convened to review 
the safety during the course of study.
4.2
Rationale for dose/regimen and duration of treatment
Rationale for dose/regimen of MBG453
The study will start with a cohort of 3 to 6 evaluable subjects treated with MBG453 at a dose 
level of 400 mg Q4W in order to minimize the risk for unexpected toxicities of this novel 
combination of MBG453 in combination with venetoclax and azacitidine. The proposed 
MBG453 dose level for evaluation of efficacy in the study is 800 mg Q4W based on data 
accumulated from 2 phase 1 studies. [CMBG453X2101] in solid tumor patients has a wide
MBG453 dose range. In MBG453 single agent arms, MBG453 doses ranged 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], [CPDR001X2105] study started evaluating MBG453 at 240 mg Q2W, 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 

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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. A dose of 800 mg 
Q4W has similar AUCtau as 400 mg Q2W at the steady state.
Clinical Efficacy:
In study [CPDR001X2105], clinical benefit was seen across 3 dose levels tested (at 240 mg 
Q2W, 400 mg Q2W, 800 mg Q4W in combination with decitabine) with CR or marrow CR in 
high risk MDS subjects and CR or CRi in newly diagnosed AML subjects. Among subjects that 
obtained CR, there were durable responses as long as 15 months (as of cut-off date of 10-Nov-
2018). No obvious dose-response relationship was observed. In a preliminary exposure-
response analysis, there was also no clear relationship between exposure and response, using a 
steady state exposure metrics of AUCtau or Ctrough and efficacy metrics of clinical benefit 
(CR/mCR/CRi) or percent of blast reduction.
Clinical Safety:
MBG453 was found to be safe and well tolerated across all dose levels tested in both studies. 
In study [CMBG453X2101], up to date, 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.
In study [CPDR001X2105], as of 01-Apr-2021, a total of 187 subjects with hematological 
malignancies have been treated with MBG453 as a single agent (n=26) or in combination with 
decitabine (n=82) or azacitidine (n=79). 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 events attributed to study treatment were AST increased, diarrhea 
and rash in two subjects (8%), each. 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 82 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. In the 79 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, diarrhea, fatigue, 
neutrophil count decrease and platelet count decrease. One participant experienced a DLT 
during the first 2 cycles, which consisted of a Grade 4 acute febrile neutrophilic dermatosis 
(Sweet’s syndrome), and discontinued the study treatment. One subject with neutropenic colitis 
reported as suspected to be related to study treatment died of septic shock. No other study 
treatment-related deaths were observed in any of the studies mentioned above.

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Preliminary analysis revealed no relationship between dose, incidence and severity of adverse 
events across the different treatment groups. No relationship was observed between Cmax and 
the incidence of potentially immune related adverse events, providing additional support for 
800 mg Q4W regimen, which has the highest Cmax among the doses tested. Please refer to the 
Investigator's Brochure for additional information of AEs reported in subjects with solid tumors 
or with hematologic malignancies treated with MBG453 as a single agent or in combination 
with other drugs.
Predicted Target Engagement:
A population pharmacokinetic model of MBG453 concentration was fit to all patients from both 
studies. This model was used to simulate the TIM-3 occupancy in the bone marrow by making 
assumptions about MBG453 biodistribution to the bone marrow and binding affinity to TIM-3. 
Using trial simulation, this model predicted that the 800 mg Q4W dose would give at least 95% 
receptor occupancy in at least 95% of patients at steady state Ctrough. This high degree of target 
engagement is also supported by a plateau in the accumulated soluble TIM-3 that is observed 
at doses of 240 mg Q2W and above, and at 800 mg Q4W and above.
In summary given the excellent safety and tolerability seen across all doses and schedules in 
[CMBG453X2101] and [CPDR001X2105], the activity seen at all three doses tested in 
study [CPDR001X2105]; the predicted saturation of TIM-3 from the soluble TIM-3 data and 
the receptor occupancy model; and the lack of clear dose-response or exposure-response 
relationship for MBG453, 800 mg Q4W was selected as the target dose regimen for this study.
4.3
Rationale for choice of combination drugs
Rationale for combining MBG453 with azacitidine and venetoclax
Venetoclax in combination with azacitidine or decitabine or low dose cytarabine has recently 
received accelerated approval from FDA based on efficacy and safety, demonstrated in two 
open-label trials (see Section 1.1). Based on these trial results, venetoclax in combination with 
HMA is emerging as a potential new standard of care.
The rationale for combining the MBG453 with azacitidine and venetoclax is based on the 
following:
Data from allogeneic HSCT and donor lymphocyte infusions have demonstrated a role for the 
immune system in the treatment of AML. However, the optimal immunotherapy has yet to be 
defined, and to date PD-1 inhibitors have demonstrated minimal single-agent activity, 
suggesting exploration of alternative approaches.
TIM-3 is a checkpoint inhibitor that plays a complex role in the negative regulation of innate 
and adaptive immune responses. Further, TIM-3 is expressed on leukemic stem cells and 
leukemic progenitor cells but not on normal hematopoietic stem cells. This suggests that TIM-
3 inhibition by MBG453 may have immunomodulatory as well as direct anti-leukemic effects.
Hypomethylating agents induce broad epigenetic effects including downregulating genes 
involved in cell cycle, cell division and mitosis, and upregulating genes involved in cell 
differentiation. However, these potentially anti-leukemic effects are accompanied by increased 

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expression of TIM-3 as well as PD-1, PD-L1, PD-L2 and CTLA4, potentially downregulating 
immune-mediated anti-leukemic effects. These latter effects justify the exploration of novel 
checkpoint inhibitors to decrease an immunosuppressive tumor microenvironment 
(Yang et al 2014, Ørskov et al 2015).
Venetoclax is an inhibitor of BCL-2. BCL-2 inhibits apoptosis of factor-deprived cells, but does 
not prevent apoptosis of immune cell mediated killing, indicating different mechanisms of 
apoptosis induction (Vaux et al 1992). Therefore, blockage of both BCL2, which promotes 
direct leukemic cell apoptosis, and TIM-3, which may promote both immune cell mediated 
killing and direct leukemia-stem cell targeting, may induce cancer cell elimination via different 
pathways and possibly create a synergistic effect.
Study [CPDR001X2105] has demonstrated that MBG453 can be administered safely in 
combination with an HMA, decitabine, and that this combination demonstrates preliminary 
efficacy including durable responses in patients with AML and high-risk MDS
(see Section 4.2).
Further, as a mAb, MBG453 is not metabolized by cytochrome P450 (CYP450) enzymes, or 
transported by P-glycoprotein (Pgp) or related ABC membrane transporters, therefore an impact 
of DDIs on the PK of MBG453 by azacitidine, or venetoclax is not anticipated. Cytokines 
produced by activated lymphocytes may impact the levels of Pgp and the activity of CYP450 
enzymes (Renton 2005, Dumais et al 2008, Harvey and Morgan 2014); the clinical relevance to 
MBG453 is unknown. However, preliminary data from the clinical study [CPDR001X2105], 
which has shown that the co-administration of MBG453 with decitabine did not result in 
changes in their PK parameters. Therefore, a clinically relevant DDI effect is considered 
unlikely.
Taken together, these data suggest that the combination of MBG453, venetoclax and azacitidine, 
can be administered safely with little overlapping toxicity contributed by MBG453, and that 
MBG453 may improve the efficacy of azacitidine and venetoclax.
4.4
Rationale for MRD assessment 
4.4.1
Rationale for MRD assessments
Measurable Residual Disease (MRD) in AML refers to the presence of leukemic blasts at a 
sensitivity of detection below the threshold of conventional morphologic methods. Patients who 
experience a CR according to morphologic assessments (<5% blasts in the bone marrow) can 
potentially still harbor a large number of leukemic cells in the bone marrow which can confer 
a poor outcome. Detection of MRD in AML has shown prognostic relevance in several studies 
(Freeman et al 2013, 
Terwijn et al 2013, 
Ivey et al 2016, 
Jongen-Lavrencic et al 2018, 
Freeman et al 2018), indicating that depth of leukemic clearance should be considered as a 
relevant prognostic endpoint in this setting. A recent study investigating efficacy of venetoclax 
in combination with HMA in unfit AML showed that, despite the impressive rate of 
morphological remission (CR/CRi: 190/286 (66.4%)), only a fraction of patient in remission 
had MRD levels below 0.1% (67/164 (41%) CR/CRi MRD-negative), as determined by 
Multiparameter Flow Cytometry (MFC) (DiNardo et al 2019; Pratz et al 2022). This indicates 
that addition of venetoclax to HMA, while delaying progression of AML, does not seem to 
effectively eradicate leukemic disease in the majority of responding patients. In addition, among 

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in cohorts at 400 mg Q4W and 800 mg Q4W will be observed for at least 2 treatment cycles 
followed by a Safety Review Meeting, before opening enrollment to a larger patient population 
in Part 2. See Section 6.5.1. In addition, a Steering Committee (see Section 10.2.2) will review 
the safety during the course of the study.
Women of child bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if a pregnancy were to occur during the 
study and must agree that in order to participate in the study they must adhere to the 
contraception requirements outlined in the exclusion criteria until at least 30 days after the last 
dose of venetoclax, 90 days after the last dose of azacitidine (or as per respective local labels, 
whichever is longer) and 150 days after the last dose of MBG453, whichever is later. If there is 
any question that the subject will not reliably comply, they should not be entered or continue in 
the study.
No substantial additional risk to patients' safety due to the SARS-CoV-2 virus and the 
COVID-19 pandemic has been identified with MBG453 based on the available knowledge at 
this time. In case of active COVID-19 infection, a careful benefit risk evaluation needs to be 
performed by the investigator to determine whether the subject should remain on study 
medication or not.
There is no contraindication for the use of an inactivated, viral-vector-, or mRNA based SARS-
CoV-2 vaccine in cancer patients on sabatolimab therapy.
COVID-19 vaccines have not been tested in patients treated with MBG453, therefore any 
additional risks are unknown at this time. Before receiving any vaccine, the risks and benefits 
should be evaluated by the investigator. 
4.7
Rationale for Public Health Emergency mitigation procedures
In the event of a Public Health emergency as declared by Local or Regional authorities (i.e.
pandemic, epidemic or natural disaster), mitigation procedures may be required to ensure
participant safety and trial integrity and are listed in relevant sections of the study protocol.
Notification of the Public health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures and permitted/approved by Local or Regional
Health Authorities and Ethics Committees as appropriate.
5
Population
The study population will include adult subjects with newly diagnosed AML, who are not 
suitable for intensive chemotherapy and not eligible for HSCT. Approximately 18 subjects 
across two dose levels, are expected to be enrolled in the safety run-in; additional subjects will 
be enrolled in the expansion part to achieve total enrollment of approximately 86 subjects.
Subjects with secondary AML, including therapy-related AML, may be included provided 
Inclusion criterion #3 is met and Exclusion criterion #4 is not met.
The investigator or designee must ensure that only subjects who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.

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5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study
2. Age ≥ 18 years at the date of signing the informed consent form (ICF)
3. Newly diagnosed with AML (based on WHO 2016 classification (Arber et al 2016), who 
are not suitable for intensive chemotherapy based on one or more of the following criteria:

age ≥ 75 years

ECOG performance status of 2 or 3

or at least one of the following comorbidities:

severe cardiac comorbidity (including congestive heart failure requiring 
treatment, ejection ≤ 50%, or chronic stable angina)

pulmonary comorbidity (including DLCO ≤ 65% or FEV1 ≤ 65%)

moderate hepatic impairment with total bilirubin > 1.5 to 3 times the upper limit 
of normal

eGFR ≥ 30 mL/min/1.73 m2 to < 45 mL/min/1.73 m2 (estimation based on
Modification of Diet in Renal Disease (MDRD) formula, by local laboratory)

any other comorbidity (to be documented in the CRF) that the physician judges to 
be incompatible with intensive chemotherapy must be reviewed and approved by 
the Novartis Medical Monitor before study enrollment.
Patients with antecedent MDS, myelofibrosis, essential thrombocythemia, or polycythemia 
vera may be included, provided no prior therapy, as specified in exclusion criterion # 1.
4. No planned hematopoietic stem-cell transplantation (HSCT).
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2, or 3
6. AST and ALT ≤ 3 × upper limit of normal (ULN)
7. Total bilirubin ≤ 3.0 × ULN (except in the setting of isolated Gilbert syndrome, in which 
case higher total bilirubin is allowed provided that conjugated bilirubin is ≤ 3.0 x ULN)
8. Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73 m2 (estimation based on 
Modification of Diet in Renal Disease (MDRD) formula, by local laboratory)
9. Subject is able to communicate with the investigator, and has the ability to comply with the 
requirements of the study procedures
10. WBC < 25x109/L (may be reduced with leukopheresis or hyroxyurea)
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study
1. Previous treatment at any time, with any of the following antineoplastic agents, approved 
or investigational; checkpoint inhibitors, venetoclax and hypomethylating agents (HMAs) 
such as decitabine or azacitidine. Previous treatment for AML, MDS, myelofibrosis, 
essential thrombocythemia, or polycythemia vera, with the exception of hydroxyurea, 
growth factors, and supportive care ruxolitinib
2. Prior exposure to TIM-3 directed therapy at any time.

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4. Subjects with AML-M3 / APL (Acute promyelocytic leukemia) with PML-RARA and 
patients with AML secondary to Down's syndrome
5. Subjects with CNS leukemia or neurologic symptoms suggestive of CNS leukemia (unless 
CNS leukemia has been excluded by a lumbar puncture)
6. Subjects with concurrent or prior malignancy, except:
a) subject with history of MDS, myelofibrosis, essential thrombocythemia, or polycythemia 
vera
b) subject with history of adequately treated malignancy for which the subject has been 
disease free (absence of residual disease) for at least 1 year and if no anticancer 
systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or 
required during the course of the study. Patients who are receiving adjuvant therapy 
such as hormonotherapy are eligible
7. History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, 
venetoclax, MBG453) or monoclonal antibodies (mAbs) and/or their excipients
8. Any concurrent severe and/or uncontrolled medical condition e.g., active uncontrolled 
infection or severe infectious disease requiring parenteral antibacterial, antiviral or 
antifungal therapy (such as severe pneumonia, meningitis, or septicemia)
9. Active autoimmune disease requiring systemic therapy (e.g. corticosteroids)
11. Subject has consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of 
study treatment (C1D1).
12. Current use, or use within 14 days prior to enrollment, of systemic steroid therapy or any 
immunosuppressive therapy (≥ 10 mg/day prednisone or equivalent). Topical, inhaled, 
nasal and ophthalmic steroids are not prohibited. Replacement therapy is allowed and not 
considered a form of systemic treatment
13. Live vaccine administered within 30 days prior to the first day of study treatment (C1D1)
14. Cardiac or cardiac repolarization abnormality, including but not limited to any of the 
following:
a) History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft 
(CABG) within 6 months prior to starting study treatment
b) QTcF > 470 ms at screening (based on mean of triplicate ECG), long QT syndrome or 
family history of unexplained cardiac death
c) Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and 
third degree AV block)
15. HIV infection not controlled by standard therapy (as permitted per protocol Section 6.2.1.1) 
and/or with known history of opportunistic infection. For countries where HIV status is 
mandatory: HIV status will be tested during screening using a local test
16. Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Subjects whose disease is 
controlled under antiviral therapy should not be excluded
17. Other co-morbidity that, in the opinion of the investigator, predisposes the subject to high 
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18. Sexually active males unless they use a condom during intercourse while taking azacitidine 
and for 3 months after stopping this drug. They should not father a child in this period. A 
condom is required to be used also by vasectomized men in order to prevent delivery of the 
drug via seminal fluid. In addition, male participants must not donate sperm for the time 
period specified above.
19. Subject is pregnant or breastfeeding
20. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
study treatment and for 30 days after the last dose of venetoclax, 90 days after the last dose 
of azacitidine (or as per their respective local labels, whichever is longer) and 150 days after 
the last dose of MBG453. It is currently unknown whether venetoclax may reduce the 
effectiveness of hormonal contraceptives, and therefore women using hormonal 
contraceptives should add a barrier method. Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the subject.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening/baseline). For female subjects 
on the study the vasectomized male partner should be the sole partner

Use of oral (estrogen and progesterone), injected or implanted combined hormonal 
methods of contraception or placement of an intrauterine device (IUD) or intrauterine 
system (IUS) or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child-bearing potential if they have had 
over 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. 
age appropriate [generally age from 40 to 59 years], history of vasomotor symptoms) in the 
absence of other medical justification or have had surgical bilateral oophorectomy (with or 
without hysterectomy) or bilateral tubal ligation at least 6 weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child-bearing potential.
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the ICF.

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6
Treatment
6.1
Study treatment
In this study, the term “investigational drug” refers to the Novartis study drug, MBG453. The 
term "study treatment” refers to the combination of study drugs: MBG453 plus venetoclax plus 
azacitidine.
All dosages prescribed, dispensed to the subject and all dose changes during the study including 
the reason for any component of the study treatment must be recorded on the appropriate eCRF 
page.
6.1.1
Investigational and control drugs
Table 6-1
Study Treatment
Investigational/ 
Combination Drug
(Name and 
Strength)
Strength 
Pharmaceutical 
dosage form and 
route of 
administration
Supply Type
Sponsor (global 
or local)
MBG453
100 mg in 1ml 
and/or 400 mg in 4 
ml
solution in vial for 
i.v. infusion
Open Label
Sponsor (global)
Venetoclax
100 mg and/or 50 
mg and/or 10 mg 
(or as per local 
supply)
tablet for oral use
Open Label
Sponsor (global) or 
provided locally 
(US)
Azacitidine*
as per local supply
solution for i.v. 
infusion or 
subcutaneous 
administration
Open Label
Provided locally
* Formulation for generic azacitidine as approved by local regulations
MBG453
MBG453 will be administered at a dose of 400 mg Q4W (safety run-in cohort 1) or 800 mg 
Q4W (safety run-in cohort 2 and expansion) via i.v. infusion over 30 minutes on Day 8 of every 
28-day cycle.
If the alternative schedule is selected for azacitidine by the investigator, azacitidine and 
MBG453 will be given on the same day (day 8 of the 28-day cycle). Azacitidine should be 
administered first, followed by MBG453. The first dose of MBG453 should be administered 
after the subject has received at least 5 doses of azacitidine.
Further instructions for the preparation, dispensation, and administration of MBG453 are 
described in the Pharmacy Manual.
Venetoclax
Venetoclax film-coated tablets should be administered at a dose of 400 mg orally or 
corresponding reduced dose for concomitant use with P-gp inhibitors or moderate or strong 
CYP3A4 inhibitors (see Table 6-3 and Venclexta® (Venetoclax) USPI 2018) , once a day, on 

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each day of the 28-day cycle. Subjects should be instructed to swallow the tablets whole (tablets 
should not be crushed or broken), with water, at approximately the same time each day. The 
tablets should be taken with a meal (ideally at breakfast).
In Cycle 1, the dose of venetoclax will be ramped-up over a period of 3 or 4 days (C1D1 - C1D3 
or C1D4) to achieve the dose of 400 mg per day (see Table 6-2), or corresponding reduced dose 
per day for concomitant with P-gp inhibitors or moderate or strong CYP3A4 inhibitors (see 
Table 6-3 and Venclexta® (Venetoclax) USPI 2018). During the ramp-up period, venetoclax 
should be taken in the morning to facilitate laboratory monitoring. See Section 8.4.4 for 
additional considerations during ramp-up and Section 6.5.4.2. For guidance on prophylaxis and 
follow-up for suspected TLS.
Table 6-2
Dosing schedule for ramp-up of venetoclax in Cycle 1
Day
Daily dose of venetoclax
Day 1
100 mg
Day 2
200 mg
Day 3 and beyond
400 mg
If a subject misses doses of venetoclax within 8 hours of the time it is usually taken, the subject 
should take the missed dose as soon as possible on the same day. If the subject misses a dose 
by more than 8 hours, the subject should not take the missed dose and should resume the usual 
dosing schedule at the usual time the following day. In the event that the missed dose occurs 
during the ramp-up period of venetoclax, the subject should resume on the following day at the 
dose that was missed in order not to skip any dose increase of venetoclax during the ramp-up. 
If a patient vomits after taking venetoclax, the dose should not be re-administered and the 
subject should take their next dose at the usual time the following day.
On the days of PK sampling, the subject will be instructed to bring his/her drug supply to the 
site, and take the dose in the clinic, under supervision of the site personnel. The exact time for 
dose administration and breakfast (if applicable) intake must be recorded in the source 
documents and electronic Case Report Form (CRF). On days of coadministration, an interval 
of 30 minutes is recommended between administration of venetoclax and other study treatment. 
Azacitidine
Azacitidine is considered Standard of Care in the population enrolled in this study and it should 
be administered according to standard local clinical practice and local 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. A standard dose 
of azacitidine (75 mg/m2; body surface area (BSA) in m2 = [height (cm) x weight (kg)/3600]0.5) 
will be given subcutaneously or intravenously every day for seven consecutive days on days 1-
7 out of a 28 days cycle (see local azacitidine package insert). In keeping with standard clinical 
practice, the alternative schedules of 75 mg/m2 for five consecutive days on days 1-5, followed 
by a two day break, then two consecutive days on days 8-9, or of 75 mg/m2 for six consecutive 
days on days 1-6, followed by a one day break, then one administration on day 8 will be 
permitted (alternative schedule).

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Azacitidine regimen used in this protocol were selected because they are the most studied 
regimens and recommended by international treatment guidelines (NCCN, ESMO) 
(O'Donnell et al 2017, Fey et al 2013).
NOTE: On days of co-administration of venetoclax, azacitidine and MBG453, venetoclax 
should be administered first followed by azacitidine, and then MBG453. Further instructions 
on co-administration of study treatment are described in the pharmacy manual.
6.1.2
Additional study treatments
Not applicable
6.1.3
Treatment arms/group
6.1.4
Guidelines for continuation of treatment
Per protocol, dose modifications, including dose interruptions, for toxicities are permitted and 
are outlined in Section 6.5.
For patients who achieve a CR and have received at least 18 cycles of study treatment, treatment 
with venetoclax and azacitidine may be discontinued at the discretion of the investigator, and 
the patient continued on study receiving only single agent MBG453.
6.1.5
Treatment duration
A subject may continue study treatment and follow the protocol-defined safety assessments as 
scheduled until:

Disease progression (see Table 8-2)

Relapse from CR, CRi

Unacceptable toxicity

Initiation of a treatment cycle is delayed due to toxicities by more than 42 consecutive 
days (measured from the intended start date of the new cycle (i.e. measured from Day 29 
of the previous cycle) in absence of clinical benefit for the patient per investigator 
assessment.

Subject is scheduled to receive HSCT or intensive chemotherapy at any time during the 
course of the study

Withdrawal of consent

Physician's decision

Pregnancy

Lost to follow-up

Death

Study termination by Novartis
6.1.5.1
Treatment beyond disease progression
Treatment beyond disease progression is not permitted.

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6.2
Other treatment(s)
6.2.1
Concomitant therapy
For 
participants 
enrolled 
all 
medications, 
procedures, 
and 
significant 
non-drug 
therapies/procedures (including physical therapy) taken within 28 days of starting study 
treatment until 150 days after the last dose of MBG453 or 30 days after the last dose of 
venetoclax or azacitidine (whichever was later) or until start of a new antineoplastic therapy 
must be recorded in the appropriate Case Report Forms. Concomitant medication administered 
to treat AE/SAEs suspected to be related to study treatment will continue to be collected up to 
the end of the safety follow-up period.
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 treatment.
Subjects should not receive pre-medication to prevent infusion reaction before the first infusion 
of MBG453. 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 subject will be discontinued from the study treatment (see Section 6.5.3 for 
guidance).
MBG453 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.
Blood transfusions received within 8 weeks before the first dose is administered, during the 
course of the study and until the end of post treatment follow-up, should be recorded in the 
appropriate Case Report Forms (see Table 8-1).
Intrathecal chemotherapy (e.g cytarabine) administered as CNS prophylaxis, at time of 
diagnostic lumbar puncture, is permitted. All other use of chemotherapy is prohibited 
(see Section 6.2.2).
Supportive therapy including prophylactic antibiotic and antifungal treatments, transfusions, 
growth factors (e.g. GCSF, ESA), etc. will be administered at the discretion of the investigators 
according to their local standard of care.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medications and local prescribing information of azacitidine (Vidaza® (Azacitidine) USPI 2008) 
and venetoclax (Venclexta® (Venetoclax) USPI 2018). If in doubt, the investigator should 
contact the Novartis medical monitor before a subject starts treatment or allowing a new 

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medication to be started. If the subject has already started treatment, contact Novartis medical 
monitor to determine if the subject should continue study treatment. 
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Medications to be used with caution during study treatment in this study are listed below. Please 
also refer to Appendix 2 (see Section 16.2) for detailed guidance.
Strong or moderate CYP3A4 inhibitors and P-gp inhibitors: If, such therapy is necessary, 
it can be introduced, under the provision that the dose of venetoclax is reduced. 
Recommendation for venetoclax dose, when given in combination with strong CYP3A 
inhibitors (e.g., posaconazole, ketoconazole, conivaptan, clarithromycin, indinavir, 
itraconazole, lopinavir, ritonavir, telaprevir, and voriconazole), moderate CYP3A inhibitors 
(e.g., erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, and verapamil) or P-gp 
inhibitors (e.g., amiodarone, azithromycin, captopril, carvedilol, felodipine, quercetin, 
quinidine, ranolazine, and ticagrelor) are provided in Table 6-3 below.
Table 6-3
Management of potential interactions of CYP3A and P-gp inhibitors 
with venetoclax
Co-administered Drug
Ramp-Up Phase
Steady Daily Dose (After Ramp-
Up Phase)
Posaconazole
Day 1 - 10 mg
Day 2 - 20 mg
Day 3 - 50 mg
Day 4 - 70 mg
Reduce venetoclax dose to 70 mg
Other strong CYP3A inhibitor
Day 1 - 10 mg
Day 2 - 20 mg
Day 3 - 50 mg
Day 4 - 100 mg
Reduce venetoclax dose to 100 
mg
Moderate CYP3A inhibitor or P-gp 
inhibitor
Day 1 - 50 mg
Day 2 - 100 mg
Day 3 - 200 mg
Reduce venetoclax dose to 200 
mg (at least 50% reduction)
The venetoclax dosage that was used prior to concomitant use with a strong or moderate CYP3A 
inhibitor or a P-gp inhibitor should be resumed 2 to 3 days after discontinuation of the inhibitor. 
Subjects should be instructed to avoid grapefruit products, Seville oranges, and starfruit during 
treatment with venetoclax as they contain inhibitors of CYP3A4.
Strong or Moderate CYP3A4 inducers: Concomitant use of venetoclax with strong CYP3A 
inducers (e.g., carbamazepine, phenytoin, rifampin, St.John's wort) or moderate CYP3A 
inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided. 
Alternative treatments with less CYP3A induction should be considered.
P-gp or BCRP substrates: Co-administration of narrow therapeutic index P-gp, or BCRP 
substrates (e.g., digoxin, sirolimus) with venetoclax should be avoided.
If a narrow therapeutic index P-gp or BCRP substrate must be used, it should be used with 
caution. For an orally administered P-gp or BCRP substrate sensitive to inhibition in the 
gastrointestinal tract (e.g., dabigatran exetilate), its administration should be separated from 
venetoclax administration as much as possible to minimise a potential interaction.

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Anticoagulation therapy is permitted if the subjects are already at stable dose of warfarin or 
stable doses of low molecular weight heparin (LMWH) for ˃ 2 weeks at time of first dose and 
International Normalized Ratio (INR) should be monitored closely. Subjects who develop a 
new requirement for anticoagulant therapy during the conduct of the study may remain on study 
after documented discussion with the Novartis medical monitor. However, ongoing 
anticoagulant therapy should be temporarily discontinued to allow bone marrow sampling 
according to the institutional guidelines.
Anti-hypertensive therapy is allowed as concomitant medications; however because transient 
hypotension has occurred during infusions of monoclonal antibodies, consideration should be 
given to withholding anti-hypertensive medications for 12 hours prior to infusion with MBG453.
6.2.2
Prohibited medication
During the course of the study, subjects must not receive additional investigational drugs, 
devices, chemotherapy (with the exception of prophylactic intrathecal chemotherapy 
(see Section 6.2.1)), 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 treatment 
unless given for the management of immune toxicity.
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed except 
for the treatment of infusion reaction, immune related adverse events (irAEs), for prophylaxis 
against imaging contrast dye allergy or replacement-dose steroids in the setting of adrenal 
insufficiency (providing this is ≤ 10 mg/day prednisone or equivalent) or transient exacerbation 
of other underlying diseases such as chronic obstructive pulmonary disease requiring treatment 
for ≤ 3 weeks. Systemic corticosteroids required for control of infusion reactions or irAEs must 
be tapered and be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) 
before the next study administration. If more than 10 mg/day prednisone is used, study treatment 
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 and 150 
days after the last dose of MBG453. Inactivated vaccines, subunits recombinant, polysaccharide 
and conjugate vaccines and toxoid vaccines are allowed. 
Vaccination against COVID-19, unless these are live vaccines, is allowed during the study but 
should not be administered on the same day of study treatment administration as recommended 
by the ASCO guidelines (Schneider et al 2021). 
In addition, prohibited medication related to azacitidine will apply according to local label.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.) that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject, 
unless the subject is re-screened. The Subject No. consists of the Center Number (Center No.) 

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(as assigned by Novartis to the investigative site) with a sequential subject number suffixed to 
it, so that each subject is numbered uniquely across the entire database. Upon signing the 
informed consent form, the site will use the electronic data capture system to assign the subject 
the next sequential Subject No.
The investigator or designated staff will contact the Interactive Response Technology (IRT) and 
provide the requested identifying information to register the subject. Once assigned, the Subject 
No. must not be reused for any other subject and the Subject No. for that individual must not 
be changed, unless the subject is re-screened. If the subject fails to start treatment for any reason, 
the reason will be entered into the appropriate eCRF page and IRT should be notified as soon 
as possible. Re-screening is allowed once for subjects that were 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 Subject No. should be assigned for all re-screened subjects.
6.3.2
Treatment assignment, randomization
This study is open label and non-randomized.
Prior to dosing at Cycle 1 Day 1, subjects who fulfill all the inclusion/exclusion criteria will be 
enrolled via IRT and a treatment number will be provided for the study treatment MBG453 and
(for all countries except the US) for study treatment venetoclax. Study treatment azacitidine 
will be sourced locally.
The Investigator (or delegate) will call or log on to the IRT and confirm that the patient fulfills 
all the inclusion/exclusion criteria by completing the eligibility criteria checklist embedded in 
the system. The IRT will assign a unique medication number for the first package of study 
treatments to be dispensed to the subject.
6.4
Treatment blinding
The study is open-label with no blinding.
6.5
Dose escalation and dose modification
Two dose levels of MBG453, 400 mg Q4W and 800 mg Q4W will be evaluated. Intra-subject 
dose escalation is not permitted. Guidance for dose modifications is provided in Section 6.5.1.
6.5.1
Guidelines for assessing the risk of overdosing for the regimen in the 
safety run-in
6.5.1.1
MBG453 dose level and regimen
MBG453 will be given at 400 mg every 4 weeks in the first approximately 6 enrolled subjects 
(3 to 6 evaluable subjects) (1st cohort of the safety run-in). If this dose level is considered safe, 
MBG453 will be given at 800 mg every 4 weeks in the next approximately 12 subjects (at least 
9 evaluable patients) (2nd cohort of the safety run-in).
In case the combination meets overdose criteria at whatever MBG453 dose tested in the safety 
run-in, the expansion phase will not be opened.

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6.5.1.2
Guidelines for assessing tolerability
For the purpose of assessing the risk of overdosing (as defined by EWOC criterion, see details 
below) of MBG453 in combination with azacitidine and venetoclax, at each MBG453 dose 
level, after the required number of evaluable subjects, 3 to 6 subjects for cohort 1 and at least 9 
subjects for cohort 2, have been included, and observed for at least 2 cycles, a safety review 
meeting will be conducted.Subject will be considered evaluable for DLT if:

Subject has received 2 infusions of MBG453 at the assigned dose level in Q4W dosing 
regimen, and has taken at least 75 % of the planned dose of azacitidine and venetoclax (i.e. 
for 2 cycles: 11 doses of azacitidine out of the 14 doses planned and 42 doses of venetoclax 
out of the 56 doses planned with a successful ramp-up to full dose), and subject has had 
safety assessments for a minimum period of 2 cycles (from Cycle 1 Day 1 to the end of 
Cycle 2). Patients receiving a reduced dose of venetoclax due to co-administration of strong 
or moderate CYP3A4 inhibitors or P-gp inhibitors as described in Table 6-3, will be 
considered to have received the planned dose.
or

Subject has experienced a DLT within the DLT observation period from first dose of 
MBG453 to the end of Cycle 2. Note that subjects who experience toxicity that meets the 
criteria for DLT but occurs prior to the first dose of MBG453 will be considered not 
evaluable.
At the Safety Review Meetings, Investigators and Novartis study personnel will review all 
relevant data available from the ongoing study including safety information, DLTs, time of 
occurrence of DLT, supported by all CTCAE v5.0 ≥ Grade 2 toxicity data during the first 2 
cycles of the study treatment, and pharmacokinetic data from evaluable patients.
The decision will be guided by a simple Bayesian model with EWOC principle evaluating the 
probability of DLT. For each cohort of the safety run-in, the probability of excessive toxicity 
(i.e. DLT rate ≥ 33%) will be assessed after the required number of evaluable subjects have 
been treated and observed for 8 weeks (up to end of Cycle 2). If the EWOC criteria is satisfied 
(probability of excessive toxicity is lower than 25%), the Bayesian model will recommend to 
start enrollment to either cohort 2 or the expansion phase.
At the safety review meetings, the available toxicity information (including adverse events and 
laboratory abnormalities that are not DLTs), the time (days from start of therapy) of occurrence 
of DLT, the recommendations from the Bayesian analysis, and the available PK and 
pharmacodynamic information will all be evaluated by the Investigators and Novartis study 
personnel. Once the results of the safety review meeting are available, the investigator will 
receive written confirmation from Novartis indicating that the results of the safety run-in part 
were evaluated and that it is permissible to start enrollment to either cohort 2 or the expansion 
phase.
6.5.2
Definitions of dose limiting toxicities (DLTs)
Dose-limiting toxicities will be collected and evaluated in subjects enrolled to the safety run-in 
part. A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
considered by the Investigator to be at least possibly related to MBG453 as a single contributor 
or in combination with other component(s) of study treatment that occurs during the 

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DLT observation period and meets any of the criteria included in Table 6-4. The DLT 
observation period is Cycle 1 Day 8 (starting from the first infusion of MBG453) to the end of 
Cycle 2. The National Cancer Institute Common Terminology Criteria for Adverse events (NCI 
CTCAE) version 5.0 will be used for all grading.
If a patient experiences a DLT (during the DLT observation period) then study treatment must 
be interrupted and may be permanently discontinued depending on the severity of the DLT, if 
the DLT resolves to CTCAE Grade 1 or baseline value, the patient may continue to receive 
study treatment following consultation with the Novartis medical monitor.
The investigator must notify the sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities.
Table 6-4
Criteria for defining dose-limiting toxicities during the safety run-in
Toxicity
DLT Criteria
Hematology
Because marrow aplasia is an expected consequence 
of AML and their therapy, for patients participating in 
this study, only persistent grade 4 neutropenia, 
thrombocytopenia and pancytopenia beyond Day 42 
from the start of a study treatment cycle and is not 
related to leukemic infiltration will be considered to be 
a DLT (bone marrow evaluation may be required to 
determine if marrow aplasia is due to leukemia).
Vascular disorders
Hypertension CTCAE Grade 3 persisting for > 7 days 
after treatment is administered.
General disorders and administration site conditions
Infusion reaction CTCAE Grade 3 that does not resolve 
to Grade 1 within 72 hours or CTCAE Grade 4 of any 
duration.
Immune
Immune-related adverse events ≥ CTCAE Grade 3 
persisting > 7 days after starting appropriate treatment* 
(e.g. with corticosteroids)
Ocular
Eye pain or reduction of visual acuity ≥CTCAE Grade 
2 that does not respond to topical therapy and does not 
improve to Grade 1 severity within 2 weeks of the 
initiation of typical therapy OR requires systemic 
treatment
Pulmonary
Pneumonitis ≥CTCAE Grade 2 persisting > 7 days 
despite treatment with corticosteroids
Pneumonitis ≥CTCAE Grade 3
Skin and subcutaneous tissue disorders
Photosensitivity ≥ CTCAE Grade 3 for > 7 days after 
treatment
Rash ≥ CTCAE Grade 3 for > 7 days after treatment
Rash CTCAE Grade 4
Gastrointestinal disorders
Diarrhea CTCAE Grade ≥ 3 ≥ 48 hrs., despite the use 
of anti-diarrhea therapy
Nausea/ vomiting CTCAE Grade ≥ 3 ≥ 48 hrs., despite 
the use of anti-emetic therapy
Pancreatitis CTCAE Grade ≥ 3
Investigations: Liver
Total blood bilirubin increase ≥ CTCAE Grade 2 with ≥ 
CTCAE Grade 2 ALT and/or AST 
Other
Other clinically significant toxicities, including a single 
event or multiple occurrences of the same event that 

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Toxicity
DLT Criteria
lead to a dosing delay of > 7 days in cycle 1, or result 
in an inability to deliver ≥ 75% of the planned dose 
intensity for any of the study drugs in a cycle of 
treatment because of treatment-related toxicity.
Any other unacceptable toxicity encountered by a 
subject as determined by the Investigators and 
Novartis.
Exceptions to DLT Criteria

Grade 3 fatigue, asthenia, fever, anorexia, or constipation

Grade 3 nausea, vomiting or diarrhea not requiring tube feeding, total parenteral nutrition, or prolonged 
hospitalization

Infection, bleeding, or other expected direct complication of cytopenias due to active underlying leukemia

Grade 3 or 4 tumor lysis syndrome if it is successfully managed clinically and resolves within 7 days without 
end-organ damage

Grade 3 or 4 isolated laboratory abnormalities that last ≤3 days
* Unless otherwise specified for organ-specific immune-related DLTs
Note:

CTCAE version 5.0 will be used for all grading.

Optimal therapy for vomiting, constipation, or diarrhea will be based upon institutional guidelines, avoiding 
the prohibited medications listed in this protocol.
6.5.3
Dose modifications
For subjects who do not tolerate the protocol-specified dosing schedule, dose interruptions (for 
MBG453, azacitidine and venetoclax), and/or dose reductions (azacitidine and venetoclax only) 
are either recommended or mandated in order to allow subjects to continue the study treatment.
Guidelines for permanent treatment discontinuation is mandatory for specific events indicated 
as such in Table 6-5 and Table 6-6.
Dose interruption at the start of a new treatment cycle
In subjects who have achieved CR, CRi or MLFS and have Grade 4 neutropenia and/or Grade 
4 thrombocytopenia lasting at least 7 days dosing of both venetoclax and azacitidine should be 
interrupted until resolution to ≤ Grade 2 or to a clinically significant threshold per investigator 
assessment (NCCN 2021). In case of a prolonged cytopenia, close blood monitoring is required, 
and the investigator should consider repeating bone marrow examination to determine if 
morphologic remission (CR, CRi, MLFS) is ongoing. Administer growth factors if indicated 
(NCCN 2021). MBG453 should not be administered during the dose interruption. After 
resolution, dosing of both azacitidine and venetoclax should be resumed on the same day with 
dose modification for venetoclax as specified in Table 6-6. The first day dosing is resumed will 
be considered as D1 of the new treatment cycle and MBG453 will be administered on Day 8 of 
the new cycle. In cases in which venetoclax and azacitidine have been permanently discontinued 
and the patient remains on MBG453, then in subjects who have achieved CR, CRi or MLFS 
and have Grade 4 neuttropenia and/or Grade 4 thrombocytopenia dosing of MBG453 should be 
interrupted until resolution to ≤ Grade 2. The first day dosing with MBG453 is resumed will be 
considered D8 of the new cycle.

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Dose modifications for MBG453
Dose modifications for MBG453 will be done according to ASCO guidelines about 
management of immune-related AEs (Schneider et al 2021).
Additionally, the guidance indicated in Table 6-5 below, provides instructions for infusion 
reaction, immune-related adverse events not covered by ASCO guidelines and a general 
guideline for non-hematologic non-immune-related toxicities that are clinically significant per 
investigator judgement and possibly attributable to the investigational drug. This general 
guideline will not apply in case of non-hematologic non-immune-related toxicities that are 
attributable to azacitidine, venetoclax and AML and its complications.
Deviations to dose interruptions, reductions and/or permanent discontinuations outlined in 
Table 6-5 are not allowed.
Administration of MBG453 may be delayed due to toxicities. A scheduled dose may be delayed 
within a cycle by up to 14 days. If a dose cannot be administered within the planned window 
within the cycle, then the dose should be skipped. Next scheduled dosing may resume once the 
adverse event has resolved to ≤ Grade 1 or baseline per the next planned treatment cycle. Dose 
reductions for MBG453 are not allowed.
Overall, for adverse events of potential immune-related etiology (irAE) that do not recover to 
≤ Grade 1 or baseline at a dose of immunosuppression of ≤ 10 mg/day prednisone or equivalent 
(or as indicated in Table 6-5) within 12 weeks after initiation of immunosuppressive therapy, 
MBG453 must be permanently discontinued.
Table 6-5
Criteria for dose interruption and re-initiation of study drug MBG453 
for adverse drug reactions
Worst Toxicity Grade (CTCAE v5.0)
Recommended Dose Modifications
Infusion Reaction
Grade 1
Decrease infusion rate until recovery
Grade 2
Stop infusion
Before restarting - pre-medicate according to local 
institutional guidelines.
Restart infusion at 50% of previous rate under 
continuous observation. Ensure that there is a 
minimum observation period of 1 hour prior to 
restarting the infusion(s).If the AE recurs at the 
reinitiated slow rate of infusion, and despite oral pre-
medication*, then discontinue MBG453
Grade 3
Stop infusion
If the AE resolves to ≤ Grade 1 within 72hrs:
At next scheduled treatment visit, pre-medicate 
according to local institutional guidelines.
Restart infusion at 50% of previous rate under 
continuous observation. Ensure that there is a 
minimum observation period of 1 hour.
If the AE recurs despite slow rate of infusion and 
pre-medication*, then discontinue MBG453
If the AE does not resolve to ≤Grade 1 within 72hrs:

Discontinue MBG453

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Worst Toxicity Grade (CTCAE v5.0)
Recommended Dose Modifications
Grade 4
Discontinue MBG453
For adverse events thought to be immune-related AEs and not covered in the ASCO Guidelines for the 
management of immune-related adverse events in subjects treated with immune checkpoint inhibitor 
therapy ( Schneider et al 2021)
Grade 1
Continue treatment with MBG453
Grade 2 or Grade 3 ≤ 7 days
Delay treatment with MBG453 until resolved to ≤ 
Grade 1 or baseline
Grade 3 lasting > 7 days but < 21 days
1st and 2nd occurrence
Delay study treatment until resolved to ≤ Grade 1 or 
baseline
3rd occurrence:
Discontinue study treatment
Grade 3 lasting ≥ 21 days Or Grade 4
Discontinue study treatment
Dermatological toxicities
Grade 1
Maintain MBG453. Use topical steroids,
antihistamines, topical emollients.
Grade 2
Consider interrupting MBG453.
Use topical or oral steroids, antihistamines.
If MBG453 is interrupted and resolution to
≤ Grade 1, restart MBG453.
Grade 3 or 4
Interrupt MBG453.
Manage per institutional practice.
After resolution to ≤ Grade 1, consider restarting
MBG453.
Bullous dermatitis
Grade 1, 2 and 3: Interrupt MBG453. Consult with
dermatologist for appropriateness to restart
MBG453.
Grade 4: Permanently discontinue MBG453.
Stevens-Johnson syndrome (SJS), or Lyell
syndrome/toxic epidermal necrolysis (TEN)
Permanently discontinue MBG453.
For non-hematological, non immune related toxicities clinically significant** and possible attributable 
to the investigational drug (NCI CTCAE v5.0)
(The guideline does not apply to for toxicities attributable to azacitidine or venetoclax or the underlying 
AML including its complications)
Grade 1 and Grade 2 tolerable
Continue treatment with MBG453
Grade 2 intolerable (includes all Grade 2 events 
defined as DLT in Table 6-4) and Grade 3
1st or 2nd occurrence:
Interrupt MBG453 until toxicity recovers to ≤ Grade 
1 or baseline

Once recovered to ≤ Grade 1 or baseline 
restart MBG453 at the same dose level and 
schedule
AE resolution to ≤ Grade 1 or baseline must occur 
within a maximum period of 56 days since 
interruption, otherwise MBG453 must be permanently 
discontinued.
3rd occurrence:

Permanently discontinue MBG453
Grade 4
Discontinue MBG453

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Worst Toxicity Grade (CTCAE v5.0)
Recommended Dose Modifications
All dose modifications should be based on the available information and worst preceding toxicity
*Prophylaxis regimens will include both paracetamol/acetaminophen and an antihistamine.
**Per investigator judgement
Dose modifications for azacitidine
If azacitidine treatment is deemed by the investigator to possibly have contributed to an 
observed adverse event, the dose or schedule of azacitidine treatment may be modified within 
a cycle and/or for subsequent cycles or temporary/permanent interruptions of azacitidine 
treatment may be decided by the investigator according to local practice and/or the country-
specific label guiding azacitidine use.
Dose modifications for venetoclax
If venetoclax treatment is deemed by the investigator to possibly have contributed to an 
observed adverse event, the dose or duration of venetoclax treatment may be modified 
according to the following guidelines:
Table 6-6
Dose modifications for venetoclax
Event
Occurrence
Action
Grade 4 neutropenia with or 
without fever or infection; or Grade 
4 thrombocytopenia
Occurrence prior to achieving 
remission (CR, CRi, MLFS)
Transfuse blood products, 
administer prophylactic and 
treatment anti-infectives as 
clinically indicated.
First occurrence after achieving 
remission (CR, CRi, MLFS) and 
lasting at least 7 days
Delay subsequent treatment and 
monitor blood counts.
Administer granulocyte-colony 
stimulating factor (G-CSF) if 
clinically indicated for neutropenia.
Once the toxicity has resolved to 
Grade 1 or 2, resume venetoclax 
therapy at the same dose
Subsequent occurrences in next
treatment cycles after achieving 
remission (CR, CRi, MLFS) and 
lasting at least 7 days
Delay subsequent treatment and 
monitor blood counts.
Administer G-CSF if clinically 
indicated for neutropenia.
Once the toxicity has resolved to 
Grade 1 or 2, resume venetoclax 
therapy at the same dose with a 
duration reduced by 7 days for 
each subsequent treatment cycle
Blood chemistry changes 
suggestive of TLS
-
Withhold treatment.
If the event is resolved within 48 
hours of last dose, treatment with 
venetoclax can be resumed at the 
same dose.

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Event
Occurrence
Action
Events of clinical TLS or blood 
chemistry changes requiring more 
than 48 hours to resolve
-
Withhold treatment.
Treatment should be resumed at a 
reduced dose (per the investigator 
discretion). When resuming 
treatment after interruption due to 
TLS, the instructions for prevention 
of TLS should be followed.
Grade 3 or 4 non-hematologic 
toxicities
First occurrence
Withhold treatment.
Once the toxicity has resolved to 
Grade 1 or baseline level, 
venetoclax therapy may be 
resumed at the same dose.
Subsequent occurrences
Withhold treatment.
Treatment should be resumed at a 
reduced dose (per the investigator 
discretion).
Permanent discontinuation of study treatment
If the study treatment (i.e. MBG453 + azacitidine + venetoclax) is interrupted for toxicities and 
the start of the subsequent study treatment cycle is delayed for more than 42 consecutive days 
(measured from the intended start date of the new cycle (Day 29 of the previous cycle) in 
absence of clinical benefit for the patient per investigator assessment, the subject should be 
discontinued from study treatment. 
At any time during the study, patients unable to tolerate one or two of the study treatment drugs 
may continue study treatment with only the tolerated drug(s) provided the subject benefits per 
investigator's judgement.
These dose changes must be recorded on the appropriate CRF.
6.5.4
Follow-up for toxicities
Subjects whose treatment is interrupted or permanently discontinued due to an AE or clinically 
significant laboratory value, must be followed-up at least once a week (or more frequently if 
required by institutional practices, or if clinically indicated) for 4 weeks, and subsequently at 
approximately 4-week intervals, until resolution or stabilization of the event, whichever comes 
first. Appropriate clinical experts should be consulted as deemed necessary.
All subjects must be followed up for AEs (including irAEs and SAEs) for 30 days following 
the last dose of venetoclax or azacitidine (whichever was later) and 150 days following the last 
dose of MBG453, whichever is later.
6.5.4.1
Follow-up for immune-related AEs
The emergence of Immune-Related AE (irAE) may be anticipated based on general experience 
in clinical studies with similar class of compounds that block the negative immune regulators.
An irAE is any clinically significant AE affecting any organ that is associated with study drug 
exposure, is consistent with an immune-mediated mechanism, and where alternative 
explanations have been investigated and ruled out or are considered to be unlikely. Serologic, 

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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 (Schneider et al 2021). See guidance in Table 6-5 for immune-related AEs not 
covered by ASCO guidelines.
In case of a suspected irAE, the relevant immunological assessments (e.g. rheumatoid factor, 
anti-DNA Ab, etc.) should be performed. In case of a toxicity suspected to be a cytokine release 
syndrome, the cytokine assessments outlined in Table 8-1 must be performed.
Subjects should be monitored carefully for any skin toxicity or mucositis and study treatment 
should be discontinued for any suspected case of SJS/TEN.
6.5.4.2
Follow-up for Tumor Lysis Syndrome (TLS)
Tumor lysis syndrome (TLS) is a clinical entity 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 (Cairo and Bishop 2004, Coiffier et al 2008).
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, all subjects should receive allopurinol, or an alternative prophylaxis 
with anti-hyperuricemic agents, as well as adequate hydration (including instructing patients to 
drink 1.5 to 2.0 L of water daily, among other measures as clinically indicated), prior to study 
treatment. Events should be managed according to local guidelines. Also see Section 8.4.4 for 
considerations during the venetoclax ramp-up.
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

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Based on laboratory and clinical TLS criteria (modified from Cairo and Bishop 2004), the 
following measures for TLS should be also followed:
Laboratory tumor lysis syndrome

Defined as two or more of the following values within three days before or in the days 
following initiation of a treatment cycle:

Uric acid ≥ 8 mg/dL or 25% increase from baseline

Potassium ≥6 mEq/L or 25% increase from baseline

Phosphorus ≥ 6.5 mg/dL (children) or ≥ 4.5 mg/dL (adults) or 25% increase from 
baseline

Calcium ≤ 7 mg/dL or 25% decrease from baseline

Regimen:

If none or one of the laboratory values above is abnormal, continue to manage with 
allopurinol or a non-allopurinol alternative (e.g., febuxostat) and oral fluids. If uric 
acid remains elevated, consider i.v. fluids, treatment with rasburicase, and hospital 
monitoring.

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 investigator's discretion.
6.5.4.3
Follow up on potential drug-induced liver injury (DILI) cases
Guidelines for follow-up on potential DILI cases are described in Table 6-7 and Table 6-8.
Table 6-7
Follow-up of abnormal liver chemistry results
ALT
TBL
Liver Symptoms
Action
ALT increase without bilirubin increase:
If normal at baseline:
ALT > 3 x ULN
Normal
None

No change to study 
treatment
If elevated at baseline:

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ALT
TBL
Liver Symptoms
Action
ALT > 2 x baseline or > 
200 U/L (whichever 
occurs first)
For patients with Gilbert’s 
syndrome: No change in 
baseline TBL

Measure ALT, AST, 
ALP, GGT, TBIL, INR, 
albumin, CK, and 
GLDH in 48-72 hours.

Follow-up for 
symptoms
If normal at baseline:
ALT > 5 x ULN for more 
than two weeks
Normal
For patients with Gilbert’s 
syndrome: No change in 
baseline TBL
None

Interrupt study drug

Measure ALT, AST, 
ALP, GGT, TBIL, INR, 
albumin, CK, and 
GLDH in 48-72 hours.

Follow-up for 
symptoms.

Initiate close 
monitoring and 
workup for competing 
etiologies.

Study drug can be 
restarted only if 
another etiology is 
identified and liver 
enzymes return to 
baseline.
If elevated at baseline:
ALT > 3 x baseline or > 
300 U/L (whichever 
occurs first) for more than 
two weeks
If normal at baseline:
ALT > 8 x ULN
Normal
None
ALT increase with bilirubin increase:
If normal at baseline:
ALT > 3 x ULN
TBL > 2 x ULN (or INR > 
1.5)
For patients with Gilbert’s 
syndrome: Doubling of 
direct bilirubin
None
If elevated at baseline:
ALT > 2 x baseline or > 
200 U/L (whichever 
occurs first)
If normal at baseline:
ALT > 3 x ULN
Normal or elevated
Severe fatigue, nausea, 
vomiting, right upper 
quadrant pain
If elevated at baseline:
ALT > 2 x baseline or > 
200 U/L (whichever 
occurs first)

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Table 6-8
Action required for isolated total bilirubin elevation
Abnormality
Action required
Any elevation > ULN
Fractionate bilirubin, evaluate for cholestatic liver 
injury (ALP) or alternative causes of bilirubin 
elevation. Treat alternative causes according to local 
institutional guidelines
Grade 2 (>1.5 - 3.0 ULN)
Maintain treatment. Repeat LFTs within 48-72 hours, 
then monitor LFTs weekly until resolution to ≤ Grade 1 
or to baseline
Grade 3 (>3.0 – 10 ULN)
Interrupt treatment. Repeat LFTs within 48-72 hours,
then monitor LFTs weekly until resolution to ≤ Grade 1 
or to baseline
Grade 4 (> 10 x ULN)
Discontinue study treatment
If abnormalities are confirmed, close observation and follow-up are required:
1. A detailed history, including relevant information, such as cardiac disease, history of any 
pre-existing liver conditions or risk factors, blood transfusions, i.v. drug abuse, travel, 
work, alcohol intake, and full clinical examination for evidence of acute or chronic liver 
disease, cardiac disease and infection etc. should be performed.
2. Review of concomitant medications, including nonprescription medications and herbal 
and dietary supplement preparations, alcohol use, recreational drug use, special diets, and 
chemicals exposed to within one month of the onset of the liver injury.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted.
4. Obtain an unscheduled PK sample, as close as possible to last dose of study treatment.
Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), autoimmune 
hepatitis or liver biopsy may be considered as clinically indicated or after consultation with 
specialist/hepatologist.
6.5.4.4
Follow-up for QTcF Prolongation
In case of QTcF >480 ms (or QTcF prolongation >60 ms from baseline):

Assess the quality of the ECG recording. Collect two additional ECGs as soon as possible 
and submit the triplicate for central review.

Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities.

Review concomitant medication use for possible causes for QT prolongation (refer to 
crediblemedicines.org). Record all concomitant medications in the appropriate eCRF 
page.

Monitor ECG per the institutional standards.

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6.6
Additional treatment guidance
6.6.1
Treatment compliance
Every time study treatment MBG453 is to be administered, IRT must be contacted to assign a 
medication (kit) number and (where applicable) for registration of the other study drugs 
dispensed to the subjects.
For study treatment taken at home (e.g. for tablets of venetoclax), the investigator must promote 
compliance by instructing the subject to take the study treatment exactly as prescribed and by 
stating that compliance is necessary for the subject’s safety and the validity of the study. The 
subject must also be instructed to contact the investigator if he/she is unable for any reason to 
take the study treatment as prescribed. Compliance will be assessed by the investigator and/or 
study personnel at each visit using pill counts and information provided by the subject. This 
information should be captured in the source document at each visit.
The date and time of all study treatment administrations (MBG453, venetoclax, and azacitidine) 
during the study and any deviations from the protocol treatment schedule will be captured by 
the investigator staff on the appropriate study treatment dispensing form. Compliance with the 
study treatment and any protocol deviations will be assessed by the field monitor on an ongoing 
basis. All study treatment dispensed and returned (if applicable) must be recorded in the Drug 
Accountability Log.
Pharmacokinetic parameters (measures of MBG453 and venetoclax) will be determined in all 
subjects treated with MBG453, as detailed in the pharmacokinetic section (Section 8.5.2).
Remote azacitidine administration compliance will be assessed by the off-site healthcare 
professional where permitted, and information provided to the Investigator and/or study 
personnel.
6.6.2
Emergency breaking of assigned treatment code
Not applicable.
6.7
Preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study treatment as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only.
All dosages for study treatment (MBG453, azacitidine and venetoclax) prescribed to the patient 
and all dose changes during the study must be recorded on the Dosage Administration Record 
eCRF.
MBG453
Each study site will be supplied by Novartis with the investigational drug MBG453 as global 
clinical open supply and will be packed and labelled under the responsibility of Novartis.
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 

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plus tear-off label), immediately before dispensing the medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document.
MBG453 will be administered i.v. Further instructions for the preparation and dispensation of 
MBG453 are described in the Pharmacy Manual.
Azacitidine
Azacitidine may be administered i.v or subcutaneously. For details on preparation refer to the 
country-specific label instructions and/or azacitidine package insert.
As per Section 4.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
azacitidine administration by a home nurse at a subject's home may be permitted (if allowed by 
Local or Regional Health Authorities and Ethics Committees as appropriate) in the event the 
Investigator has decided that an on-site visit by the subject is no longer appropriate or possible, 
and that it is in the interest of the subject's health to administer the study treatment even without 
performing an on-site visit.
Venetoclax
Patients will be provided with adequate supply of venetoclax (tablets for oral administration) 
for on site administration, if applicable, or for self-administration at home, including 
instructions for administration, until at least their next scheduled study visit. Supply of 
venetoclax will either be global supply (supplied by Novartis and dispensed via IRT) or local 
supply depended on the country.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
the respective Novartis CO Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.

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At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
The study drug supply can be destroyed at the local Novartis facility or third party, as 
appropriate, or locally at site only if permitted by local regulations and authorized by Novartis.
6.7.1.2
Handling of additional treatment
Not Applicable
6.7.2
Instruction for prescribing and taking study treatment
Refer to Section 6.1.1
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her 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.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and 21 CFR 50, privacy, data protection, local 
regulatory requirements and is considered appropriate for this study. Any changes to the 
proposed consent form suggested by the investigator must be agreed by Novartis before 
submission to the IRB/IEC. Information about common side effects already known about the 
investigational drug can be found in the Investigator's Brochure (IB). This information will be 
included in the 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.
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 for the duration 
of the study. If there is any question that the patient will not reliably comply, they should not 
be entered in the study.

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Male participants, including vasectomized men, in the study, must agree not to father a child 
and to use a condom during intercourse, to prevent delivery of the drug via seminal fluid during 
the study, and for the period of 3 months after the last dose of azacitidine.
Prior to starting treatment, male subjects are advised to seek consultation on sperm storage and 
female subjects of child-bearing potential should seek consultation regarding oocyte 
cryopreservation.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
Subjects will be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience (Trial Feedback Questionnaire (TFQ) see Section 8.5.1.2) per the 
schedule indicated in Table 8-1.
As per Section 4.7 during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that 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.
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.).
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.
Each treatment cycle is 28 days. Screening evaluations should be performed within ≤ 28 days 
of Cycle 1 Day 1 (except for the pregnancy test which has to be performed within 72 hours 
before the first dose).
During the course of the study visits, test and/or procedures should occur on schedule whenever 
possible. A visit window of +/- 3 days is allowed for study procedures (including treatment 
administration). If MBG453 administration on Day 8 is delayed within a cycle due to toxicities, 
visit assessments for Day 8 should be shifted accordingly or occur on Day 22, in case of no 
administration. See Section 6.1 for details on study treatment. A window of +/- 8 days from the 
planned visit date is allowed for BMA procedures. Further, a maximum of 8 days is allowed 
between BMA efficacy, extramedullary disease assessment (if applicable) and hematology 
assessments of the same visit.
Note: If a treatment cycle is delayed at any time during the study, all study visits and safety and 
efficacy assessments should continue according to the appropriate number of calendar days 
measured from Day 1 of the previous cycle, or more often if clinically indicated. When 
treatment is resumed, the first day of azacitidine and venetoclax administration will be 
considered as D1 of the new treatment cycle and visit schedule will be shifted accordingly.
On PK collection days the windows are provided in Section 8.5.2. Subjects who discontinue the 
study treatment for any reason should be scheduled for an end of treatment (EOT) visit within 

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14 days from the decision to permanently discontinue study treatment, at which time all of the 
assessments listed for the EOT visit will be performed.
Patient Reported Outcomes must be completed before any clinical assessments are performed 
at any given visit.
For post-treatment follow-up and survival information, please refer to Section 8.3.1, Section 9.1.
As per Section 4.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowable by a local Health Authority, national and local regulations
and depending on operational capabilities, phone calls, virtual contacts (e.g. tele consult) or 
visits by site staff/ off-site healthcare professional(s) staff to the subject´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. If the Investigator delegates tasks to an off-site healthcare professional, the 
Investigator must ensure the individual(s) is/are qualified and appropriately trained to perform 
assigned duties. The Investigator must oversee their conduct and remain responsible for the 
evaluation of the data collected. 

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8.1
Screening
All subjects must provide signed ICFs prior to performing any study specific procedures. 
Screening assessments to confirm eligibility should be performed as per the schedule of 
assessments detailed in Table 8-1. Subjects will be evaluated against all study inclusion and 
exclusion criteria and safety assessments which must be completed within 28 days prior to the 
start of study treatment (C1D1), with the exception of the local serum pregnancy test (for 
women of child-bearing potential) which must be conducted and confirmed as negative within 
72 hrs prior to the start of study treatment. Laboratory parameters may be retested within the 
28-day screening period. If the repeat value remains outside of the specified ranges, the subject
will be considered a screen failure.
An individual subject may only be re-screened once for the study. A new ICF will need to be 
signed if the investigator chooses to re-screen the subject. Any re-screened subject should 
receive a new Subject No., and the original subject number must be noted on the Re-Screening 
CRF. All required screening activities must be performed when the subject is re-screened for 
participation in the study.
8.1.1
Eligibility screening
Following registering in the IRT for screening, subject eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
8.1.2
Information to be collected on screening failures
Subjects who sign an informed consent form and subsequently found to be ineligible prior 
to administration of study treatment (C1D1) will be considered a screen failure. The reason for 
screen failure should be recorded on the appropriate Case Report Form (CRF). The 
demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for screen failure subjects. No other data will be entered into the clinical database 
for subjects who are screen failures, unless the subject experienced a serious adverse event 
during the screening phase (see Section 10.1.3 for reporting details). If the subject is screen 
failed or will not be treated, the IRT is to be notified as soon as possible that the subject was 
not enrolled.
8.2
Subject demographics/other baseline characteristics
Demographics and other baseline characteristics data to be collected on all subjects include:

Disease history, including date of diagnosis, WHO sub-classification, prior antineoplastic 
therapies.

Race/ethnicity (are collected and analyzed to identify variations in safety or efficacy due 
to these factors as well as to assess the diversity of the study population as required by 
Health Authorities)

All prior and concomitant medications and medical procedure

Blood transfusion administered within 8 weeks before the first dose is administered

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Other assessments will be completed for the purpose of determining eligibility for inclusion in 
the study as reported in Table 8-1.
Assessments to be performed at screening include:

After all study ICFs are signed the subject will be registered with the IRT

Inclusion/exclusion criteria

Medical history/current medical conditions

Disposition

Physical examination

ECOG Performance Status, body height, weight, vital signs (blood pressure (supine 
position preferred when ECGs are collected) and pulse, and body temperature).

Laboratory - hematology, blood chemistry, coagulation, urinalysis, serum pregnancy test 
for women of child-bearing potential, thyroid function, cytogenetics, virology hepatitis B 
and C, HIV serology (only if required per local regulation)

Triplicate 12-lead central ECG

Bone marrow aspirate collection for MRD and other biomarkers

Bone marrow biopsy / aspirate must be collected for efficacy assessment

Imaging assessment if extramedullary disease is present or suspected


Blood sample for Cytokines

Adverse events

8.3
Efficacy
8.3.1
Efficacy assessments
Diagnosis at presentation according to WHO definition of AML will apply and be recorded in 
the eCRFs.
Response assessments (bone marrow aspirate (BMA)/bone marrow biopsies (BMB)), 
peripheral blood, hematology, transfusion independence, extramedullary disease assessments) 
will be performed locally, by the Investigator, according to the assessment schedule depicted in 
Table 8-1 for assessment of disease.
Bone marrow assessments will be performed at screening and pre-dose on C2D1 and C5D1 and 
every 3 cycles D1 thereafter until confirmed CR, and then every 6 cycles thereafter until 
progression, start of a new anti-neoplastic treatment (including HSCT), death, lost to follow-up 
or withdrawal of consent.
Hematology assessments will be performed at screening, and pre-dose on D1 and D8 of each 
cycle, on Day 22 of Cycle 1 and Cycle 2, at the end of treatment visit and every 12 weeks for 
subjects who enter post-treatment follow-up. In the absence of blood count recovery at C2D1 
and beyond, complete blood count can be collected weekly for up to 2 weeks. Complete blood 
count results used for the response assessment will be derived from the best accompanying 

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laboratory hematology result within the time window from 1 week before and up to 2 weeks 
after the bone marrow assessment used to support the efficacy response assessment. All 
components (eg, platelets, absolute neutrophils) should come from the same test.
Response evaluation will be based on the Investigator’s assessment based on standardized 
criteria as proposed by the International Working Group (IWG) and European Leukemia 
Network (ELN) for AML (Cheson et al 2003, Döhner et al 2017) (see Table 8-2). Disease 
classification at baseline and evaluation of response during study treatment will rely on bone 
marrow and peripheral blood assessment, as well as on the presence or absence of 
extramedullary disease, and status of transfusion dependence. For disease characterization at 
baseline, the last assessment of bone marrow (within 28 days before study treatment starts) and 
peripheral blood counts (within 14 days before study treatment starts) at the screening visit
should be used. In case of missing data for the full assessment required to qualify for a given 
response, the overall assessment “unknown” will be assigned unless disease progression was 
seen in at least one compartment (i.e. bone marrow or blood, or appearance of extramedullary 
disease).
Subjects can be assessed for disease response (bone marrow assessment, hematology, 
transfusion dependence, extramedullary disease assessment) at any time if clinically indicated, 
for example in case of suspicion of progression/relapse. Therefore more frequent efficacy 
assessments may be performed at the investigator’s discretion and recorded as an unscheduled 
visit in the eCRFs. Clinical suspicion of disease progression at any time will require a disease 
evaluation promptly, rather than waiting for the next scheduled assessment. In case of an 
unscheduled or delayed disease evaluation of any reason, subsequent assessments should be 
performed according to the originally planned schedule.
More frequent efficacy assessments may be performed at the Investigator’s discretion, if 
medically indicated, and recorded on the Unscheduled Visit CRFs. All assessments will be 
analyzed.
Table 8-2
Response classification in AML at a given evaluation time (based on 
IWG Cheson et al 2003, ELN 2017 Döhner et al 2017)
Response Category
Definition1
Complete Remission
Bone marrow:

< 5% blasts

no blasts with Auer rods
Peripheral blood:

neutrophils ≥ 1.0x109/L

platelets ≥ 100x109/L

no circulating blasts
No evidence of extramedullary disease (such as CNS or soft tissue 
involvement).
Complete remission with incomplete 
hematologic recovery (CRi)
Bone marrow:

< 5% blasts

no blasts with Auer rods
Peripheral blood:

neutrophils < 1.0x109/L or platelets < 100x109/L

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Response Category
Definition1

no circulating blasts
No evidence of extramedullary disease (such as CNS or soft tissue 
involvement).
Morphologic leukemia free state 
(MLFS)
Bone marrow

< 5% blast

no blasts with Auer rods
No evidence of extramedullary disease (such as CNS or soft tissue 
involvement)
Partial Remission (PR)
Bone marrow:

< 5% blasts AND presence of blasts with Auer rods
OR

≥ 50% decrease from baseline in blasts in bone marrow AND 
blast count in bone marrow is 5% to 25%
Peripheral blood:

neutrophils ≥ 1.0 x 109/L

platelets ≥ 100 x 109/L

no blasts
Progressive Disease (PD)
Evidence for an increase in bone marrow blast percentage and/or 
increase of absolute blast counts in the blood

>50% increase in marrow blasts from maximum remission or 
baseline ,whatever is lower (a minimum 15% point increase is 
required in cases with <30% blasts at baseline; or persistent marrow 
blast percentage of >70% over at least 3 mo; without at least a 
100% improvement in ANC to an absolute level (>0.5 X 10⁹/L 
[500/μL], and/or platelet count to >50 X 10⁹/L [50 000/μL] 
nontransfused); or

>50% increase in peripheral blasts (WBC X % blasts) to >5 X 
10⁹/L (>25 000/ μL) (in the absence of differentiation syndrome); or

New extramedullary disease
Stable disease
Absence of CR, CRi, PR, MLFS, and criteria for PD or relapse 
are not met
Relapse from CR or CRi
Only in patients with a CR or CRi. Any of the following:

Reappearance of blasts in peripheral blood
OR

≥ 5% blasts in bone marrow
OR

(Re-)appearance of extramedullary disease
Unknown
In case the response assessment was not done or the assessment 
was incomplete
1 If not defined otherwise, all of these criteria apply

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Evaluation of transfusion dependency
RBC and platelet transfusions will be assessed at baseline as well as during the course of the 
trial for all patients. Transfusion of blood products will be recorded in a separate module of the 
CRF. The type of transfusion, start and end date as well as the volume of blood product will be 
captured at each visit with hematologic assessment. A period of at least 8 weeks without any 
transfusion has been taken as a convention to define the status of transfusion independence.
Transfusion dependence and independence for RBC and/or platelets are defined below:
Transfusions for intercurrent diseases or events not due to AML (e.g. bleeding due to trauma, 
surgical procedures) should not be taken into account for the following:
Transfusion independence:

Before first day of study treatment (C1D1): subjects having received no RBC or platelet 
transfusions within the 8 consecutive weeks prior to enrollment/first day of study 
treatment (C1D1)

On or after first day of study treatment (C1D1) : absence of any RBC or platelet 
transfusion during any consecutive 8 weeks
Transfusion dependence:

Transfusion dependence at baseline is defined as at least one RBC or platelet transfusion 
in the 8 weeks prior to C1D1
Extramedullary disease assessment
If clinical suspicion of extramedullary disease (EMD) exists or the subject has a clinical history 
of EMD, further evaluation using imaging assessments and other diagnostics (as clinically 
indicated) are required for subjects at screening. Presence or absence and physical location of 
EMD is to be captured in the CRF.
EMD is to be assessed via physical examination, cerebrospinal fluid (CSF) assessment in case 
of symptoms suggestive of meningeosis leukemia, and if clinically appropriate relevant imaging 
techniques.
In case of EMD at baseline or (re-) appearance during the study, the lesions should be 
considered for confirmation by imaging or biopsy if technically and/or clinically feasible. 
Imaging modalities and techniques should be performed as clinically indicated and per standard 
of care. Selected modalities should be used consistently for a given subject, if feasible.
If clinically indicated, post baseline imaging should only be performed in these anatomical 
regions that demonstrate possible disease. 
EMD assessment, if applicable, will be performed at screening, C2D1 and every 3 cycles 
thereafter thereafter until confirmed CR, and then every 6 cycles thereafter until disease 
progression, start of a new anti-neoplastic treatment (including HSCT), death, lost to follow-up 
or withdrawal of consent.

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8.3.3
Appropriateness of efficacy assessments
The assessment of response to study treatment is based on standardized criteria as proposed by 
the European Leukemia Network (ELN) and the International Working Group (IWG) 
(Cheson et al 2003, Döhner et al 2017) in Table 8-2.
8.4
Safety
Safety assessments are specified in Table 8-4 below with the assessment schedule detailing 
when each assessment is to be performed.
For details on AE collection and reporting, refer to AE section.
Table 8-4
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 and D22, 
an abbreviated examination can be done at investigator's discretion.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior to 
signing informed consent must be recorded on the appropriate CRF that captures 
medical history. Significant findings made after signing informed consent which 
meet the definition of an Adverse Event must be recorded as an adverse event.
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is 
collected), pulse measurement, and body temperature.
Height and weight
Height in centimeters (cm) will be measured at Screening. Body weight (to the 
nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be measured at 
screening and at subsequent timepoints as specified in Table 8-1.
Performance status:
ECOG Performance status scale will be used as described in Table 8-5.
Table 8-5
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

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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 8-6) and the results will be collected in the eCRF.
Unscheduled assessments of these parameters can be performed more often as clinically 
indicated. It is preferable to use the same laboratory for all the assessments performed, 
especially for the hematology assessments.
A central laboratory will be used for the parameters listed in Table 8-7 and as per the schedule 
in Table 8-1.
Laboratory values obtained during the Screening phase will be used to assess subject’s 
eligibility.
Novartis must be provided with a copy of the certification and a tabulation of the normal ranges 
and units for all local laboratories used to in the trial.
Table 8-6
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hemoglobin (Hgb), white blood cells (WBC), differential (including basophils, 
eosinophils, lymphocytes, monocytes, neutrophils, bands, metamyelocytes, 
myelocytes, promyelocytes, blasts), atypical cells (e.g. LUC, erythroblasts), platelets
(absolute value preferred, %s are acceptable)
Chemistry
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Calcium, Magnesium, Phosphorus, Sodium, Potassium, 
Bicarbonate, Creatinine, Creatine kinase, Total Bilirubin, (Indirect Bilirubin, Direct 
Bilirubin)*, Total Cholesterol, Total Protein, Blood Urea Nitrogen (BUN) or Urea, Uric 
Acid, Amylase, Lipase, Glucose (fasting), Troponin-T***
Virology**
HBsAg, HBcAb, HBV DNA (in subjects positive for HBcAb), HCV RNA (PCR)
HIV (Only if required by local regulation)
Coagulation
International normalized ratio [INR]), Activated partial thromboplastin time (APTT)
Thyroid
At baseline: TSH, Free-T3 and Free-T4.
During treatment: TSH at timepoints indicated in Table 8-1 and as clinically indicated. If 
TSH is abnormal, then test free-T3 and free-T4
Urinalysis**
(dipstick)
Dipstick examination includes specific gravity, pH, glucose, protein, blood, bilirubin, 
ketones and WBC as clinically indicated.If urinalysis dipstick shows abnormalities, the 
site should perform a more detailed urinalysis follow-up as clinically indicated and per 
local practice.
Pregnancy Test**
Serum / Urine pregnancy test (refer to Section 8.4.3 'Pregnancy and assessments of 
fertility'
* Indirect and direct bilirubin only required if total bilirubin is abnormal
** Virology, urinalysis, and pregnancy test will only be reported in the source documentation
***If Troponin-T is not available, Troponin-I may be reported
Table 8-7
Central clinical laboratory parameters collection plan
Test Category
Test Name
Cytokines
IFN-γ, IL-6, IL-1b, TNF-α
Chemistry for DILI1
Glutamate dehydrogenase (GLDH)
1 at baseline and as clinically indicated for follow-up of DILI per Section 6.5.4.3

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8.4.2
Electrocardiogram (ECG)
Standard triplicate 12 lead ECG recording will be performed according to Table 8-8. The 
Fridericia QT correction formula (QTcF) should be used for clinical decisions.
The ECGs are to be collected with ECG machines supplied by the central ECG vendor at the 
timepoints indicated in the ECG collection plan (Table 8-8).
Table 8-8
ECG collection plan
Cycle
Day
Time point
Screening
Day -28 to Day -1
Anytime
Cycle 1
Day 1
Pre-dose1
Day 8
Post-dose2
Cycle 3
Day 8
Post-dose2
EOT
N/A
Anytime
Unscheduled
Any
As clinically indicated
* all ECGs to be collected in 12-lead triplicate, at least 3 minutes apart
1 ECG collection prior to any study drug dosing
2 ECG collection at end of MBG453 infusion
Clinically significant ECG abnormalities present at screening should be reported on the 
appropriate CRF. New or worsened clinically significant findings occurring after informed 
consent must be recorded as adverse events. All ECGs must be recorded using the machines 
supported by the central ECG vendor and transmitted electronically to the central ECG 
vendor to be centrally reviewed by an independent reviewer. Any original ECG not transmitted 
electronically to the central laboratory should be forwarded for central review.
Any identifier details must be redacted e.g. subject initials, date of birth, where local regulations 
require it.
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated, and transmitted electronically to the central 
laboratory as unscheduled timepoints.
In case of QTcF prolongation, please refer to Section 6.5.4.4.
8.4.3
Pregnancy and assessments of fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
subject regardless of reported reproductive/menopausal status at screening/baseline.
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.

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At screening, a serum pregnancy test (serum ß-HCG) must be performed within 3 days before 
the first dose.
During the study, a urine/serum pregnancy test should be performed at Day 1 of each cycle 
(except Cycle 1 if a pregnancy test had been performed within 72 hours of the first dose) and a 
serum pregnancy test at EOT visit. Pregnancy testing (urine/serum) should occur at monthly 
intervals during the 150-day safety follow-up period. Refer to Table 8-1 for pregnancy testing 
schedule.
A positive urine pregnancy needs to be confirmed with a serum test. Confirmed positive 
pregnancy test requires immediate discontinuation of study treatment and discontinuation from 
study. See Section 10.1.4 for pregnancy reporting.
The pregnancy tests will be recorded only in the source documentation, not in the CRF.
Women of childbearing potential should employ the use of highly effective contraception 
during study treatment, for 90 days after the last dose of azacitidine, 30 days after the last dose 
of venetoclax (or as per their respective local labels, whichever is longer) and 150 days after 
the last dose of MBG453. Highly effective contraception methods are defined in Section 5.2.
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner while taking 
azacitidine and for 3 months after stopping this drug. In addition, male participants should not 
donate sperm for the time period specified above.
8.4.4
Additional safety monitoring and considerations during venetoclax 
ramp-up
The dose of venetoclax will be ramped up over 3 or 4 days to achieve the daily dose of 400 mg 
(see Table 6-2 for ramp-up procedure).
Blood chemistry should be taken pre-dose and at 7 hrs (+/- 1 hr) on during the ramp-up and 
approximately 24 hrs after reaching the final dose (pre-dose of the following dosing day, see 
Table 8-1).
Due to the known risk of TLS with venetoclax treatment, prior to first venetoclax dose on Cycle 
1 Day 1, the subject should be provided with prophylactic measures including adequate 
hydration and anti-hyperuricemic agents and these measures should be continued during the 
ramp-up phase.
High risk patients may need additional measures like i.v. hydration and hospitalization, events 
should be managed per local guidelines.
Refer to Section 6.5.4.2 for guidance on minimising the risk of TLS and procedures to be 
followed before initiation of a treatment cycle and during the treatment cycle.

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8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
8.5.1.2
Trial Feedback Questionnaire (TFQ)
This trial will include an anonymized questionnaire, ‘Trial Feedback Questionnaire’ for 
subjects to provide feedback on their clinical trial experience. Individual subject level responses 
will not be reviewed by investigators. Responses would be used by the sponsor (Novartis) to 
understand where improvements can be made in the clinical trial process. This questionnaire 
does not collect data about the subject's disease, symptoms, treatment effect or adverse events 
and therefore would not be considered trial data and will be received electronically outside of 
the Clinical database.

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8.5.2.1
Pharmacokinetic and Immunogenicity blood collection and handling
The MBG453 PK, 
 and IG blood sampling schedule is outlined in Table 8-9. A single 
blood sample of approximately 5 mL will be collected at each time point.
The venetoclax PK blood sampling schedule is outlined in Table 8-10. A single blood sample 
of approximately 3 mL will be collected at each time point.
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein opposite to the arm used for infusion. When PK is collected at the same time 
point as ECG, the PK sample should be taken immediately after ECG.
The exact date and clock times of drug administration and blood draws for PK, IG 
 
assessment will be recorded on the appropriate eCRF.
After permanent discontinuation of MBG453, the samples scheduled for pre-MBG453 infusion 
and end of MBG453 infusion (within 2 hours) should no longer be collected.
Detailed instructions for the collection procedures, handling, and shipment of MBG453 PK, IG 
 samples, and venetoclax PK samples will be provided in the [CMBG453C12201 
Laboratory Manual].
Table 8-9
MBG453 PK, IG 
 blood collection log
Cycle
Day
Scheduled 
Time Point*
PK sample 
(MBG453)
IG sample
1
1
Pre-azacitidine 
dose
8
Pre-MBG453 
infusion
X
X
End of MBG453 
infusion (within 
2 hours)
X
2
8
Pre-MBG453 
infusion
X
X
3
8
Pre-MBG453 
infusion
X
X
End of MBG453 
infusion (within 
2 hours)
X
6
8
Pre-MBG453 
infusion
X
X
9
8
Pre-MBG453 
infusion
X
X
12
8
Pre-MBG453 
infusion
X
X
18
8
Pre-MBG453 
infusion
X
X
24
8
Pre-MBG453 
infusion
X
X
EOT1
Anytime
X
X
30-Day Safety Follow-up
Anytime
X
X
150-Day Safety Follow-up2
Anytime
X
X

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If discontinuation of study treatment occurs due to circumstances other that the protocol defined 
criteria in Section 6.1.4 and Section 6.1.5, the investigator should make a reasonable effort to 
understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' Section 9.1.2). Where possible, they 
should return for the assessments indicated in the Assessment Schedule. If they fail to 
return for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) 
should be made to contact the subject/pre-designated contact as specified in the lost to follow-
up section. This contact should preferably be done according to the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
If discontinuation of study treatment occurs due to protocol defined reasons, subjects will be 
followed for efficacy, safety and survival as detailed in Section 9.1.1.1, Section 9.1.1.2
and Section 9.1.1.3.
9.1.1.1
Safety Follow-up
All patients must be followed for safety for 150 days after the last dose of MBG453 or 30 days 
after the last dose of azacitidine or venetoclax whichever is longer.
After the 30-Day on-site safety follow-up visit, patients will be followed via telephone call (or 
on-site visit if patient happens to be visiting the site) at 90 and 150 days after the last dose of 
MBG453. All safety assessments should be completed as per Table 8-1. However, if the patient 
begins new antineoplastic medication before the end of the safety follow-up period, the 
collection of new SAEs and AEs unrelated to study medication will stop and thereafter only 
suspected AEs and suspected SAEs will continue to be collected up to the end of the safety 
follow-up period. Patients continuing on MBG453 through an alternative setting (e.g. managed 
access program or a roll-over study) after the end of the study, should be followed for safety
until the EOT visit. For female patients of child bearing potential, a pregnancy test will be 
performed at the timepoints listed in Table 8-1
9.1.1.2
Post-Treatment Follow-up
For subjects who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent, efficacy assessments will continue to be 
performed as per the assessment schedule (Table 8-1) with hematological assessments every 12 
weeks and bone marrow assessments every 12 weeks (for patients who achieve CR: every 24 
weeks) (see Table 8-1) or as clinically indicated until documented disease progression/ relapse 
from CR, start of a new anti-neoplastic treatment (including HSCT), death, lost to follow-up, 
or withdrawal of consent.

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9.1.1.3
Survival Follow-up
Patients will enter the survival follow-up period once they complete the safety follow-up period 
or have disease progression (whichever is later). Patients will then be contacted by telephone 
every 12 weeks to follow-up on their survival status. Any new anti-neoplastic therapy that has 
been started since the last contact date (including HSCT) and any SAEs related to study 
treatment, as well as information about the remission status and the date of progression/relapse 
from CR for patients who receive a HSCT will also be collected during these phone calls.
9.1.1.4
Replacement policy
Subjects will not be replaced on study. However, if a subject is considered as non-evaluable for 
the safety run-in (see Section 6.5.1), enrolment of a new subject to the safety run-in will be 
considered if there are less than the required number of evaluable subjects.
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 of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and 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

Does not want any further visits or assessments (including further study-related contacts)
This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation.
Withdrawal of consent impacts ability to further contact the subject, collect follow-up data (e.g. 
to respond to data queries) and potentially other country-specific restrictions. It is therefore very 
important to ensure accurate recording of withdrawal vs. discontinuation based on the protocol 
definitions of these terms. 
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/exercise privacy rights and record this information. The 
Investigator shall clearly document if the subject has withdrawn his/her consent for the use of 
data in addition to a study discontinuation.
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/exercise privacy rights should be made as detailed in 
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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 will be collected 
following withdrawal of consent/opposition to use data.
Further details on withdrawal of consent or the exercise of subjects' data privacy rights are 
included in the corresponding informed consent form.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits or fail to respond 
to any site attempts to contact them without stating an intention to discontinue from study 
treatment or discontinue from study or withdraw consent (or exercise other subjects’ data 
privacy rights), the investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the subject, e.g. dates of telephone calls, registered letters, etc. 
A subject should not be considered as lost to follow-up until due diligence has been completed 
or until the end of the study.
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 as soon as possible to perform their End of Treatment Visit 
(EOT) and the assessments for EOT as described in Table 8-1. The subject will be 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.
In the event that the study is terminated prematurely, e.g. based on recommendation of the 
steering committee (see also Section 10.2.2), patients still receiving study treatment and who, 
according to investigator assessment, continue to benefit from the treatment, will be offered to 
complete study treatment as per protocol or through an alternate setting see Section 9.2.
9.2
Study completion and post-study treatment
Following completion of the safety follow-up period and/or post-treatment follow-up period, 
all subjects will be followed for survival (see Section 9.1.1.3).
The information collected is kept as source documentation. All SAEs reported during this time 
period must be reported as described in Section 10.1.3. Documentation of attempts to contact 
the subject should be recorded in the source documentation.
The CR rate analysis will be conducted after the last patient enrolled has completed at least 12
cycles of treatment or discontinued earlier. Following the cut-off date for the analysis reported 
in the primary Clinical Study Report (CSR), the study will remain open and ongoing subjects 
will continue to receive study treatment and be followed per the schedule of assessments until 
discontinuation criteria is met per Section 9.1.1.

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The end of study is defined as the earliest occurrence of one of the following:

All subjects have been followed for at least 3 years have discontinued treatment or have 
died, been lost to follow-up or have withdrawn consent to further participation in the study.

The last subject on treatment has been enrolled into a separate rollover study or another 
option of continued treatment with MBG453.
At the end of the study, every effort will be made to continue the provision of MBG453 outside 
this study through an alternative setting for subjects who are still receiving treatment with 
MBG453 and deriving clinical benefit in the opinion of the investigator. Options for continued 
treatment with MBG453 may include access to commercially available drug, or a managed 
access program, or a roll-over study.
The final analysis will occur at the end of the study. All available data from all patients up to 
this cut-off date will be analyzed and summarized in a final CSR.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a 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 AEs must be sought by non-directive questioning of the subject at each visit 
during the study. AEs 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):
Adverse events will be assessed and graded according to:
1. the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
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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 if the event is ongoing, an outcome of not recovered/not 
resolved must be reported
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
6. its outcome (i.e. recovery status or whether it was fatal)
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse event monitoring should be continued for at least:

150 days after the last administration of MBG453, or 30 days after the last administration 
of azacitidine, or 30 days after the last administration of venetoclax, whichever is later.
OR

until the start of a new post treatment antineoplastic medication if sooner than the 150 days 
mentioned above. If a 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.

until the EOT visit for patients continuing on MBG453 through an alternative setting (e.g. 
managed access program or a roll-over study) after the end of the study.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as separate 
adverse event.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Adverse events separate from the progression of malignancy (i.e. deep vein thrombosis at the 
time of progression or hemoptysis concurrent with finding of disease progression) will be 
reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.

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Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease.
10.1.2
Serious adverse events
A serious adverse event (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 

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do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per ELN 2017 guidelines (Döhner et al 2017)), should not be reported 
as an SAE, except if the investigator considers that the progression of malignancy is related to 
study treatment.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until the end of the safety follow-up period (Section 9.1.1.1), 
must be reported to Novartis safety immediately, without undue delay, 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). Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site. Information about all SAEs is collected and recorded on the Serious 
Adverse Event Report Form; all applicable sections of the form must be completed in order to 
provide a clinically thorough report.
SAE reporting timeframes:
1. Screen Failures (e.g. a subject who is screened but is not treated or randomized): All SAEs 
occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis.
2. Treated Subjects (including randomized subjects in the Randomized Part): SAEs collected 
between time subject signs ICF until 30 days after the subject has discontinued or stopped 
azacitidine or venetoclax or 150 days after stopping MBG453, whichever is later. If a patient 
starts post treatment antineoplastic medication, then only SAEs suspected to be related to 
study treatment should be collected, up to 150 days or beyond after discontinuation of 
MBG453.
3. Patients continuing on MBG453 through an alternative setting (e.g. managed access 
program or a roll-over study) after the end of the study: SAEs should be collected until the 
EOT visit.
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, but 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 

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otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the subject has completed the safety follow-up period should only 
be reported to Novartis Safety if the investigator suspects a causal relationship to study 
treatment, unless otherwise specified by local law/regulations.
10.1.4
Pregnancy reporting
Pregnancies
If a female trial participant becomes pregnant, the study treatment should be stopped, and
the pregnancy consent form should be presented to the trial participant. The participant 
must be given adequate time to read, review and sign the pregnancy consent form. This
consent form is necessary to allow the 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 (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.
Pregnancy outcomes will not be collected for the female partners of any males who took study 
treatment in this study.
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery.
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 
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Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including misuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with an 
AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
Data Monitoring Committee
A Data Monitoring Committee (DMC) will not be required for this study considering that it is 
open-label single-arm study. However, close monitoring of safety is planned; 
specifically, Novartis and the study investigators involved in the safety run-in will conduct at 
least one safety review meeting for each cohort: once all evaluable subjects in that cohort are 
observed for at least 2 cycles of treatment or experienced a DLT, whichever occurs first, in 
order to review and discuss safety data, including adverse events, dose interruptions and dose 
modifications, as well as available pharmacokinetic data. At the planned safety review meeting, 
Novartis and the investigators must reach a consensus based on the available safety and clinical 
pharmacology data, to decide whether to continue with enrolment on the study.
10.2.2
Steering Committee
The steering committee (SC) will be established comprising investigators participating in the 
trial, i.e. not being Novartis representatives from the Clinical Trial Team. The SC will ensure 
transparent management of the study according to the protocol through recommending and 
approving modifications as circumstances require. The SC will periodically review the study 
data and will make recommendations on the study conduct (including study termination). The 
SC will review protocol amendments as appropriate. Together with the clinical trial team, the 
SC will also develop recommendations for publications of study results including authorship 
rules. The details of the role of the Steering Committee will be defined in a Steering Committee 
charter.

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11
Data Collection and Database management
11.1
Data collection
The designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRFs). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the 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 verificatio’’;fd
n. In addition to data entered into the eCRF , 
requisition forms may also need to be completed for (e.g. PK, 
 etc.) sample 
collection.
11.2
Database management and quality control
Novartis personnel will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 
EDC system. Designated investigator site staff are required to respond promptly to queries and 
to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Kit numbers and data about MBG453 (and venetoclax for all countries other than the US) 
dispensed to the subject and all dose interruptions (for MBG453 only) will be tracked using an 
Interactive Response Technology (IRT). The system will be supplied by a vendor, who will also 
manage the database. The data will be sent electronically to Novartis at specific timelines. 
Azacitidine will not be tracked through IRT.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management.
Samples collected for all third party data such as biological samples (including PK, IG, 
 and ECGs will be processed centrally, and the results will be sent 
electronically to Novartis.

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Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis or delegated CRO CRA organization. Additionally, a 
central analytics organization may analyze data, identify risks and trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each 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
The primary safety analysis (safety run-in part) will be conducted for each cohort when patients 
have received MBG453 + azacitidine + venetoclax for at least two cycles.
The primary efficacy analysis (CR rate analysis) will be performed on all subject data (from 
both safety run-in and expansion parts) at the time all subjects who are still receiving study 
treatment will have completed at least 12 cycles or discontinued earlier.
The long-term efficacy and safety analyses will be conducted on all subject data at the time all 
subjects will discontinue the study treatment or have been followed up for at least 3 years after 
the last patient enrolled whichever occurs first (see Section 9.2 for details). If required or 
requested by Health Authorities, updated analyses after the primary CR rate analysis may be 
conducted prior to the final analysis.

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Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented when applicable.
12.1
Analysis sets
The Full Analysis Set (FAS) comprises all subjects who received at least one dose of study 
treatment (i.e. at least one dose of MBG453 or at least one dose of azacitidine or at least one 
dose venetoclax). This will include patients in the safety run-in part and in the expansion part.
The Safety Set includes all subjects from the FAS.
The Dose-Determining Set (DDS) includes all subjects from the FAS enrolled the safety run-in 
part who met the minimum exposure criterion and had sufficient safety evaluations, or 
experienced a dose limiting toxicity (DLT) between Cycle 1 Day 8 and the end of Cycle 2 of 
treatment. The definition for the minimum exposure criterion and the sufficient safety 
evaluations is detailed in Section 6.5.1.
The MBG453 and venetoclax pharmacokinetic analysis sets include all subjects from the Safety 
Set who provide at least one evaluable MBG453/venetoclax PK concentration.
For a concentration to be evaluable:

Dosing information must be properly documented (data and time of administration)

For post-dose samples: planned dose of MBG453/venetoclax must be taken prior to 
sampling

For pre-dose samples: the sample is collected before the next dose administration
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for all subjects from 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 Safety set will be used for the analyses below.
The duration of exposure to MBG453 and to each study drug (azacitidine and venetoclax) as 
well as the dose intensity (computed as the ratio of actual cumulative dose received and actual 
duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity 
and planned dose intensity) will be summarized by descriptive statistics.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system.

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The number of subjects with dose adjustments (reductions for azacitidine and venetoclax, 
interruptions, or permanent discontinuation) and the reasons will be summarized by study drug 
and all dosing data will be listed.
12.4
Analysis of the primary endpoint(s)
The primary objectives of the study are to determine whether MBG453 at the two tested dose 
levels is not meeting overdose criteria when added in combination with azacitidine and 
venetoclax (safety run-in part) and to assess the complete remission rate (CR) of MBG453, 
administered at 800 mg Q4W in combination with azacitidine and venetoclax (safety run-in and 
expansion part).
12.4.1
Definition of primary endpoint(s)
For the safety run-in part, the primary endpoint is the incidence of DLTs between Cycle 1 Day 
8 and the end of Cycle 2 of treatment for subjects in each cohort and included in the DDS.
The primary endpoint of the study (combining data from the safety run-in part and the expansion 
part) is the proportion of patients treated with MBG453 800 mg Q4W achieving a complete 
remission (CR) as per investigator assessment (Cheson et al 2003, Döhner et al 2017 and 
Table 8-2).
A subject with CR is classified as a responder.
The following events that could occur after enrollment, may affect the interpretation of the 
results:

Stopping study treatment (including due to toxicities): all CR will be taken into account 
regardless of any study treatment interruption or permanent discontinuation.

Start of further anti-neoplastic therapy: A subject with a first CR after the time he/she 
receives any further anti-cancer therapy would not be considered responder.

Hematopoetic stem cell transplantation (HSCT): A subject with a first CR after the time 
he/she receives a SCT would not be considered responder.
12.4.2
Statistical model, hypothesis, and method of analysis
DLT analysis (safety run-in part)
Assessing whether MBG453 at the two tested dose levels is not meeting overdose criteria when 
added to azacitidine and venetoclax will be based on the estimation of the probability of DLT 
within the DLT observation period (Cycle 1 Day 8 to the end of Cycle 2) for patients in the 
DDS.
The assessment in safety run-in part will be guided by a Bayesian analysis of DLT data for 
MBG453 with azacitidine and venetoclax within the DLT observation period (Cycle 1 Day 8 
to the end of Cycle 2) of treatment. The probability of DLT is modeled using a Bayesian 
approach detailed in Section 16.1.
After each cohort of the safety run-in part, posterior distributions for the risk of DLT will be 
summarized to provide the posterior probability that the risk of excessive toxicity (DLT rate 
≥33%) is less than 25% (EWOC principle, Babb et al 1998).

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CR analysis (safety run-in and expansion parts)
A Bayesian design will be used in order to estimate the CR rate in patients from the FAS treated 
with MBG453 800 mg Q4W and to provide inferential summaries (e.g., mean, median, standard 
deviation, 95% credible intervals, and interval probabilities) based on Bayesian posterior 
distribution of the CR rate. Assuming a uniform informative prior distribution (Beta(1,1)), the 
distribution of the CR rate will be updated with all available data from the patients included in 
the FAS and treated with MBG453 800 mg Q4W. This dual-criterion design will allow to base 
trial success not only on the statistical significance for superiority against the control (CR 
exceeds the null-value) but also by considering a minimum clinically estimated effect size 
(CR exceeds the decision value).
The decision criteria for trial success are the following:
1. Statistical significance: the posterior probability that CR rate is > 50% (null value) is at least 
97.5%
2. Clinical relevance: the posterior median of CR rate is ≥ 61% (decision value).
The posterior distribution will be used to derive the probability that the true CR rate is superior 
to 50%. Based on preliminary efficacy data observed with the combination azacitidine + 
venetoclax, a 50% CR rate is a reasonable threshold to be considered in this specific setting 
(Daniel A. et al 2018).
The results will be also presented with a frequentist formulation. The CR rate and the exact 95% 
confidence interval (CI) (Clopper and Pearson 1934), as well as the 1-sided p-value will be 
provided in patients from the FAS treated with MBG453 800 mg Q4W. The test will be 
performed using an overall one-sided 2.5% level of significance. Thus, the null hypothesis 
(H0:CR ≤ 50%) will be rejected if the lower bound of the two-sided 95% exact CI is >50%.
The analysis will be performed using data up to the analysis data cut-off date, which will be at 
the time all subjects who are still receiving study treatment will have completed at least 12
cycles or discontinued earlier.
12.4.3
Handling of missing values/censoring/discontinuations
For the determination of CR, only assessments after first dose of study treatment and prior start 
of any other anti-neoplastic therapy or HSCT are considered. An adequate response assessment 
is considered any disease assessment indicating response status apart from “unknown” or “not 
done”.
12.4.4
Sensitivity and Supportive analyses
Sensitivity analyses (if appropriate) will be described in the Statistical Analysis Plan.
12.5
Analysis of secondary endpoints
The secondary objectives in this study are to assess the effect of MBG453 in combination with 
azacitidine and venetoclax on duration of response (CR, CR/CRi and CR/CRh), Event-Free 
Survival (EFS), Overall Survival (OS), CR/CRi rate, CR/CRh rate, MRD negativity rate, 
pharmacokinetic, immunogenicity, transfusion independency, as well as on safety and 
tolerability.

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12.5.1
Efficacy endpoint(s)
Efficacy endpoints will be analyzed and summarized for the FAS and by dose level of MBG453.
Time-to-event endpoints will be analyzed using Kaplan-Meier method: the Kaplan-Meier 
curves, medians and 95% CI of the medians will be presented.
No formal statistical tests will be performed for any of the secondary efficacy endpoints and 
hence no multiplicity adjustment will be applied.
Of note, all response assessments used for efficacy analysis below will be based on investigator 
assessment (Cheson et al 2003, Döhner et al 2017 and Table 8-2), unless otherwise stated. 
Duration of response: duration of complete remission (CR), duration of complete 
remission/complete remission with incomplete blood count recovery (CR/CRi), duration 
of complete remission/complete remission with partial hematological recovery (CR/CRh)
The duration of CR will be assessed in patients with CR as per investigator assessment, defined 
as the time from achievement of CR to the first documented relapse or progressive disease or 
death due to any cause, whichever occurs first. For subject without event, duration of CR is 
censored at the date of last adequate response assessment. 
The duration of CR/CRi will be assessed in patients with CR or CRi as per investigator 
assessment, defined as the time from achievement of CR or CRi to the first documented relapse 
or progressive disease or death due to any cause, whichever occurs first.  Same censoring rule
as duration of CR will be applied. 
Similarly, the duration of CR/CRh will be assessed in patients with CR or CRh as per derivation 
(Döhner et al 2022), defined as the time from achievement of CR or CRh to the first relapse or 
progressive disease or death due to any cause, whichever occurs first.  Same censoring rule as 
duration of CR will be applied. 
Besides, CRh will be derived by Novartis following the below criteria (Döhner et al 2022): 
neutrophils ≥0.5x109/L and platelets ≥50x109/L and otherwise all other CR criteria met (see 
Table 8-2). 
Event-Free Survival (EFS)
Event-free survival (EFS) is the time from date of start of treatment until date of death due to 
any cause, relapse from CR, or treatment failure, whichever occurs first. Treatment failure is 
defined as lack of reaching CR until C8D1 or earlier permanent discontinuation (set to Day 1). 
A subject without EFS event will have their EFS censored at the time of the last adequate 
assessment performed on or before the cut-off date.
Overall Survival (OS)
OS is defined as the time from start date of treatment to date of death due to any cause. If a 
subject is not known to have died, then OS will be censored at the latest date the subject was 
known to be alive (on or before the cut-off date). All deaths will be taken into account whenever 
the death occurred, i.e. even after new anti-neoplastic therapy, HSCT, interruptions, or 
discontinuation of study treatment due to any reason.

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CR/CRi rate
CR/CRi rate is defined as the proportion of subjects with best overall response of either 
complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) 
as per investigator assessment (Table 8-2). CR/CRi rate will be provided with exact 95% 
confidence interval (Clopper and Pearson 1934).
CR/CRh rate
CR/CRh rate is defined as the proportion of subjects with best overall response of either 
complete remission (CR) or complete remission with partial hematologic recovery (CRh) as per 
derivation (Döhner et al 2022). CR/CRh rate will be provided with exact 95% confidence 
interval (Clopper and Pearson 1934).
MRD negativity rate
MRD negativity is defined as a MRD negative sample (frequency of LAIP below 0.1%, as 
determined by MFC-MRD at Central Lab) and bone marrow remission (below 5%). The subject 
had to achieve an MRD-negative response at or after morphological remission. MRD negativity 
rate is defined as the proportion of subject with MRD negativity. Best MRD status will be 
summarized descriptively with 95% exact confidence intervals in full population (i.e. FAS), 
and/or any subgroup of interest (CR, CR/CRi, CR/CRh, etc.)
Red blood cells (RBC)/Platelets transfusion independence
Red blood cells (RBC)/Platelets transfusion independence RBC/Platelets transfusion 
independence rate is defined as the proportion of subjects having received no 
RBC/Platelets transfusions during at least 8 consecutive weeks (see Section 8.3.1 for details). 
The number and percentage of subjects will be shown for the overall FAS and then also in only 
those with transfusion dependence at baseline (i.e ≥ 1 RBC or platelet transfusion in 8 
consecutive weeks prior to start of treatment). Percentages will be provided with exact 95% 
confidence intervals (Clopper and Pearson 1934). For subjects with at least one period of 
transfusion independence, the total duration of all transfusion independence periods will be also 
summarized. The duration of the transfusion independence is defined from the end date of the 
last transfusion received until the date transfusions are given again or last treatment in case
transfusions had not (re-)started during treatment.
12.5.2
Safety endpoints
Safety analyses will be summarized for the safety set and by dose level of MBG453.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
The overall observation period will be divided into three mutually exclusive segments:

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1. Pre-treatment period: from day of subject’s informed consent to the day before first 
administration of study treatment
2. On-treatment period: from date of first administration of study treatment to 30 days after 
date of last administration of study treatment
3. Post-treatment period: any observation starting at day 31 after last administration of study 
treatment
An overall safety period will be defined from date of first administration of study treatment to 
150 days after the last dose of MBG453.
Adverse events
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period. The number (and percentage) of subjects with treatment emergent 
adverse events will be summarized by primary system organ class, preferred term and maximum 
severity.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment.
Serious adverse events and non-serious adverse events will be tabulated. All deaths (on-
treatment and post-treatment) will be summarized.
In addition, all AEs and SAEs which started during the overall safety period will be summarized. 
All reported AEs will be listed and those that started during the pre-treatment, overall safety 
period and post-treatment period will be flagged.
Vital signs
All vital signs abnormalities will be summarized by visit.
12-lead ECG
HR and QTcF will be obtained from 12-lead ECGs for each subject at screening and during the 
study. ECG data will be read and interpreted centrally.
Categorical analysis of QTcF interval and HR data will be based on the summary of number of 
subjects meeting or exceeding predefined limits.
Clinical laboratory evaluations
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 
calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher.
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low/normal/high based on laboratory normal ranges.

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For laboratory tests where grades are defined by CTCAE v5.0:

Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value
For laboratory tests where grades are not defined by CTCAE v5.0:

Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value
Other safety evaluations
ECOG PS
ECOG PS will be summarized at each timepoint during the study.
12.5.3
Pharmacokinetics
The respective PAS for MBG453 and venetoclax will be used in all pharmacokinetic data 
analysis.
MBG453 and venetoclax drug concentrations
MBG453 and venetoclax concentration data will be listed by subject, and visit/sampling time 
point. Descriptive summary statistics for MBG453 and venetoclax concentrations will be 
provided by visit/sampling time point. Summary statistics will include mean (arithmetic and 
geometric), SD, CV (arithmetic and geometric), median, minimum, and maximum, as well as 
the frequency (n, %) of concentrations below the lower limit of quantification (LLOQ) and 
reported as zero. Values below the LLOQ will be treated as missing for the calculation of the 
geometric means and geometric CV%. PK parameters (the minimum observed plasma or serum 
drug concentration (Cmin or Ctrough) and the maximum (peak) observed plasma or serum drug 
concentration (Cmax)) will be estimated and reported. Missing values for any PK parameters 
or concentrations will not be imputed and will be treated as missing.
All concentration data for MBG453 and venetoclax vs. time profiles will be displayed 
graphically. The concentrations collected before dose administration on Day 8 of Cycle 3 and 
beyond are Ctrough for MBG453.
As the half life of venetoclax is approximately 26 hours, the sample collected at Cycle 1 Day 8 
will be considered as the baseline venetoclax concentration at steady state before any dose 
administration of MBG453. The impact of MBG453 on the venetoclax concentrations may be 
assessed by comparing concentrations before and after 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.

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and expansion parts). The hypotheses to be tested and details of the testing strategy are 
described in Section 12.4.2.
Based on available data (Daniel A. et al 2018), the CR rate with the combination 
azacitidine+venetoclax is expected to be around 50%. The first criteria to declare the trial 
successful is to test if the CR with MBG453 in combination with azacitidine and venetoclax is 
superior to 50% (statistical significance). The second criteria is to obtain a minimum estimated 
effect size of at least 61% for the CR (clinical relevance).
The Bayesian formulation of this dual criterion design can be expressed as below:

Bayesian statistical significance: probability for a positive treatment effect (i.e. CR rate ≥ 
50% | data) ≥ 0.975

Clinical relevance: posterior median of CR rate ≥ 61%
With two criteria stated above the minimally required sample (nmin) size is 76 and the final 
sample size was set to 80. For 80 patients, the table below shows data scenarios (number of 
responders) with respective inferential results and decisions. The minimum number of 
responders to declare this trial successful (both statistical significance and clinical relevance 
met) is 49 out of 80 patients (61%). Based on simulations (Table 12-2), a total of 49 responders 
out of 80 results in a posterior median CR rate of 61.1% and a posterior probability for a positive 
effect (CR>50%) of 0.978. If the number of responders is less than 49, both criteria are missed 
(NO-GO). A uniform informative Beta (1,1) prior with mean 50% has been used in these 
calculations.
Table 12-1
Data scenarios, inferential results and decisions (n=80)
True CR rate
Posterior median CR
Posterior probability for 
a positive effect 
(CR>50%)
Decision for trial 
success
44/80 (55.0%)
54.9%
0.813
Failed
45/80 (56.3%)
56.1%
0.867
Failed
46/80 (57.5%)
57.4%
0.909
Failed
47/80 (58.8%)
58.6%
0.940
Failed
48/80 (60.0%)
59.8%
0.962
Failed
49/80 (61.3%)
61.1%
0.978
Successful
50/80 (62.5%)
62.3%
0.987
Successful
Operating characteristics for various true CR rates are presented in the table below. The type-I 
error under the null value (CR rate = 50%) is 2.8% and power is 79.5% assuming a true CR of 
65%.
Table 12-2
Operating characteristics for various true CR rate (n=80)
True CR rate
Probability of success (Go)
Probability of failure (No-Go)
40/80 (50.0%)*
0.028
0.972
44/80 (55.0%)
0.156
0.844
46/80 (57.5%)
0.287
0.713
48/80 (60.0%)
0.458
0.542
49/80 (61.3%)
0.549
0.451
50/80 (62.5%)
0.639
0.361

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True CR rate
Probability of success (Go)
Probability of failure (No-Go)
52/80 (65.0%)**
0.795
0.205
54/80 (67.5%)
0.904
0.096
56/80 (70.0%)
0.964
0.036
*For a true CR rate of 50% (null value), the probability for a trial success is 2.8% (type-I error).
**For a true CR rate of 65%, the probability for a trial success is 79.5% (power).
These calculations were made using the software R (version 3.4.3) using the RBesT package.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines 
for Good Clinical Practice, with applicable local law and regulations (including European 
Directive 2001/20/EC or European Clinical Trial Regulation 536/2014, US CFR 21), and with 
the ethical principles derived from international guidelines including the Declaration of 
Helsinki and Council for International Organizations of Medical Sciences (CIOMS).
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,
protocol amendments, written informed consent form, consent form updates, Investigator’s 
Brochure, subject recruitment procedures (e.g. advertisements) and any other written 
information to be provided to subjects.
Any amendments to the protocol will require IRB/IEC approval before implementation of
changes made to the study design, except for changes necessary to eliminate an immediate
hazard to subjects.
Protocols and any substantial amendments/modifications to the protocol will require health
authority approval prior to initiation except for changes necessary to eliminate an immediate
hazard to subjects.
The Investigator will be responsible for the following:

Signing 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.

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures

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
Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 CFR, ICH guidelines, the IRB/IEC, European Directive 2001/20/EC or European 
regulation 536/2014 for clinical studies, and all other applicable local regulations

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 or Clinical Trials Information System (CTIS) public website. 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 or CTIS public website 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.
Any data analysis carried out independently by the Investigator should be submitted to Novartis
before publication or presentation.
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Patient Last Visit (LPLV) date, since multinational studies are locked and reported based 
upon the global LPLV.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 

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Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for 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.

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Ørskov AD, Treppendahl MB, Skovbo A, et al (2015) Hypomethylation and up-regulation of 
PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of 
PD-1 and DNA methylation. Oncotarget p. 9612-26.

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16
Appendices
16.1
Appendix 1: Statistical Details for Safety Run-in Part: Bayesian 
model: prior and design properties for hypothetical data 
scenarios
This appendix provides details of the statistical model, the dosing decisions for some 
hypothetical data scenarios and the operating characteristics.
16.1.1
Statistical Models
The safety run-in part of this study to confirm that the combination is safe will be guided by a 
Bayesian analysis of dose limiting toxicity (DLT) data. The Bayesian analysis will be based on 
a standard logistic regression model to assess the integrated toxicity risk of the combination 
MBG453 with azacitidine and venetoclax. We assume that the triple combination has some 
background toxicity with what we have already observed with the combination MBG453 and 
azacitidine for the following reasons: 1/ azacitidine and venetoclax will be administered at fixed 
doses during the study; 2/ no DLT was observed for the combination azacitidine and venetoclax 
(study conducted by AbbVie and published in February 2018 (Lancet 2018)); 3/ a clinically 
relevant drug-drug interaction effect is considered unlikely; 4/ no dose-safety relationship was 
observed so far in clinical studies in patients treated with MBG453 and azacitidine. Thus, we 
decided to use only one model to assess the toxicity risk of this triple combination rather then 
quantifying the contribution of each of the three compounds.
Let π(d) be the risk of DLT for the combination MBG453+azacitidine+venetoclax given at dose 
d every 4 weeks (Q4W) for MBG453 (all other doses, for azacitidine and venetoclax, being 
fixed). This dose-DLT model is logistic:
logit(π(d))=log(α)+β log(d/d*) where d*= MBG453 800 mg Q4W (scaling dose)
Hence, α (>0) are the odd of a DLT at MBG453 800 mg Q4W in combination with azacitidine 
and venetoclax and β (>0) are the increase in the log-odds of a DLT by a unit increase in log-
dose of MBG453.
A meta-analytic-predictive (MAP) approach was used to derive the prior distribution for the 
logistic model parameters for the triple combination. The aim of the MAP approach is to derive 
a prior distribution for the logistic parameters (log(α* ),log(β* )) of the new trial using DLT 
data from historical studies. To make the prior more robust, an additional mixture component 
corresponding to high toxicity was introduced.
Description of the meta-analytic-predictive (MAP) approach
Let rds and nds be the number of patients with a DLT, and the total number of patients at dose d 
in historical trial s (s=1,…,S). The corresponding probability of a DLT is πds. The model 
specifications for the derivation of the MAP prior are as follows:
rds|πds ~ Bin (πds,nds )
logit (πds )=log(αs ) + βs log(d/d*)
(log(αs ),log(βs ))| μ,ψ ~ BVN(μ,ψ), s=1,…,S

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(log(α* ),log(β* )) | μ,ψ ~ BVN(μ,ψ)
The parameters μ =(μ1,μ2) and ψ are the mean and between-trial covariance matrix for the 
logistic parameters, the latter with standard deviations τ1, τ2, and correlation ρ. The parameters 
τ1 and τ2 quantify the degree of between trial heterogeneity. The following priors will be used 
for these parameters:

normal priors for μ1 and μ2,

log-normal priors for τ1 and τ2, and

a uniform prior for ρ
The MAP prior for model parameters in the new trial, (log(α* ),log(β* )), is the predictive 
distribution:
(log(α* ), log(β* )) | (rds, nds  s=1,…,S)
Since the predictive distribution is not available analytically, Markov chain Monte Carlo 
(MCMC) is used to simulate values from this distribution. This is implemented using JAGS 
version 3.12. The sample from this distribution is then approximated by a mixture of bivariate 
normal (BVN) distributions. BVN mixtures with increasing numbers of mixture components 
are fitted to the sample using the expectation-maximization (EM) algorithm (Dempster 1977). 
The optimal number of components of the mixture is then identified using the Akaike 
information criterion (AIC) (Akaike 1974).
Prior specifications for the MAP components
Firstly, weakly informative priors are assumed for log(α) and log(β), with mean (μ1) equal to 
logit (0.10) corresponding to the anticipated DLT rate at the reference dose (MBG453 800 mg 
Q4W) and with mean (μ2) equal to -2 corresponding to a slope parameter closed to 0 resulting 
from the absence of dose-safety relationship observed so far with MBG453 in combination with 
decitabine or azacitidine. Priors for τ1 and τ2 are assigned such that (1) their medians 
correspond to substantial between trial heterogeneity, and (2) their uncertainty (95% prior 
interval) cover plausible between trial standard deviations (Neuenschwander 2014). The prior 
distributions for the model used for deriving the MAP priors are specified in Table 16-1.
Table 16-1
Prior distributions for the parameters of the MAP model used to derive 
the prior for the logistic model parameters
Parameter
Prior distribution
μ1
N(mean = logit(0.10), sd = 2)
μ2
N(mean = -2, sd=1)
τ1
log-normal(mean = 0.25, sd = log(2)/1.96)
τ2
log-normal(mean = 0.125, sd = log(2)/1.96)
ρ
uniform(-1,1)
The prior described above was then updated by using the dose-DLT data from a Novartis study 
[MBG453X2105] in patients treated with MBG453 (single therapy or in combination with 
decitabine or azacitidine) (5.6%, 1 DLT out of 18 newly diagnosed AML patients). Historical 
data are presented in Table 16-2 and Table 16-3.

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Table 16-2
Historical data from [MBG453X2105] for MBG453 administered every 2 
weeks in combination with decitabine or azacitidine
MBG453 dose level 
(mg)
Number of evaluable 
patients
Number of patients 
treated with decitabine 
D or azacitidine A
Number of patients 
with a DLT defined as: 
240 mg Q2W
2
D:2, A:0
1
400 mg Q2W
10
D:5, A:5
0
Table 16-3
Historical data from [MBG453X2105] for MBG453 administered every 4 
weeks in combination with decitabine or azacitidine
MBG453 dose level 
(mg)
Number of evaluable 
patients
Number of patients 
treated with decitabine 
D or azacitidine A
Number of patients 
with a DLT defined as: 
800 mg Q4W
6
D:6, A:0
0
Prior specifications for the robustification component
To take into account the potential situation that MBG453+(decitabine or azacitidine) in 
combination with venetoclax could be substantially more toxic than when administered in 
combination with decitabine or azacitidine, a second prior component with vague bivariate 
normal distribution centered around a higher toxicity is added to improve the robustness of the 
final prior. The prior distributions for this robustness component are described below:

The mean (log(α) and log(β)) = (logit(0.33), -2), i.e. the median DLT rate at the reference 
dose (800 mg Q4W) was assumed to be 0.33 and the slope parameter was assumed to be 
closed to 0 resulting from the absence of dose-safety relationship observed so far with 
MBG453 in combination with decitabine or azacitidine.

To complete the specification, the prior standard deviation, sd(log(α) and log(β)), was set 
equal to (2,1), which allows for considerable prior uncertainty for the dose-toxicity profile.

The correlation, corr(log(α) and log(β)) was set equal to 0.
Summary of prior distributions
The prior distributions of the model parameters are summarized in Table 16-4.
The prior summaries for DLT rates are summarized in Table 16-5.
Table 16-4
Prior distribution (BVN Mixture (log(α, β))
Parameter
Mean
Standard 
deviations
correlation
weight
Component 1 (MAP 
prior)
(-2.682 ; -2.077)
(0.779 ; 0.971)
0.013
0.710
Component 2 (MAP 
prior)
(-4.090 ; -2.024)
(0.939 ; 0.967)
0.040
0.190
Component 3 (high 
toxicity)
(-0.708 ; -2.000)
(2 ; 1)
0
0.10

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Table 16-5
Summary of prior distribution of DLT rates
Prior probabilities that P(DLT) is 
in the interval :
Mean
SD
Quantiles
[0, 0.16)
[0.16, 
0.33)
[0.33,1]
2.5%
50%
97.5%
MBG453 
400 mg 
Q4W
0.883
0.068
0.049
0.092
0.142
0.005
0.050
0.617
MBG453 
800 mg 
Q4W
0.863
0.084
0.054
0.101
0.148
0.006
0.057
0.649
16.1.2
Hypothetical on-study scenarios
To illustrate the performance of the Bayesian model used to guide the tolerability assessment 
in the safety run-in part for MBG453 in combination with venetoclax plus azacitidine, 
hypothetical data scenarios are displayed in Table 16-6 and Table 16-7 below. Decision might 
be based on additional safety, PK or PD information.
The study will continue if probability of excessive toxicity (i.e. DLT rate ≥ 33% i.e. excessive 
toxicity) is less than 0.25, satisfying the EWOC criteria.
Table 16-6
Probability of excessive toxicity estimated by the Bayesian model 
after the first cohort
Scenario
MBG453 
regimen in the 
1st cohort
Number of 
patients in the 
1st cohort
Number of 
DLTs in the 1st
cohort
DLT rate in the 
1st cohort (%)
Probability of 
excessive 
toxicity
1
400 mg Q4W
3
0
0
0.005
2
400 mg Q4W
3
1
33.3
0.079
3
400 mg Q4W
3
2
66.7
0.474
4
400 mg Q4W
4
2
50.0
0.292
5
400 mg Q4W
4
3
75.0
0.787
6
400 mg Q4W
5
2
40.0
0.181
7
400 mg Q4W
5
3
60.0
0.612
8
400 mg Q4W
6
2
33.3
0.113
9
400 mg Q4W
6
3
50.0
0.450
Note that the EWOC (escalation with overdose control) criterion is defined as P (excessive toxicity) < 0.25.
If ≤ 1 DLTs out of 3 or 4 patients or ≤ 2 DLTs out of 5 or 6 patients are observed in the first 
cohort, the probability of excessive toxicity (i.e. DLT rate of ≥ 33%) with dosing regimen of 
MBG453 400 mg Q4W is < 25%, satisfying the EWOC criteria. In this case, it would be 
recommended to start the second cohort treated with MBG453 800 mg Q4W.
If ≥ 2 DLTs out of 3 or 4 patients or ≥ 3 DLTs out of 5 or 6 patients are observed in this first 
cohort, the probability of excessive toxicity with dosing regimen of MBG453 400 mg Q4W 
does not satisfy the EWOC criteria. In this case, it would be recommended to stop the trial.

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Table 16-7
Probability of excessive toxicity estimated by the Bayesian model 
after the second cohort
Scenario
MBG453 
regimen in 
the 2nd
cohort
Number of 
DLT/patient
s in the 1st
cohort
Number of 
patients in 
the 2nd
cohort
Number of 
DLTs in the 
2nd cohort
DLT rate in 
both 
cohorts (%)
Probability 
of excessive 
toxicity
1
800 mg Q4W
0/3
9
0
0
<0.001
2
800 mg Q4W
0/3
9
1
8.3
0.002
3
800 mg Q4W
0/3
9
2
16.7
0.011
4
800 mg Q4W
0/3
9
3
25.0
0.058
5
800 mg Q4W
0/3
9
4
33.3
0.188
6
800 mg Q4W
0/3
9
5
41.7
0.452
7
800 mg Q4W
1/3
9
3
33.3
0.188
8
800 mg Q4W
1/3
9
4
41.7
0.436
9
800 mg Q4W
2/4
9
2
30.8
0.134
10
800 mg Q4W
2/4
9
3
38.5
0.348
11
800 mg Q4W
2/5
9
2
28.6
0.103
12
800 mg Q4W
2/5
9
3
35.7
0.278
13
800 mg Q4W
2/5
9
4
42.9
0.539
14
800 mg Q4W
2/6
9
2
26.7
0.084
15
800 mg Q4W
2/6
9
3
33.3
0.223
16
800 mg Q4W
2/6
9
4
40.0
0.459
Note that the EWOC (escalation with overdose control) criterion is defined as P (excessive toxicity) < 0.25.
In case of no DLT observed in the first cohort:
If ≤ 4 DLTs out of 9 patients are observed in the second cohort, the probability of excessive 
toxicity (i.e. DLT rate of ≥ 33%) with dosing regimen of MBG453 800 mg Q4W is < 25%, 
satisfying the EWOC criteria. In this case, it would be recommended to start the expansion part.
If 5 or more DLTs out of 9 patients are observed in this second cohort, the probability of 
excessive toxicity with dosing regimen of MBG453 800 mg Q4W does not satisfy the EWOC 
criteria. In this case, it would be recommended to stop the trial.
In case of 1 or 2 DLT observed in the first cohort:
If ≤ 4 DLTs out of 12, 13 or 14 patients or ≤ 5 DLTs out of 15 patients are observed in both 
cohorts, the probability of excessive toxicity (i.e. DLT rate of ≥ 33%) with dosing regimen of 
MBG453 800 mg Q4W is < 25%, satisfying the EWOC criteria. In this case, it would be 
recommended to start the expansion part.
If ≥ 5 DLTs out of 12, 13 or 14 patients or ≥ 6 DLTs out of 15 patients are observed in both 
cohorts, the probability of excessive toxicity with dosing regimen of MBG453 800 mg Q4W 
does not satisfy the EWOC criteria. In this case, it would be recommended to stop the trial.

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16.1.3
Operating characteristics
Table 16-8 presents the probability to declare an excessive toxicity (i.e. the number of 
simulations for which the probability that the true DLT rate is ≥ 33% is equal or higher than 
25%) for different scenarios:

Scenario 1 (Prior Toxicity): the true DLT rate in both cohorts (MBG453 400 mg and 800 
mg Q4W) are similar to prior information; the combination of MBG453 with azacitidine 
and venetoclax is safe whatever the dose of MBG453 tested.

Scenario 2 (Low Toxicity with dose-DLT slope): the true DLT rate in the first cohort is 
equal to 10% (defined as safe) and the true DLT rate in the second cohort is equal to 20% 
(defined as safe).

Scenario 3 (Threshold Toxicity): the true DLT rate in both cohorts are equal to 33% 
(threshold to declare an excessive toxicity) without a dose-DLT relationship.

Scenario 4 (High Toxicity without dose-DLT slope): the true DLT rate in both cohorts are 
equal to 40% (defined as an excessive toxicity) without a dose-DLT relationship.

Scenario 5 (High Toxicity with dose-DLT slope): the true DLT rate in the first cohort is 
equal to 20% (defined as safe) and the true DLT rate in the second cohort is equal to 40% 
(defined as an excessive toxicity).

Scenario 6 (Very High Toxicity with dose-DLT slope): the true DLT rate in the first cohort 
is equal to 25% (defined as safe) and the true DLT rate in the second cohort is equal to 50% 
(defined as an excessive toxicity).
Table 16-8
Operating characteristics for different true values of DLT rate
Scenario
True DLT 
rate in the 
first cohort
True DLT 
rate in the 
second 
cohort
Probability 
to declare 
an 
excessive 
toxicity after 
the first 
cohorta
Probability 
to declare 
an 
excessive 
toxicity after 
the second 
cohortb
Probability 
to declare 
an 
excessive 
toxicity for 
at least one 
cohort
Mean 
number of 
patients 
enrolled in 
the safety 
run-in
1 (Prior 
Toxicity)
5.0%
5.7%
0.005
0
0.005
15.0
2 (Low 
Toxicity with 
dose-DLT 
slope)
10%
20%
0.023
0.039
0.061
14.7
3 (Threshold 
Toxicity)
33%
33%
0.269
0.316
0.500
12.2
4 (High 
Toxicity 
without dose-
DLT slope)
40%
40%
0.427
0.494
0.710
10.5
5 (High 
Toxicity with 
dose-DLT 
slope)
20%
40%
0.117
0.428
0.495
13.8

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Scenario
True DLT 
rate in the 
first cohort
True DLT 
rate in the 
second 
cohort
Probability 
to declare 
an 
excessive 
toxicity after 
the first 
cohorta
Probability 
to declare 
an 
excessive 
toxicity after 
the second 
cohortb
Probability 
to declare 
an 
excessive 
toxicity for 
at least one 
cohort
Mean 
number of 
patients 
enrolled in 
the safety 
run-in
6 (Very High 
Toxicity with 
dose-DLT 
slope)
25%
50%
0.175
0.674
0.731
13.2
Note: Simulations are performed in R3.4.3 with number of simulations = 1000 and randomization seed =12345;
a: probability to declare an excessive toxicity after the first cohort (cohort size of 3, 4, 5 or 6 patients) out of 
1000 simulated trials;
b: probability to declare an excessive toxicity after the second cohort (cohort size of 9, 10, 11 or 12 patients) 
given that over toxicity was not declared after the first cohort (conditional probability).
16.1.4
References
Akaike H (1974) A New Look at the Statistical Model Identification. IEEE Trans Automat 
Contr AC;19, p 716-723.
Dempster AP, Laird NM, Rubin DB (1977) Maximum likelihood from incomplete data via the 
EM algorithm. J Royal Stat Soc, p 1-38.
DiNardo CD, Pratz KW, Letai A (2018) Safety and preliminary efficacy of venetoclax with 
decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: 
a non-randomised, open-label, phase 1b study. Lancet Oncol, p 216-28.
Neuenschwander B, Matano A, Tang Z (2014) A Bayesian Industry Approach to Phase I 
Combination Trials in Oncology. In Zhao, W., & In Yang, H. (2015). Statistical methods in 
drug combination studies, p 95-136.

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16.2
Appendix 2: Concomitant medications to be used with caution 
and/or requiring action
The following lists are not comprehensive and are only meant to be used as a guide. The lists 
are based on the Novartis Internal Oncology Clinical Pharmacology Guidance, Drug-Drug 
Interaction and Co-Medication Considerations (v05, release date: 2015), which was compiled 
from the Indiana University School of Medicine’s P450 Drug Interaction Table 
(medicine.iupui.edu/clinpharm/ddis/main- table/) and supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies –Study Design, Data Analysis, and 
Implications 
for 
Dosing 
and 
Labeling 
(February 
2012) 
(fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.p
df), and the University of Washington’s Drug Interaction Database (druginteractioninfo.org/).
Please refer to Section 6.2.1.1 for actions that need to be taken when using these concomitant 
medications. Please contact the Novartis medical monitor with any questions.
Table 16-9
List of medications to be used with caution and/or requiring action 
during study drug treatment
Strong inhibitors of CYP3A
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak), 
indinavir/ritonavir, tipranavir/ritonavir, ritonavir, cobicistat, indinavir, 
ketoconazole, troleandomycin, telaprevir, danoprevir/ritonavir, 
elvitegravir/ritonavir, saquinavir/ritonavir, lopinavir/ritonavir, itraconazole, 
voriconazole, mibefradil, clarithromycin, posaconazole, telithromycin, 
grapefruit juice1, conivaptan, nefazodone, nelfinavir, idelalisib, 
boceprevir, atazanavir/ritonavir, darunavir/ritonavir
Moderate inhibitors of CYP3A
aprepitant, amprenavir, atazanavir, cimetidine, ciprofloxacin, crizotinib, 
cyclosporine, darunavir, diltiazem, dronedarone, erythromycin, 
faldaprevir, fluconazole, grapefruit juice1, imatinib, isavuconazole, 
netupitant, nilotinib, tofisopam, Schisandra sphenanthera (nan wu wei 
zi), asafoetida resin (Ferula asafoetida), verapamil
Strong inducers of CYP3A
carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, 
rifabutin, rifampicin, mitotane, St. John’s wort (Hypericum perforatum)
Moderate inducers of CYP3A
bosentan, dabrafenib, efavirenz, etravirine, genistein, modafinil, nafcillin, 
tipranavir/ritonavir, lopinavir, telotristat, thioridazine
Inhibitors of P-gp
alogliptin, amiodarone, azithromycin, canaglifozin, captopril, carvedilol, 
clarithromycin, clopidrogel, conivaptan, cremophor EL and RH40, 
curcumin, daclatasvir, diltiazem, dronedarone, eliglustat, erythromycin, 
felodipine, fluvoxamine, fostamatinib, ginkgo (Ginkgo biloba), green tea, 
indinavir, isavuconazole, itraconazole, ivacaftor, ketoconazole, lapatinib, 
lopinavir, mibefradil, milk thistle (silymarin, silibinin), mirabegron, 
nelfinavir, nifedipine, nitrendipine, 
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak), paroxetine, 
propafenone, quercetin, quinidine, quinine, ranolazine, rifampicin, 
ritonavir, rolapitant, saquinavir, Schisandra chinensis extract (wuweizi), 
simeprevir, St. John’s wort extract (Hypericum perforatum) , survorexant, 
talinolol, telaprevir, telmisartan, ticagrelor, tipranavir, tolvaptan, 
valspodar, vandetanib, velpatasvir, verapamil, voclosporin, vorapaxar
NTI substrates of P-gp
cyclosporine, digoxin, fentanyl, paclitaxel, phenytoin, quinidine, 
sirolimus, tacrolimus
Substrates of P-gp (≥2X AUC 
change)
aliskiren, ambrisentan, atorvastatin, azithromycin, colchicine, dabigatran, 
digoxin, docetaxel, domperidone, doxorubicin, fentanyl, fexofenadine, 
lapatinib, linezolid, loperamide, maraviroc, nadolol, nevirapine, 
paclitaxel, proguanil, quinidine, ranolazine, ritonavir, saquinavir, 
simvastatin, sirolimus, sofosbuvir, tacrolimus, ticagrelor, topotecan

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Substrates of P-gp mentioned in 
USPI
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, 
apremilast, aprepitant, boceprevir, bosentan, carvedilol, carvedilol, 
caspofungin, ceritinib, citalopram, colchicine, cyclosporine, dabigatran, 
digoxin, doxepin, doxorubicin, eribulin, everolimus, fidaxomicin, 
fluvastatin, fosamprenavir, gatifloxacin, idelalisib, iloperidone, 
indacaterol, irbesartan, lacosamide, lapatinib, levetiracetam, 
levofloxacin, linagliptin, losartan, maraviroc, mirabegron, moxifloxacin, 
naloxegol, nateglinide, nintedanib, olodaterol, pantoprazole, paroxetine, 
pazopanib, posaconazole, pravastatin, quinine, ranolazine, riociguat, 
risperidone, rivaroxaban, saquinavir, silodosin, simeprevir, sirolimus, 
sitagliptin, sorafenib, telaprevir, tenofovir, ticagrelor, tipranavir, tolvaptan, 
topotecan, umeclidinium, valsartan, vardenafil, vincristine, voriconazole
Substrates of BCRP
Atorvastatin, daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, 
imatinib, methotrexate, mitoxantrone, paritaprevir, pitavastatin, 
rosuvastatin, irinotecan, ethinyl estradiol, simvastatin, sofosbuvir, 
sulfasalazine, tenofovir, topotecan, venetoclax
1 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent.