A Phase III, Multi-center, Open-label, Randomized Study of Oral Asciminib Versus Investigator Selected TKI in Patients With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase
Phase: PHASE3
Conditions: Chronic Myeloid Leukemia (CML) Philadelphia Chromosome Positive
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
ABL001/asciminib
Clinical Trial Protocol CABL001J12301
A phase III, multi-center, open-label, randomized study of 
oral asciminib versus Investigator selected TKI in patients 
with newly diagnosed Philadelphia Chromosome Positive 
Chronic Myelogenous Leukemia in Chronic Phase
Document type:
Amended Protocol Version (Clean)
EUDRACT number:
2021-000678-27
Version number:
02 
Clinical Trial Phase:
III
Release date:
15-May-2023 (final)
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020

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Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................6
List of figures.......................................................................................................................7
List of abbreviations ............................................................................................................8
Glossary of terms...............................................................................................................12
Amendment 02 (15-May-2023).........................................................................................15
Amendment 01 (09-May-2022).........................................................................................19
Protocol summary..............................................................................................................24
1
Introduction........................................................................................................................29
1.1
Background............................................................................................................29
1.1.1
Disease background...............................................................................29
1.1.2
Current management recommendations and unmet medical need........30
1.2
Purpose...................................................................................................................31
1.2.1
Scientific rationale and purpose ............................................................31
1.2.2
Preliminary efficacy and safety.............................................................32
1.2.3
Preliminary pharmacokinetics...............................................................36
2
Objectives, endpoints, and estimands................................................................................38
2.1
Primary estimands..................................................................................................41
2.2
Secondary estimands..............................................................................................42
2.2.1
Key Secondary Estimands.....................................................................42
2.2.2
Other secondary estimands....................................................................44
3
Study design.......................................................................................................................44
4
Rationale ............................................................................................................................47
4.1
Rationale for study design......................................................................................47
4.2
Rationale for dose/regimen and duration of treatment...........................................49
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs.......................................................................................................................52
4.4
Purpose and timing of interim analyses/design adaptations ..................................53
4.5
Risks and benefits ..................................................................................................53
4.6
Rationale for Public Health Emergency mitigation procedures.............................54
5
Study Population................................................................................................................55
5.1
Inclusion criteria ....................................................................................................55
5.2
Exclusion criteria ...................................................................................................56
6
Treatment...........................................................................................................................58
6.1
Study treatment ......................................................................................................58
6.1.1
Investigational and control drugs ..........................................................59

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6.1.2
Additional study treatments...................................................................59
6.1.3
Supply of study treatment......................................................................59
6.1.4
Treatment arms/group ...........................................................................59
6.1.5
Post-trial access to treatment.................................................................60
6.1.6
Treatment duration ................................................................................60
6.2
Other treatment(s) ..................................................................................................61
6.2.1
Concomitant therapy .............................................................................61
6.2.2
Prohibited medication............................................................................63
6.3
Participant numbering, treatment assignment, randomization...............................63
6.3.1
Participant numbering ...........................................................................63
6.3.2
Treatment assignment, randomization...................................................64
6.4
Treatment blinding.................................................................................................64
6.5
Dose escalation and dose modification..................................................................64
6.5.1
Dose modifications................................................................................65
6.5.2
Follow-up for toxicities.........................................................................72
6.5.3
Anticipated risks and safety concerns of the study drug .......................74
6.6
Additional treatment guidance...............................................................................74
6.6.1
Treatment compliance ...........................................................................74
6.6.2
Emergency breaking of assigned treatment code ..................................74
6.7
Preparation and dispensation .................................................................................75
6.7.1
Handling of study treatment and additional treatment ..........................75
6.7.2
Instruction for prescribing and taking study treatment..........................76
7
Informed consent procedures.............................................................................................77
8
Visit schedule and assessments..........................................................................................79
8.1
Screening................................................................................................................92
8.1.1
Eligibility screening...............................................................................93
8.1.2
Information to be collected on screening failures .................................93
8.2
Participant demographics/other baseline characteristics........................................93
8.3
Efficacy..................................................................................................................93
8.3.1
Molecular response................................................................................93
8.3.2
Cytogenetic Response ...........................................................................95
8.3.3
Hematological Response .......................................................................95
8.3.4
Appropriateness of efficacy assessments ..............................................95
8.4
Safety .....................................................................................................................96
8.4.1
Laboratory evaluations..........................................................................96
8.4.2
Electrocardiogram (ECG)......................................................................98
8.4.3
Pregnancy and assessments of fertility..................................................99

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8.4.4
Appropriateness of safety measurements ............................................100
8.5
Additional assessments ........................................................................................100
8.5.1
Clinical Outcome Assessments (COAs)..............................................101
8.5.2
Pharmacokinetics.................................................................................104
8.5.3
Biomarkers ..........................................................................................105
8.5.4
Resource utilization.............................................................................107
9
Discontinuation and completion ......................................................................................107
9.1
Discontinuation from study treatment and from study ........................................108
9.1.1
Discontinuation from study treatment.................................................108
9.1.2
Discontinuation from study.................................................................110
9.1.3
Withdrawal of informed consent/Opposition to use data/biological 
samples ................................................................................................110
9.1.4
Lost to follow-up.................................................................................111
9.1.5
Early study termination by the sponsor...............................................111
9.2
Study completion and post-study treatment.........................................................111
10 Safety monitoring, reporting and committees..................................................................112
10.1
Definition of adverse events and reporting requirements....................................112
10.1.1
Adverse events.....................................................................................112
10.1.2
Serious adverse events.........................................................................114
10.1.3
SAE reporting......................................................................................115
10.1.4
Pregnancy reporting.............................................................................116
10.1.5
Reporting of study treatment errors including misuse/abuse ..............117
10.1.6
Adverse events of special interest .......................................................117
10.2
Additional Safety Monitoring..............................................................................117
10.2.1
Liver safety monitoring.......................................................................117
10.2.2
Renal safety monitoring ......................................................................118
10.2.3
Data Monitoring Committee................................................................118
10.2.4
Steering Committee.............................................................................119
11 Data Collection and Database management ....................................................................119
11.1
Data collection .....................................................................................................119
11.2
Database management and quality control ..........................................................119
11.3
Site monitoring.....................................................................................................120
12 Data analysis and statistical methods...............................................................................121
12.1
Analysis sets.........................................................................................................121
12.2
Participant demographics and other baseline characteristics...............................122
12.3
Treatments............................................................................................................122
12.4
Analysis of the primary endpoint(s)/estimand(s).................................................123

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12.4.1
Definition of primary endpoint(s)/estimand(s)....................................123
12.4.2
Statistical model, hypothesis, and method of analysis ........................124
12.4.3
Handling of remaining intercurrent events of primary estimand ........125
12.4.4
Handling of missing values not related to intercurrent event..............125
12.4.5
Sensitivity analyses for primary endpoint/estimand............................126
12.4.6
Supplementary analysis.......................................................................126
12.4.7
Supportive analyses.............................................................................128
12.5
Analysis of the key secondary endpoint(s)/estimand(s) ......................................128
12.5.1
Definition of key secondary endpoint(s)/estimand(s) .........................128
12.5.2
Statistical model, hypothesis and methods of analysis........................129
12.5.3
Handling of remaining intercurrent events of key secondary 
estimand...............................................................................................130
12.5.4
Handling of missing values not related to intercurrent event..............130
12.5.5
Sensitivity analysis for key secondary endpoint/estimand..................131
12.5.6
Supplementary analysis.......................................................................131
12.5.7
Supportive analyses.............................................................................133
12.6
Analysis of the secondary safety end-point of Time to Discontinuation of 
Study Treatment due to AE (TTDAE).................................................................133
12.7
Testing Strategy and Type-I Error Control for the multiple primary and key 
secondary objectives; and for the secondary safety objective .............................134
12.8
Analysis of secondary endpoints/estimands ........................................................139
12.8.1
Efficacy and/or Pharmacodynamic endpoint(s) ..................................139
12.8.2
Safety endpoints ..................................................................................146
12.8.3
Tolerability ..........................................................................................147
12.8.4
Pharmacokinetics.................................................................................147
12.8.5
Patient reported outcomes ...................................................................148
12.9
Analysis of exploratory endpoints .......................................................................149
12.9.1
Exploratory Biomarkers ......................................................................149
12.9.2
Pharmacogenomics..............................................................................150
12.9.3
Exploratory Efficacy ...........................................................................150
12.9.4
Exploratory Patient Reported Outcomes.............................................150
12.9.5
Exploratory Heath Care Resource Utilization.....................................151
12.10 Interim analyses ...................................................................................................151
12.11 Sample size calculation........................................................................................151
13 Ethical considerations and administrative procedures.....................................................154
13.1
Regulatory and ethical compliance......................................................................154
13.2
Responsibilities of the Investigator and IRB/IEC................................................154

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13.3
Publication of study protocol and results.............................................................155
13.4
Quality Control and Quality Assurance...............................................................155
13.5
Data Protection.....................................................................................................156
13.6
Participant Engagement .......................................................................................156
14 Protocol adherence...........................................................................................................156
14.1
Protocol amendments...........................................................................................157
15 References........................................................................................................................158
16 Appendices.......................................................................................................................162
16.1
Appendix 1: Concomitant Medications. Prohibited medication and 
medication to be used with caution......................................................................162
16.2
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements.........................................................................................................163
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up....165
16.4
Appendix 4: Eligibility based on serologic markers for hepatitis B and C..........165
List of tables
Table 2-1
Objectives and related endpoints...........................................................38
Table 6-1
Investigational and control drugs* ........................................................59
Table 6-2
Criteria for dose reduction / interruption and re-initiation of 
asciminib treatment for adverse drug reactions.....................................66
Table 6-3
Dose reduction steps for asciminib........................................................71
Table 6-4
Clinical and diagnostic assessments to rule out possible alternative 
causes of observed Liver Test abnormalities.........................................73
Table 6-5
Dose and treatment schedule*...............................................................76
Table 8-1
Assessment Schedule.............................................................................81
Table 8-2
Blood samples (Molecular response) ....................................................94
Table 8-3
Safety and tolerability assessments .......................................................96
Table 8-4
Laboratory Assessments........................................................................97
Table 8-5
Central ECG collection plan in all randomized arms............................99
Table 8-6
Pharmacokinetic blood collection log .................................................105
106
Table 12-1
Non compartmental pharmacokinetic parameters in full PK group....148
Table 12-2
Historic MMR rates from pivotal TKI trials in newly diagnosed 
patients with CML-CP.........................................................................151
Table 12-3
Sensitivity of power to changes in the MMR assumptions (N=402) ..154
Table 16-1
Concomitant medications to be used with caution..............................162
Table 16-2
Liver event and laboratory trigger definitions.....................................163

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Table 16-3
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia..............................................................................163
Table 16-4
Specific Renal Alert Criteria and Actions...........................................165
Table 16-5
Eligibility based on serologic marker for hepatitis B and C ...............165
List of figures
Figure 3-1
Study design ..........................................................................................45
Figure 12-1
Testing hierarchy (graphical gatekeeping procedure) .........................136

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List of abbreviations
2G
Second Generation
ABL
Abelson proto-oncogene
AE
Adverse Event
AESI
Adverse event of special interest
ALL
Acute lymphoblastic leukemia
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANC
Absolute neutrophil count
AP
Accelerated phase
AST
Aspartate Aminotransferase
ATP
Adenosine triphosphate
AUC
Area under the curve
AV block
Atrioventricular block
BC
Blast crisis
BCR
Breakpoint Cluster Region gene
BCR-ABL1 
BCR-ABL1 fusion gene (considered equivalent to BCR::ABL1)
BCR::ABL1
BCR::ABL1 fusion gene (considered equivalent to BCR-ABL1)
BCR-ABL1
BCR::ABL1
BCR-ABL- fusion protein (considered equivalent to BCR::ABL1)
BCR::ABL1 fusion protein (considered equivalent to BCR-ABL1)
BCRP
Breast Cancer Resistant Protein
BID
bis in diem/twice a day
BLQ
Below the Limit of Quantification
BP
Blood Pressure
CABG
Coronary Artery Bypass Graft
CBC
Complete Blood Count
CCI
Charlson Comorbidity Index
CCyR
Complete Cytogenetic Response
CD-transferrin
Carbohydrate Deficient transferrin
CFR
Code of Federal Regulations
CHR
Complete Hematological Response
CI
Confidence Interval
CrlCl
Creatinine Clearance
CML
Chronic Myelogenous Leukemia
CML-AP
Chronic Myelogenous Leukemia-Accelerated Phase
CMO&PS
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
CNS
Central Nervous System
COA
Clinical Outcome Assessment
CP
Chronic phase
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical study report
CT
Computed tomography

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CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events 
CTT
Clinical Trial Team
CV
coefficient of variation
CYP3A4
Cytochrome P450 3A4
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DS&E
Drug Safety and Epidemiology
DTI
Direct Thrombin Inhibitors
EBV
Epstein-Barr virus
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
EFS
Event free survival
EGFR
Epidermal Growth Factor Receptor
ELN
European Leukemia Network
ELTS
EUTOS Long-Term Survival
EMA
European Medicines Agency
EORTC QLQ
European Organization for Research and Treatment of Cancer Quality of life Questionnaire
EOT
End of Treatment
EQ
EuroQol
EQ-VAS
EuroQol Visual analog scale
ER
Emergency Room
ERCP
Endoscopic Retrograde Cholangio Pancreatography
eSAE
electronic Serious Adverse Event
eSource
electronic Source
EU
European Union
EU CTR
European Union Clinical Trial Regulation
EUTOS
EUropean Treatment Outcome Study
FAS
Full Analysis Set
FDA
Food and Drug Administration
FFS
Failure Free Survival
FIH
First In Human
FSH
Follicle Stimulating Hormone
FU
Follow Up
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
GLDH
Glutamate Dehydrogenase
GP
General Practitioner

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h
Hour
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B Virus
HCRU 
Healthcare Resource Utilization 
HCV
Hepatitis C Virus
HDL
High density lipoprotein
HEV
Hepatitis E Virus
HIV
Human immunodeficiency virus
HR
Hematological Response
HRQoL
Health-Related Quality of Life
HSV
Herpes Simplex Virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
IE
Intercurrent Events
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IHC
Immunohistochemistry
IMA
Imatinib
IMP
Investigational Medicinal Product
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IS
International Scale
KM
Kaplan-Meier
LDH
lactate dehydrogenase
LDL
Low density lipoprotein
LLN
lower limit of normal
LLOQ
lower limit of quantification
MCV
Mean Corpuscular Volume
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
MI
Myocardial Infarction
mL
milliliter(s)
MMR
Major Molecular Response
MR
Molecular Response
MRI
Magnetic resonance imaging
MTD
Maximum Tolerated Dose
NCCN
National Comprehensive Cancer Network
OATP1B
Organic anion-transporting polypeptide 1B
OHP
Off-site Healthcare Professional
OS
Overall survival
P-gp
Permeability glycoprotein
PAS
Pharmacokinetic analysis set
PBPK
Physiologically based pharmacokinetic

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PCR
Polymerase Chain Reaction
PD
Pharmacodynamic(s)
PDGF
Platelet-derived growth factor 
PFS
Progression-Free Survival 
Ph+
Philadelphia chromosome positive
PK
Pharmacokinetic(s)
PLT
Platelets
PRO
Patient Reported Outcomes
PSDS
Post-Study Drug Supply
PT
prothrombin time
PTA
Post Trial Access
QD
Once a day
QMS 
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
R Value
ALT/ALP x ULN
RD
Recommended Dose
RDE
Recommended dose for expansion
RNA
Ribonucleic acid
RoW 
Rest of World
RQ-PCR
Real time quantitative polymerase chain reaction
RU
Resource Utilization
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Steering committee
SD
standard deviation
SOP
Standard Operating Procedure
Sp
Specialist
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
Total bilirubin
TdP
Torsades de Pointes
TFQ
Trial Feedback Questionnaires
TKI
Tyrosine Kinase Inhibitor
TSH
Thyroid Stimulation Hormone
TTDAE
Time To Discontinuation of study treatment due to AE
TTF
Time to treatment failure
UC
Urgent Care
UGT
Uridin diPhospho-glucuronosyltransferase
ULN
upper limit of normal
US
United States
WBC
white blood cell(s)
WHO
World Health Organization 
WoC
Withdrawal of Consent

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Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study participant 
CE marking
A marking by which a manufacturer indicates that a device is in conformity with the 
applicable requirements set out in European Union legislation providing for its affixing.  
CE marking of medical devices is required prior to lawfully placing them on the 
European Union market.
Clinical Outcome 
Assessment (COA)
A measure that described or reflects how a person feels, functions or survives
Clinical Trial Team
A group of people responsible for planning, execution and reporting of all clinical trial 
activities. Examples of team members include the Study Lead, Medical Monitor, Trial 
Statistician, etc.
Coded Data
Personal Data which has been de-identified by the investigative center team by 
replacing personal identifiers with a code.
Cohort
A group of individuals who share a common exposure, experience or characteristic, or 
a group of individuals followed- up or traced over time
Control drug
A study intervention (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Cycles
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g., q28 days)
Discontinuation from 
study
Point/time when the participant permanently stops receiving the study treatment and 
further protocol required assessments or follow-up, for any reason. No specific 
request is made to stop the use of their samples or data.
Discontinuation from 
study treatment
Point/time when the participant permanently stops receiving the study treatment for 
any reason (prior to the planned completion of study drug administration, if any). 
Participant agrees to the other protocol required assessments including follow-up. No 
specific request is made to stop the use of their samples or data.
Dosage
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data using 
data collection systems, such as Web-based applications, interactive voice response 
systems and clinical laboratory interfaces. EDC includes the use of Electronic Case 
Report Forms (eCRFs) which are used to capture data transcribed from source 
data/documents used at the point of care
End of the clinical trial
The end of the clinical trial is defined as the last visit of the last participant or at a later 
point in time as defined by the protocol 
Enrollment
Point/time of participant entry into the study at which informed consent must be 
obtained; The action of enrolling one or more participants
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines source 
documents and case report forms (eCRFs) into one application, allowing for the real 
time collection of clinical trial information to Novartis/Sponsors and other oversight 
authorities, as appropriate
Estimand 
As defined in the ICH E9 (R1) addendum, estimand is a precise description of the 
treatment effect reflecting the clinical question posed by the trial objective. It 
summarizes at a population-level what the outcomes would be in the same 
participants under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, as 

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well as the specification of how the remaining intercurrent events are addressed and a 
population- level summary for the variable.
Healthy volunteer
A person with no known significant health problems who volunteers to be a study 
participant 
Intercurrent events
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest.
Investigational drug/ 
treatment
The drug whose properties are being tested in the study
Investigational 
Product/ 
Investigational 
Medicinal product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference (such as an active comparator) in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way 
different from the approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use.
Investigational 
Medical Device
Medical Device being assessed for safety or performance in a clinical investigation. 
This includes devices already on the market and being evaluated for new intended 
uses, new populations, new materials, or design changes
Medication number
A unique identifier on the label of medication kits
Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for randomization and 
who did not take study treatment, but have been inadvertently randomized into the 
study or the participant allocated to an invalid stratification factor
Off-site
Describes trial activities that are performed at remote location by an off-site healthcare 
professional, such as procedures performed at the participant's home.
Off-site healthcare 
Professional (OHP)
A qualified healthcare professional, who performs certain protocol procedures for the 
participant in an off-site location such as a participant's home.
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Part 
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple 
dose part, or a part in participants with established disease and in those with newly-
diagnosed disease
Participant
A trial participant (can be a healthy volunteer or a patient) "Participant" terminology is 
used in the protocol whereas term "Subject" is used in data collection
Participant number
A unique number assigned to each participant upon signing the informed consent. 
This number is the definitive, unique identifier for the participant and should be used to 
identify the participant throughout the study for all data collected, sample labels, etc.
Patient-Reported 
Outcome (PRO)
A measurement based on a report that comes directly from the participant about the 
status of a participant's health condition without amendment or interpretation of the 
participant's report by a clinician or anyone else
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical 
trial database setup and eventually in analysis
Perpetrator drug
A drug which affects the pharmacokinetics of the other drug
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 participant 
identifier information, study information and biological samples.
Premature participant 
withdrawal
Point/time when the participant exits from the study prior to the planned completion of 
all study drug administration and/or assessments; at this time all study drug 
administration is discontinued and no further assessments are planned
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.
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 
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Remote
Describes any trial activities performed at a location that is not the investigative site
Run-in Failure
A participant who is screened but not randomized/treated after the run-in period 
(where run-in period requires adjustment to participant’s intervention or other 
treatment)
Screen Failure
A participant who did not meet one or more criteria that were required for participation 
in the study
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 in cancer
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the 
original site to other parts of the body
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent by the 
first participant
Study device
Study device is a medical device (marketed or investigational) that is used in a 
circumstance that makes it part of the investigation.
Study treatment
Any drug or combination of drugs   or intervention administered to the study 
participants as part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy
Tele-visit
Procedures or communications conducted using technology such as telephone or 
video-conference, whereby the participant is not at the Investigative site where 
the Investigator will conduct the trial
Treatment arm/group 
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts.
Treatment of interest
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g. as add-on to standard of care, or might 
consist of an overall regimen involving a complex sequence of interventions. This is 
the treatment of interest used in describing the related clinical question of interest, 
which might or might not be the same as the study treatment.
Variable (or endpoint)
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include whether 
the participant experiences an intercurrent event.
Withdrawal of 
consent
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 02 (Clean)
Protocol No. CABL001J12301
Amendment 02 (15-May-2023) 
Amendment rationale 
As of 15-May-2023 the enrollment in the study is complete, 475 participants have been screened, 
and 405 participants have been randomized and 347 are receiving treatment. The study is 
ongoing.
The main purpose of this protocol amendment is to:
Clarify dose modification guidelines for hepatotoxicity for asciminib and dose discontinuation 
rule as applicable to both treatment arms:
1. As the study includes patients with baseline total bilirubin elevation (< 3xULN are 
eligible), the dose modification guidelines for patients with elevated bilirubin or 
ALT/AST at baseline have been clarified as follows:
•
For ALT/AST elevations (when baseline elevated): Dose modification criteria have 
been revised to ensure that the combination of baseline values (3x, 5x etc. change from 
baseline) with ULN levels (5x ULN, 8x ULN, etc.) are taken into consideration
•
Update dose modification criteria for baseline elevated total bilirubin levels: The 
reference to baseline elevated bilirubin levels was removed in the recommendations for 
dose modification of asciminib in response to drug-induced elevation of bilirubin.
In addition, guidance for discontinuing treatment for elevations of AST and ALT > 20 x 
ULN has been also clarified. In the current protocol, patients with (higher than 20 x ULN) 
may continue in the study as per guidelines “hold the dose and resume at a lower dose upon 
resolution”. Although based on the current safety data on asciminib there is a low likelihood 
of a >20 x ULN of AST/ALT occurrence at first presentation of a hepatic adverse event, as 
a conservative measure guidance for discontinuing treatment for elevations > 20 x ULN has 
been clarified in this protocol amendment as below. Of note, no patient in this study has met 
this criterion till date. For additional information on liver abnormalities, please refer to 
ABL001 IB Ed10- 7.2.7.
•
For isolated ALT/AST elevations (when baseline normal): Permanently discontinue if 
ALT/AST is > 20x ULN
The rules for discontinuation due to hematologic and non-hematologic AEs were placed more 
prominently in the protocol to clarify that these rules apply to both treatment arms for prolonged 
treatment interruption. 
If a participant requires a dose interruption more than 28 days for a non-hematologic toxicity, 
then the participant must be discontinued from the study treatment. If a hematologic toxicity 
(cytopenia Grade 3 or 4) lasts for more than 42 days without recovery to at least a Grade 2, 
despite the study treatment interruption and adequate management (including hematopoietic 
growth factors), then the participant must be discontinued from the study treatment.
Additionally, the following changes have been implemented:
2. Re-escalation rules for participants receiving asciminib have been changed to allow more 
than one re-escalation in case the event is considered to be significantly different than the 
one(s) experienced previously.

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3. The concomitant medications to be used with caution have been updated. OATP1B and 
BCRP substrates have been added to this list. This is based on the results of a PBPK 
simulation study done as part of protocol marketing requirements request per FDA 
(ABL001 IB Ed.10 – Section 1.4.2).
Editorial changes to correct typos and provide clarifications have been implemented throughout 
the protocol to improve readability and are summarized as follows:
•
Clarification to the visit assessment section
•
Clarification on the blood sampling for confirmed loss of MMR
•
Clarification on the requirements of ePRO assessments
•
Update on the duration of the storage of source documents and ICF documents of 15 years
•
Clarification to the ELN treatment failure criteria at 3 months
•
Requirement of unscheduled assessments of any type as per the Investigator’s decision and 
their documentation in the eCRF
•
Clarification on the post-trial access of asciminib. The eligibility criteria for the post-trial 
access were removed as they are specified in the rollover study protocol CABL001A2001B.
•
The CRFs for collection of smoking history and Charlson comorbidity index were already 
a part of the study, the VES and Screening sections have been updated to reiterate that these 
should be collected as a part of baseline medical and cardiovascular history
•
Definition of confirmed loss of MMR has been clarified where previously stated 
“subsequent sample analysis within 4-6 weeks” has been replaced by “analysis of another 
sample taken after an interval of not less than 4 weeks and not more than 6 weeks”. This 
update does not change the collection of data, schedule of assessment or analysis for this 
molecular response parameter.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track-changes version of the 
protocol using red underlined font for insertions. 
The following sections, tables and figures were changed:
•
List of abbreviations
•
Glossary of terms: Added the definition for 'Investigational Product/ Investigational 
Medicinal product' per latest mandatory template modification
•
Section 1.2.2 Preliminary efficacy and safety: The whole section was updated based on 
ABL001 IB Ed.10
•
Section 4.6 Rationale for Public Health Emergency mitigation procedures: Updated per 
latest mandatory template modification
•
Section 6.1.5 The previous title “Guidelines for continuation of treatment” was updated to 
“Post-trial access to treatment” to be more precise. Clarification on post-trial access 
added. Removed the criteria to continue asciminib administration and to discontinue the 
treatment
•
Section 6.1.6 Treatment duration: Treatment failure added to be consistent in wording 
throughout the protocol

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•
Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action: Updated 
for OATP1B, BCRP substrates as per ABL001 IB Ed.10
•
Section 6.5.1 Dose modifications:
•
The rules for discontinuation due to hematologic and non-hematologic AEs were placed 
more prominently in the protocol to clarify that these rules apply to both treatment arms 
for prolonged treatment interruption
•
Change of re-escalation instructions. More than one re-escalation may be allowed under 
certain circumstances 
•
Updates of table 6-2 Criteria for dose reduction / interruption and re-initiation of 
asciminib treatment for adverse drug reactions for hepatic investigations
•
Repetitive wording for dose interruption and discontinuation criteria removed
•
Updates and clarification on hepatic investigations: Isolated Total bilirubin 
(TBL) elevations, isolated Aspartate (AST) and Alanine (ALT) 
aminotransferases elevations, and combined AST and ALT and TBL elevations
•
Clarification added for participants treated with the Investigator selected TKI
•
Wording updated from Liver Function Tests (LFT) to liver tests to be more precise
•
Section 6.5.2.1 Follow up on potential drug-induced liver injury (DILI) cases: 
•
Information regarding pediatric patients was removed as it is not applicable for the 
trial.
•
Wording updated from Liver Function Tests (LFT) to liver tests to be more precise
•
Section 8 Visit schedule and assessments: 
•
Clarification for unscheduled visits added “In case unscheduled assessments of any 
type are required, they may be performed as per Investigator’s decision and will be 
recorded in the appropriate eCRF.” 
•
Table 8-1 Assessment Schedule updated to include Smoking History and CCI 
assessments, Serum Pregnancy Test and Prior/ Concomitant Medication were updated
•
Section 8.1 Screening: Clarification added for Smoking History and Charlson comorbidity 
index CCI assessments
•
Section 8.3.1 Molecular Response: Clarification added for blood sampling for confirmed 
loss of MMR, for additional unscheduled samples and for discontinuation of treatment
•
Section 8.4 Safety: Table 8-3 Safety and tolerability assessments updated to include the 
spleen size if extramedullary involvement is detected
•
Section 8.5.1 Clinical Outcome Assessments (COAs): Clarification added that COA are 
required for patients who discontinued the treatment
•
Section 8.5.2.3 Pharmacogenomics: Clarification for treatment arm for pharmacogenetics 
samples collection added
•
Section 9.1.1 Discontinuation from study treatment: Added clarification in the Treatment 
Failure Criteria and for discontinuation of treatment
•
Section 11.3 Site monitoring: Added the requirement to retain source documents and 
original ICFs signed by the participants for 15 years
•
Section 12.8.1.1 Other Efficacy Endpoints: 

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•
Lack of efficacy was updated to unsatisfactory treatment response to be consistent in 
wording throughout the protocol
•
Clarification on treatment failure criteria at 3 months added
•
Section 12.9.4 Exploratory Patient Reported Outcomes: Update of questionnaire naming
•
Section 12.11 Sample size calculation: Typo corrected for primary endpoint
•
Section 16.1 Appendix 1: Concomitant Medications. 
•
Information for prohibited medication removed as the table for prohibited medication 
has been removed in a previous protocol amendment
•
OATP1B and BCRP substrates updated as per ABL001 IB Ed.10
•
Section 16.2 Appendix 2: Wording updated from Liver Function Tests (LFT) to liver tests 
to be more precise
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.

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Amendment 01 (09-May-2022) 
Amendment rationale 
As of 28-Mar-2022, 101 participants have been screened in the study and 69 participants have 
been randomized and are receiving treatment. The study is ongoing.
The main purpose of this protocol amendment is to:
•
Further clarify requirements for eligibility, dose administration and pregnancy testing in 
view of the comparator arm being approved TKIs selected by Investigators with the below 
changes:
•
Clarify Inclusion Criterion 3 defining diagnosis of CML-CP to align with updated 
treatment recommendations (ELN 2020) and clinical practice
•
Exclusion criterion 1 has been updated to allow either imatinib, or nilotinib, or dasatinib 
or bosutinib for ≤ 2 weeks prior to randomization (Original Protocol only allowed 
imatinib). Based on feedback from Investigators, the use of any of these TKIs is 
standard for initial disease control, and is especially applicable to sites that are referral 
centers. It is not expected that a short course of TKI will impact on the efficacy 
endpoints. Allowing all comparators rather than only one will allow reduction of any 
selection bias based on early intolerance to any specific TKI.
•
Update of Exclusion Criteria 14 (ii) concerning use of effective contraception during 
treatment with asciminib 
•
ONLY for US Original Protocol: the requirement for male contraception from the US 
Version of the protocol has now been removed following FDA acceptance of the non-
requirement in the approved label for asciminib. Asciminib is not genotoxic, and no 
embryo- and fetotoxic effects can be anticipated via seminal fluid. Thus, male 
contraception is not required by the male participants in asciminib clinical trials.
•
Exclusion Criterion 15 updated to include known hypersensitivity to study treatment. 
•
For drug administration of study treatments other than asciminib, instructions on 
following local labels have been emphasized, including for participants with hepatic 
and renal impairment for Investigator selected TKIs
•
Additional clarity has been provided for pregnancy testing which must be performed 
monthly during the treatment period and at the 30-days follow up visit when applicable.
•
Analysis for BCR-ABL≤1% has been added as a secondary endpoint. BCR-ABL1 ≤1% is 
considered an important milestone for assessing response to treatment for patients with 
CML-CP. The NCCN and ELN treatment guidelines consider the achievement of this level 
of response at 1 year of treatment to be an optimal response to treatment. The statement that 
BCR-ABL≤1% is equivalent to CCyR has been removed as this is now being included as a 
separate endpoint.
•
Update based on asciminib IB Ed.9 
•
Addition of information concerning FDA (US) and PMDA (Japan) approval of asciminib.
•
Update based on Novartis template version implementation plan and guidance for protocols 
in the context of the upcoming transition for the European Clinical Trial Directive (EU 
CTD) 2011/C 172/01 to the European Union Clinical Trial Regulation (EU CTR) 536/2014    

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•
Provide additional clarity on Exclusion Criterion 10 regarding eligibility based on serologic 
markers for hepatitis B
•
Add details on remote procedures that can be implemented in case of a Public Health 
emergency that limits or prevents on-site study visits
•
Add use of hydroxyurea for urgent control of high cell counts during the first 2 weeks of 
study treatments
•
Mention vaccines in concomitant therapy to be recorded
•
Add information on re-screening 
•
Update guidance for missed doses and compliance requirements  
•
Clarify the timing for visit schedule for assessment 
•
Add information on fasting condition for lab analysis
•
Add collection of EORTC QLQ-C30 and QLQ-CML24 questionnaires 4, 8 and 12 weeks 
after EOT
•
Add PROs guidance in case questionnaire(s) is/are not available in local language and 
specify timelines for ePRO completion
•
Update for biomarker testing for patients enrolled in China
•
Remove the recommendation to use sunblock and avoid tanning beds
•
Preclinical studies suggested that asciminib could cause phototoxicity and 
photosensitization. However, at the NOAEL of 60 mg/kg/day in animal studies, the 
Cmax was 12,000 ng/mL, an exposure that is 15- or 6-fold higher than the Cmax 
exposure in patients at the dose of 40 mg b.i.d. or 80 mg q.d respectively. . Among all 
patients with CML-CP/AP treated with any dose of asciminib as single agent 
phototoxicity AEs were reported in 12/356 patients (3.4%). Reported events included 
photosensitivity reaction (2.5%), sunburn (0.8%) and retinal phototoxicity (0.3%). 
These events were Grade 1-2 and resolved without dose interruption of asciminib. In 
study CABL001X2101, patients with CML-CP harboring the T315I mutation treated 
with single agent asciminib 200 mg BID, phototoxicity AEs (photosensitivity reaction) 
were reported in one patient (2.1%) only. Importantly, no serious adverse events of 
phototoxicity have been observed in any population investigated. Thus, as a minimal 
number of patients have shown low grade phototoxicity AEs, and symptoms can be 
managed with routine clinical practice guidelines
•
Implement editorial changes throughout the protocol to correct typos and provide 
clarifications where required 
These amendment items are considered to contribute to improved readability and accessibility 
of the protocol.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track-changes version of the 
protocol using red underlined font for insertions. This amendment is considered substantial.
The following sections, tables and figures were changed:
•
List of abbreviation: updated based on Protocol Amendment changes

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•
Glossary of terms: updated based on new Novartis template version implementation plan
•
Protocol Summary: updated based on Protocol Amendment changes 
•
Section 1.1.1: The new nomenclature of BCR::ABL1 is mentioned.
•
Section 1.2.2.2: 
•
updated based on asciminib IB Ed.9 and  
•
information concerning FDA (US) and PMDA (Japan) approval was added 
•
Section 2: Added secondary endpoint of BCR-ABL≤1% 
•
Section 3 and Section 4: 
•
information on timelines for pre-randomization selection, dosing requirements for 
participants with baseline renal or hepatic impairment, remote procedure, updated 
wording regarding treatment allowed prior to randomization
•
Also in Section 5: Exclusion criterion 1 (renumbered from 1 to 1a) has been updated to 
allow either imatinib, or nilotinib, dasatinib or bosutinib for ≤ 2 weeks prior to 
randomization (Original Protocol only allowed imatinib) 
•
Section 4.5: ONLY for US Original Protocol - removed male contraception requirement
•
Section 5.1: updated wording of Inclusion Criterion 3 (renumbered from 3 to 3a) defining 
diagnosis of CML-CP; clarified Inclusion criterion 6 (renumbered from 6 to 6a) for limits 
for laboratory values
•
Section 5.2: 
•
exclusion criterion 1 (renumbered from 1 to 1a) has been updated to allow either 
imatinib, or nilotinib, dasatinib or bosutinib for ≤ 2 weeks prior to randomization 
(Original Protocol only allowed imatinib) 
•
included testing details for Exclusion Criterion 10 (renumbered from 10 to 10a)
•
updated Exclusion criterion 14 (renumbered from 14 to 14a) to: 
•
update use of effective contraception during treatment with asciminib (subpoint ii)
•
ONLY for US Original Protocol: removed sub-point from the US local protocol to 
remove the requirement for male contraception by the male participants (following 
FDA approval) 
•
update subpoint to address that males participants taking asciminib do not require 
contraception 
•
added Exclusion Criterion 15 for known hypersensitivity to the study treatment
•
Section 6.1 / 6.1.1 / 6.5: Inclusion of comment regarding for dosing requirements for 
participants with renal or hepatic impairment
•
Section 6.1.1: update of Table 6-1 with additional dosage; updated information 
•
Sections 6.2 / 6.2.1 / 6.2.2:
•
clarification of local label use for study treatments other than asciminib
•
added vaccines in concomitant therapy to be recorded 
•
also in Section 5: added use of hydroxyurea for urgent control of high cell counts during 
the first 2 weeks of study treatments 
•
Section 6.3.1: added information on re-screening in case 3 months are exceeded

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•
Section 6.3.2: clarity on ELTS score assessment at diagnosis
•
Section 6.6 / 6.7: updated text in remote procedure 
•
Section 6.7.2: 
•
inclusion of comment regarding dosing requirements for participants with renal or 
hepatic impairment and clarification of local label 
•
update guidance for missed doses and compliance requirements
•
removal of the recommendation to use sunblock and avoid tanning beds
•
Section 7: 
•
updated text in remote procedure and ICF procedure based on Novartis template 
version implementation plan. 
•
ONLY for US Original Protocol: removed section on male contraception
•
Section 8: Clarification on the required timing for visit schedule for assessment and remote 
procedure
•
Table 8-1: VES alignment with protocol text; addition of EORTC QLQ-C30 and QLQ-
CML24 questionnaires 4, 8 and 12 weeks after EOT, added notes on study windows based 
on visits and assessments; Pregnancy Test (Urine) merged cells from Baseline to 30 Days 
Safety follow- up, update of footnotes
•
Section 8.1: clarity on ELTS score assessment at diagnosis
•
Section 8.1.2: based on Novartis template version implementation plan
•
Section 8.3.1: clarify definitions for loss of MR4 and MR 4.5
•
Section 8.3.2: removed statement of equivalence between BCR-ABL≤1% and CCyR 
•
Section 8.3.4: clarify timeline
•
Section 8.4.1: clarity on fasting condition for lab analysis
•
Section 8.4.2: update of ECG schedule and information
•
Section 8.4.3: added 30 Days Safety follow- up urine pregnancy test; updated information 
on childbearing potential definition; updated childbearing potential definition due to new 
protocol template text; ONLY for US Original Protocol: removed section on male 
contraception
•
Table 8-2 / 8-5 /8-6 / 8-7: footnote update
•
Section 8.5.1: added clarity on PROs schedule and added guidance on PROs in case 
questionnaire is/are not available in local language; added information on TFQ data 
•
Section 8.5.2.3: updated amount of blood needed for pharmacogenomics
•
Section 8.5.3: updated China biomarker testing and mutation analysis to support 
discontinuation criteria; whole blood analysis of cytokines removed from exploratory 
biomarkers due to technical infeasibility
•
Section 9.1: update in Section title
•
Section 9.1.1: inclusion of information on treatment failure criteria; update in Section title
•
Section 9.1.2: new section added with updated text for discontinuation from study; 
subsequent numbering in Section 9 is updated accordingly:
•
Previous Section 9.1.2 is now 9.1.3
•
Previous Section 9.1.3 is now 9.1.4

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•
Previous Section 9.1.4 is now 9.1.5
•
Section 9.1.5: updated text for on early study termination
•
Section 10.1.2: remove repetition 
•
Section 10.1.3: added requirements for SAE reporting timeline; update based on Novartis 
template version 5 implementation plan and guidance for protocols that will be submitted 
under European Union Clinical Trial Regulation (EU CTR)
•
Section 10.1.4: ONLY for US Original Protocol - removed section on female partner
•
Section 10.1.5: update to align to current safety guidance
•
Section 10.2.1: update in categories information and Table references 
•
Section 12.8.1.1: added analysis for BCR-ABL≤1% as efficacy endpoint; added loss of 
MR4 and MR 4.5 definition; updated end-point of MMR and CCyR
•
Section 12.8.2: update in AEs section
•
Section 12.8.2: clarify timelines and data information 
•
Section 13.1 – 13.2 – 13.3: Update based on Novartis template version 5 implementation 
plan and guidance for protocols that will be submitted under European Union Clinical Trial 
Regulation (EU CTR)
•
Section 13.5: new section added to meet the needs of protocols that will be submitted under 
EU CTR
•
Appendix 16.1: 
•
removed table for Prohibited concomitant medication since not applicable 
•
updated table for Concomitant Medication 
•
updated release date of the Pharmacokinetic Sciences memorandum on Drug-Drug 
Interaction list;  
•
Appendix 16.4: added new appendix to provide additional clarity on eligibility based on 
serologic markers for hepatitis B and C
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
CABL001J12301
Full Title
A phase III, multi-center, open-label, randomized study of oral asciminib versus 
Investigator selected Tyrosine Kinase Inhibitor (TKI) in patients with newly 
diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in 
Chronic Phase
Brief title
A study of oral asciminib versus other TKIs in adult patients with newly diagnosed 
Ph+ CML-CP.
Sponsor and Clinical 
Phase
Novartis Phase III
Investigation type
Drug
Study type
Interventional
Purpose and rationale
Asciminib inhibits the Abelson proto-oncogene 1 (ABL1) kinase activity of the 
BCR-ABL1 fusion protein, by specifically targeting the ABL myristoyl pocket. Due 
to asciminib specifically targeting the ABL kinase family (ABL1, ABL2, BCR-ABL1), 
asciminib offers the potential for improved safety and tolerability than currently 
approved Adenosine triphosphate (ATP)-competitive TKIs for treatment of patients 
with CML-CP.
Primary Objective(s)
To compare the efficacy of asciminib versus Investigator selected TKI with respect 
to the proportion of participants that are in Major Molecular Response (MMR) at 
Week 48.
To compare the efficacy of asciminib versus Investigator selected TKI, within the 
stratum of participants with imatinib as the pre-randomization selected TKI, with 
respect to the proportion of participants that are in MMR at Week 48
Secondary Objectives
To compare the efficacy of asciminib versus Investigator selected TKI, with 
respect to the proportion of participants that are in MMR at Week 96.
To compare the efficacy of asciminib versus Investigator selected TKI, within the 
stratum of participants with imatinib as the pre-randomization selected TKI, with 
respect to the proportion of participants that are in MMR at Week 96.
Study design
The study is designed to compare the efficacy of asciminib 80 mg QD versus 
Investigator selected TKI for the treatment of newly diagnosed, previously 
untreated patients with Ph+ CML-CP. The Investigator selected TKI will be one of 
the following treatment options for first-line treatment of CML-CP - imatinib 400 mg 
QD or nilotinib 300 mg BID (total daily dose of 600 mg) or dasatinib 100 mg QD or 
bosutinib 400 mg QD. Dose recommendations as per local label should be 
followed for participants with hepatic and renal impairment.
Study population
Adult patients with newly diagnosed Ph+ CML-CP.
It is planned to randomize approximately 402 participants in the study in a 1:1 ratio 
to asciminib or Investigator selected TKI. 
Key Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Male or female participants ≥ 18 years of age.
2. Participants with CML-CP within 3 months of diagnosis.
3a. Diagnosis of CML-CP (ELN 2020 criteria) with cytogenetic confirmation of the 
Philadelphia chromosome
•
Documented chronic phase CML will meet all the below criteria 
(Hochhaus et al 2020A):
•
< 15% blasts in peripheral blood and bone marrow,
•
< 30% blasts plus promyelocytes in peripheral blood and bone marrow,
•
< 20% basophils in the peripheral blood,
•
Platelet (PLT) count ≥ 100 x 109/L (≥ 100,000/mm3),
•
No evidence of extramedullary leukemic involvement, with the exception of 
hepatosplenomegaly.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

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5. Adequate end organ function as defined by:
•
Total bilirubin (TBL) < 3 x upper limit of normal (ULN); participants with 
Gilbert’s syndrome may only be included if TBL ≤ 3.0 x ULN or direct bilirubin 
≤ 1.5 x ULN
•
Creatinine clearance (CrCl) ≥ 30 mL/min as calculated using Cockcroft-Gault 
formula
•
Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value must 
be considered not clinically significant and not associated with risk factors for 
acute pancreatitis
6a. Participants must have the following laboratory values within normal limits or 
corrected to within normal limits with supplements prior to randomization:
•
Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated 
with CrCl* ≥ 90 mL/min)
•
Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 
mg/dl or 3.1 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min)
•
Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if 
associated with CrCl* ≥ 90 mL/min)
•
For participants with mild to moderate renal impairment (CrCl* ≥ 30 mL/min 
and <90 mL/min) - potassium, total calcium (corrected for serum albumin) and 
magnesium should be ≥ LLN or corrected to within normal limits with 
supplements prior to randomization.
•
CrCl* as calculated using Cockcroft-Gault formula
7. Signed informed consent must be obtained prior to any study related screening 
procedures being performed.
8. Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of 
screening which is amenable to standardized Real time quantitative 
polymerase chain reaction (RQ-PCR) quantification.
Key Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this 
study.
1a. Previous treatment of CML with any other anticancer agents including 
chemotherapy and/or biologic agents or prior stem cell transplant, with the 
exception of hydroxyurea and/or anagrelide. Treatment with either imatinib, or 
nilotinib, or dasatinib or bosutinib for ≤ 2 weeks is allowed. No treatment with 
other tyrosine kinase inhibitors prior to randomization is permitted. 
2. Known cytopathologically confirmed CNS infiltration (in absence of suspicion of 
CNS involvement, lumbar puncture not required).
3. Impaired cardiac function or cardiac repolarization abnormality including but 
not limited to any one of the following:
•
History within 6 months prior to starting study treatment of myocardial 
infarction (MI), angina pectoris, coronary artery bypass graft (CABG).
•
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).
•
QTc ≥ 450 ms (male participants), ≥ 460 ms (female participants) on the 
average of three serial baseline ECG (using the QTcF formula) as 
determined by central reading. If QTcF ≥ 450 ms and electrolytes are not 
within normal ranges, electrolytes should be corrected and then the 
participant re-screened for QTc.
•
Long QT syndrome, family history of idiopathic sudden death or congenital 
long QT syndrome, or any of the following:
•
Risk factors for Torsades de Pointes (TdP) including uncorrected 
hypokalemia or hypomagnesemia, history of cardiac failure, or history 
of clinically significant/symptomatic bradycardia.

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•
Concomitant medication(s) with a “Known risk of Torsades de 
Pointes” per //.crediblemeds.org/ that cannot be discontinued or 
replaced 7 days prior to starting study drug by safe alternative 
medication.
•
Inability to determine the QTcF interval.
4. Severe and/or uncontrolled concurrent medical disease that in the opinion of 
the Investigator could cause unacceptable safety risks or compromise 
compliance with the protocol (e.g., uncontrolled diabetes, active or 
uncontrolled infection; uncontrolled arterial or pulmonary hypertension, 
uncontrolled clinically significant hyperlipidemia).
5. History of significant congenital or acquired bleeding disorder unrelated to 
cancer.
6. Major surgery within 4 weeks prior to study entry or who have not recovered 
from prior surgery.
7. History of other active malignancy within 3 years prior to study entry with the 
exception of previous or concomitant basal cell skin cancer and previous 
carcinoma in situ treated curatively.
8. History of acute pancreatitis within 1 year prior to randomization or medical 
history of chronic pancreatitis.
9. History of chronic liver disease leading to severe hepatic impairment, or 
ongoing acute liver disease.
10a. Known history of chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) 
infection. Testing for Hepatitis B surface antigen (HBs Ag) and Hepatitis B 
core antibody (HBc Ab/anti HBc) will be performed at screening. If anti-HBc is 
positive, HBV-DNA evaluation must be carried out at screening. Patients 
having positive HBV-DNA must not be enrolled in the study. Also, patients with 
positive HBsAg must not be enrolled in the study. For details criteria see 
Appendix 16.4.
11. History of Human Immunodeficiency Virus (HIV) unless well-controlled on a 
stable dose of anti-retroviral therapy at the time of screening.
12. Impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of study drug (e.g., ulcerative disease, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, 
or gastric bypass surgery).
13. Participation in a prior investigational study within 30 days prior to 
randomization or within 5 half-lives of the investigational product, whichever is 
longer.
14a. If local regulations deviate from the contraception methods listed below to 
prevent pregnancy, local regulations apply and will be described in the ICF.
i.
Pregnant or nursing (lactating) women
ii.
Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 
methods of contraception while taking study treatment and for a period of 
time after stopping study medication. For asciminib, this period of time is 
3 days after the last dose; if local regulations or locally approved 
prescribing information differ from the protocol required duration of 
contraception, the longer duration must be followed and the same 
requirements will be described in the ICF. Participants taking Investigator 
selected TKI should be willing to follow contraception requirements in the 
locally-applicable prescribing information for the TKI received in the 
study.
Highly effective contraception methods include:
•
Total abstinence (when this is in line with the preferred and usual lifestyle of 
the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.

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•
Female bilateral tubal ligation, female sterilization (have had surgical bilateral 
oophorectomy (with or without hysterectomy), or total hysterectomy at least 
six 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 partner's sterilization (at least 6 months prior to screening): the 
vasectomized male partner should be the sole partner for that participant.
•
Use of oral, injected or implanted hormonal methods of contraception or 
placement of an intrauterine device (IUD) or intrauterine system (IUS) or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone 
contraception. In case of use of oral contraception women should have been 
stable on the same pill for a minimum of 3 months before taking study 
treatment.
•
Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms). Women are considered not of 
child bearing potential if they are post-menopausal or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy or 
bilateral tubal ligation at least six weeks before taking study medication. In the 
case of oophorectomy alone, women are considered post-menopausal and 
not of child bearing potential only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment.
iii.
Sexually active males taking Investigator selected TKI should be willing to 
follow contraception requirements in the locally-applicable prescribing 
information for the TKI received in the study. Sexually active males taking 
asciminib do not require contraception.
15. Known hypersensitivity to the study treatment.
Study treatment
Asciminib vs imatinib, or nilotinib, or dasatinib, or bosutinib
Treatment of interest
Asciminib versus Investigator selected TKI, in patients with newly diagnosed CML-
CP, with respect to the proportion of participants achieving major molecular 
response (MMR) at Week 48.
Asciminib versus Investigator selected TKI, within the stratum of participants with 
imatinib as their pre-randomization selection of TKI, in patients with newly 
diagnosed CML-CP, with respect to the proportion of participants that are in MMR 
at Week 48.
Efficacy assessments
Molecular, Cytogenetic and Hematological response are assessed:
To estimate the efficacy of asciminib versus Investigator selected TKI, within the 
strata of participants with a second generation (2G) TKI as their pre-randomization 
selected TKI, with respect to achieving MMR 
To compare the efficacy of asciminib versus Investigator selected TKI with respect 
to the additional efficacy endpoints.
To compare the efficacy of asciminib versus Investigator selected TKI, within the 
stratum of participants with imatinib as their pre-randomization selected TKI, with 
respect to the additional efficacy endpoints.
To estimate the efficacy of asciminib versus Investigator selected TKI, within the 
strata of participants with a 2G TKI as their pre-randomization selected TKI, with 
respect to the additional efficacy endpoints.
Pharmacokinetic 
assessments 
To characterize the pharmacokinetics (PK) of asciminib. The PK parameters will 
be determined by using the PK profile of asciminib in participants with full PK 
sampling. All PK samples may be used for popPK analysis.
Trough plasma concentrations.
PK parameters in full PK group: Cmax, Tmax, Area under the curve (AUC)tau, 
AUClast, CL/F.
Key safety assessments
To characterize the safety and tolerability profile of asciminib versus Investigator 
selected TKI (imatinib, nilotinib, dasatinib, or bosutinib) during the course of study:
The type, frequency and severity of adverse events (AEs),
Changes in laboratory values that fall outside the pre-determined ranges

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1
Introduction
1.1
Background
1.1.1
Disease background
Chronic Myelogenous Leukemia (CML) is a clonal myeloproliferative disorder of transformed, 
primitive hematopoietic progenitor cells characterized by overproduction of immature myeloid 
cells and mature granulocytes in the spleen, bone marrow, and peripheral blood. The hallmark 
of CML is the Philadelphia (Ph) chromosome found in up to 95% of patients (Seong et al 1999). 
The Ph chromosome results from a reciprocal translocation t(9;22)(q34;q11) which fuses a 
portion of the Abelson (ABL1) gene on chromosome 9 with a portion of the breakpoint cluster 
region (BCR) gene on chromosome 22. The new nomenclature for the fusion gene of 
BCR::ABL1 is considered equivalent to BCR-ABL1 for this protocol (Bruford et al 2021). The 
resulting fusion gene encodes a chimeric protein (BCR-ABL1), which lacks an autoregulatory 
N-terminal segment of ABL1, resulting in it having a constitutively active tyrosine kinase 
domain (Faderl et al 1999, Soverini et al 2019). This oncoprotein promotes aberrant cell growth 
and replication through downstream signaling pathways such as RAS, RAF, JUN kinase, MYC, 
and STAT (Jabbour and Kantarjian 2018). 
With a constant worldwide incidence of 1-2/100000 per year the prevalence of CML is steadily 
increasing due to improved long term outcomes with tyrosine kinase inhibitor (TKI) treatment 
(Jabbour and Kantarjian 2018, Hochhaus et al 2020A). CML mainly affects adult patients with 
a median age at diagnosis of 67 years. In the US, it is estimated that approximately 8,450 new 
cases of CML will be diagnosed and about 1,130 people will die of the malignancy during 2020 
(NCCN 2020). In Europe, a similar CML incidence has been reported with 10 to 15 
cases/million/year, without any major geographic or ethnic differences (Hochhaus et al 2017B).
Clinically, CML can progress through three distinct phases which become increasingly 
refractory to therapy: chronic phase (CP), accelerated phase (AP), and blast crisis (BC) 
(Enright and McGlave 2000). Most patients are diagnosed in the CP, characterized by anemia, 
splenomegaly and leukocytosis with generally few constitutional symptoms like fatigue, weight 
loss, malaise, easy satiety, and left upper quadrant fullness or pain. CML-AP might be insidious 
or present with worsening anemia, splenomegaly and organ infiltration; most patients evolve 
into AP prior to BC, but without treatment around 20% may transition into BC without a 
preceding AP (Faderl et al 1999).
The response to treatment in CML is monitored based on hematological, cytogenetic and 
molecular responses. Monitoring of molecular response using a real-time quantitative 
polymerase chain reaction (RQ-PCR) test for BCR-ABL1 deoxyribonucleic acid (DNA) in 
peripheral blood or bone marrow aspirates, is a sensitive measure of burden of disease in CML 
and results are standardized to an International scale (IS) as the ratio of BCR-ABL1 transcripts 
to ABL1 transcripts. Molecular responses provide an objective measure of efficacy for guiding 
treatment and monitoring patients with CML (Press 2010, Cross et al 2012, Greiner et al 2020). 
Treatment guidelines consider BCR‑ABL1 transcript levels at mainly 3, 6, and 12 months time 
points to determine the patient’s response to treatment and to guide treatment decisions. A 
BCR- ABL1 IS level of > 1% at 12 months is considered a failure of treatment, whereas 

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BCR- ABL1 IS level of ≤ 0.1% (Major Molecular Response; MMR) at 12 months is considered 
an optimal response to treatment (Hochhaus et al 2020A, NCCN 2020).
1.1.2
Current management recommendations and unmet medical need  
In 2001, the introduction of the TKI imatinib (Glivec®), the first drug to be targeted against an 
oncogenic mutation, revolutionized the treatment of patients with CML. Subsequently, several 
second generation (2G) TKI agents, nilotinib, dasatinib, bosutinib, have been approved for the 
first-line treatment of CML. TKI treatment has improved the survival rates for patients with 
CML, and patients with optimal treatment response may expect near-normal life expectancy 
(Jabbour and Kantarjian 2018, 
García-Gutiérrez and Hernández-Boluda 2019). 
Increased 
survival rates and the requirement of chronic therapy for CML has underlined the importance 
of selection of first-line treatment for newly diagnosed patients. The treatment for newly 
diagnosed patients with CML aims to deliver early optimal responses to decrease the possibility 
of disease progression, maintain the quality of life for patients requiring potentially life-long 
treatment, and to decrease possibility of serious side effects.
Treatment guidelines recommend selection of the first-line option for the treatment of CML- CP 
based on individual patient and disease characteristics determining risk score (Sokal, Hasford, 
EUTOS or ELTS), as well as the preexisting comorbidities and concomitant medications 
determining the ability of the patient to tolerate therapy (Saglio and Jabbour 2018, 
Hochhaus et al 2020A, NCCN 2020). Considering the differences in safety and efficacy 
profiles of imatinib and 2G TKIs, i.e. nilotinib, dasatinib and bosutinib, first-line treatment 
recommendations vary for these agents.
In general, newly diagnosed patients with a low risk score, elderly patients or patients with 
multiple comorbidities are treated with imatinib, which has been shown to provide good 
efficacy with a tolerable safety profile. However, many patients treated with imatinib 
experience events such as fluid retention or muscle cramps (Cortes and Kantarjian 2016). From 
an efficacy perspective, imatinib is less potent than 2G TKIs, delivering lower cytogenetic and 
molecular response rates, as demonstrated in many comparative studies against 2G TKIs 
(Hochhaus et al 2016, Cortes and Kantarjian 2016, Cortes 2018). The sub-optimal responses to 
imatinib lead to poor disease control which correlates with higher rates of advanced disease in 
CML, namely progression to AP or BC (Hochhaus et al 2016, Cortes and Kantarjian 2016, 
Cortes 2018). The rate of emergent mutations with frontline imatinib has been shown to be 
higher than that with dasatinib leading to higher rates of resistance and loss of responses on 
treatment with frontline imatinib (Hughes et al 2015).
Newly diagnosed younger patients with CML-CP and those with high risk scores are 
recommended to be treated with 2G TKIs which have shown to be more potent than imatinib 
(Hochhaus et al 2020A, NCCN 2020). Studies comparing 2G TKIs to imatinib demonstrated 
higher rates of efficacy responses and reduced rates of progression to AP or BC; however, the 
safety profile of these drugs is significantly more adverse as compared to imatinib. The 
development of vascular side effects such as peripheral arterial occlusive disease, 
cerebrovascular accidents, and coronary artery disease with nilotinib, cardiopulmonary 
toxicities such as pleural effusions, interstitial pneumonitis and pulmonary hypertension with 
dasatinib and gastrointestinal and liver related events with bosutinib, warrant caution while 

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prescribing these agents for first-line treatment of newly diagnosed patients with CML-CP 
(Hochhaus et al 2016, Cortes and Kantarjian 2016, Cortes 2018).
Many AEs associated with imatinib and 2G TKIs are attributable to off-target activities of these 
inhibitors as they are not specific for ABL / BCR-ABL1 inhibition. For example, 
hypophosphatemia with imatinib has been attributed to inhibition of PDGF (PLT-derived 
growth factor) signaling affecting the formation and resorption of bone (Berman et al 2006). 
Multi-kinase inhibitor-induced rash is common in patients on imatinib therapy 
(Grávalos et al 2019). For bosutinib, a higher rate of diarrhea is considered to be due to EGFR 
(Epidermal Growth Factor Receptor) inhibition (Rugo et al 2019). Off-target inhibition by TKIs 
of SRC family kinases have been implicated in occurrence of fluid retention and pleural effusion 
(Eliceiri et al 1999).
Asciminib has been shown to be highly selective against BCR–ABL1-positive cell lines when 
compared with imatinib, nilotinib, dasatinib, and bosutinib, which varied considerably in their 
degree of specificity (Wylie et al 2017 ). Hence, it is anticipated that the specificity of asciminib 
for ABL1 and ABL2, may limit off-target effects resulting in an improved safety profile as 
compared with ATP-binding TKIs.
Considerable advancements in treatment of patients with CML-CP have been made in the last 
two decades. Increase in life expectancy of patients living with CML have made it a chronic 
disease requiring long term medication. This emphasizes the need for treatments that combine 
high efficacy with a favorable safety profile as compared to the available options. There remains 
an unmet medical need for newly diagnosed patients with CML-CP requiring chronic treatment 
for a specific targeted treatment option that is highly efficacious while minimizing AEs.
1.2
Purpose
1.2.1
Scientific rationale and purpose
Asciminib is an oral, potent inhibitor of BCR-ABL1 tyrosine kinase with a novel mechanism 
of action. In contrast to BCR-ABL1 TKIs, such as imatinib, nilotinib, dasatinib, bosutinib and 
ponatinib that bind to the ATP-site on the SH1 domain of the enzyme, asciminib inhibits the 
ABL1 kinase activity by specifically targeting the ABL myristoyl pocket. Asciminib 
functionally mimics the role of the myristoylated Gly2 residue by occupying the vacant binding 
site and restoring the negative regulation to the kinase activity.
Asciminib does not directly interact with the ATP-binding site and inhibits ABL tyrosine kinase 
activity by binding to a particular allosteric site on the kinase domain. This site has only been 
implicated in the autoregulation of ABL1, ABL2 and BCR-ABL1, thus explaining the 
specificity of asciminib towards these three enzymes (Manley et al 2020). As most AEs 
associated with TKIs are attributable to off-target activity, the lack of specificity to ABL kinases 
leads 
to 
off-target 
effects 
in 
a 
substantial 
proportion 
of 
patients 
(Steegmann et al 2012, Hantschel 2015). Asciminib is specific for ABL kinases and it is 
expected that this limited off-target kinase inhibition will translate into a better safety profile 
than currently approved ATP-competitive TKIs.The purpose of this pivotal study is to compare 
the efficacy of asciminib with that of BCR-ABL1 TKIs, such as imatinib, nilotinib, dasatinib, 
bosutinib in adult patients with newly diagnosed Philadelphia Chromosome Positive Chronic 

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Myelogenous Leukemia in Chronic Phase (Ph+ CML-CP). For additional information please 
see Section 4.3.
1.2.2
Preliminary efficacy and safety
Asciminib is mainly being studied in clinical studies in CML. As of 15-Jan-2023, asciminib has 
been investigated in 11 completed studies and 11 ongoing studies [Asciminib Investigator's 
Brochure]. In completed studies, 388 healthy volunteers, including 24 participants with hepatic 
impairment, and 8 participants with renal impairment were exposed to asciminib. In addition, 
200 patients with CML-CP/ AP have been treated with single agent asciminib in 
CABL001X2101. This ongoing first-in-human (FIH) phase I clinical study provides 
preliminary evidence of safety and efficacy of asciminib in patients with CML-CP/AP who 
have been previously treated with two or more TKIs over a wide range of doses. In addition, 
safety and efficacy of asciminib in 233 patients with CML-CP who had treatment failure on or 
were intolerant to at least 2 prior TKIs is available from the ongoing randomized, controlled 
study CABL001A2301. Asciminib as an add-on to imatinib is also being studied in patients 
with CML-CP who did not achieve deep molecular response after at least 1 year of treatment 
with imatinib [Study CABL001E2201].
1.2.2.1
Study CABL001X2101
Study CABL001X2101 is an ongoing first-in-human (FIH), multi-center, open-label, dose 
escalation study of asciminib given as single agent or in combination with either nilotinib, 
imatinib or dasatinib in patients with CML or Ph+ Acute Lymphoblastic Leukemia (ALL). The 
objectives of this study include the determination of the maximum tolerated dose (MTD)/ 
recommended dose for expansion (RDE) and the characterization of the safety profile of single 
agent asciminib, as well as to provide preliminary evidence for efficacy of asciminib in CML.
At the time of the primary analysis, a total of 317 patients with Ph+ CML (chronic phase, CP; 
accelerated phase, AP; or blast crisis, BC) or Ph+ ALL who have failed or are intolerant to at 
least two prior TKIs, had been enrolled in the study. Patients in the study have been treated with 
increasing doses of single agent asciminib or with asciminib in combination with nilotinib, 
imatinib, or dasatinib [CABL001X2101 CSR]. The results from Arm 1 evaluating single agent 
asciminib are presented below. The results from Arm 2 (single agent asciminib for treatment of 
CML-BC or Ph+ ALL) and Arm 3, 4, 5 (asciminib in combination with nilotinib, imatinib or 
dasatinib, respectively) are not included.
As a single agent, asciminib has been studied in 200 heavily pre-treated patients with CML-CP/ 
AP in Arm 1 of the CABL001X2101 study. In this Arm of the study, asciminib was evaluated 
at the following dose levels and regimens: 10 mg BID (n=1), 20 mg BID (n=14), 40 mg BID 
(n=35) which was declared as RDE, 80 mg BID (n=12), 150 mg BID (n=13), 160 mg BID 
(n=11), 200 mg BID (n=62) which was declared as RDE in CML-CP/AP harboring the T315I 
mutation, 80 mg QD (n=18), 120 mg QD (n=22), and 200 mg QD (n=12). Among 200 patients 
with CML-CP/-AP enrolled across treatment cohorts, 185 (92.5%) patients had CML-CP of 
which 115 had CML-CP without T315I mutation and 70 with CML-CP harbored T315I 
mutation. The majority of patients had received at least two prior TKIs (185 (92.5%) patients); 
with dasatinib being the TKI received by a majority of patients (79.0%), followed by imatinib 
(70.0%), and nilotinib (69.0%).

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As of the data cut-off date, 123 (61.5%) patients in Arm 1 were receiving treatment with 
asciminib single agent and 77 (38.5%) patients had discontinued treatment. Physician's decision 
was the most frequent reason for discontinuation of treatment in 32 (16.0%) patients followed 
by discontinuation due to AEs in 19 (9.5%) patients. The median duration of exposure was 
124.6 weeks (min-max: 0 to 302 weeks).
The most common AEs reported in at least 50 patients among the 200 with CML-CP/-AP 
treated with asciminib single agent when considering all doses and all grades were fatigue 
(29.0%), headache, lipase increase, nausea (26.0%, each) and diarrhea (25.5%). Eighteen 
patients with CML-CP/-AP who were treated with asciminib single agent (9.0%) had at least 
one SAE assessed by the investigator as suspected to be related to the study  drug. No pattern for 
dose-dependent increase in frequency of AEs was observed with the multiple doses of asciminib 
monotherapy, up to the highest evaluated dose of 200 mg BID in CML-CP and -AP patients 
treated. Six (3.0%) patients died on-treatment (within 30 days after last dose of study treatment). 
Of these, 3 deaths were due to underlying disease and 3 were due to other primary causes of 
death being 
, 
, and 
, respectively. None 
of these events due to ‘other causes’ were considered to be related to study treatment.
Efficacy data from the study CABL001X2101 show that asciminib demonstrates anti-leukemic 
activity in the broad range of doses tested and across later lines of therapy. Among the 200 
patients with CML-CP/-AP treated with asciminib single agent across treatment cohorts, 164 
were evaluable for MMR analysis. A clinically meaningful and durable MMR rate was observed 
across all asciminib dose levels ≥ 20 mg BID and across all lines of therapy. In 164 MMR 
evaluable patients with CML-CP/-AP, MMR was achieved by 77/164 (47.0%) patients. The 
cumulative MMR was 26.2% by Week 24 (25.0% at Week 24).
In this study, the MTD for single agent asciminib was not reached. Based on totality of data 
available from study CABL001X2101, a single agent dose of asciminib 40 mg BID was 
determined as the RDE for patients with CML-CP or CML-AP and further investigated in study 
CABL001A2301.
1.2.2.2
Study CABL001A2301
Study CABL001A2301 (ASCEMBL) is an ongoing phase III, multi-center, active-controlled, 
open-label randomized study that compares the efficacy and safety of asciminib with that of 
bosutinib in the treatment of patients with CML-CP who received at least 2 prior ATP-binding 
site TKIs. 
A total of 233 patients were randomized in a 2:1 ratio and stratified according to patients’ 
cytogenetic response at screening (major or no major cytogenetic response) to receive either 
asciminib 40 mg BID (157 patients) or bosutinib 500 mg QD (76 patients). The primary study 
endpoint was MMR at week 24. Patients in the study were heavily pre-treated, with 
approximately half (52.2%) of the patients in the asciminib arm having received asciminib as 
3rd-line therapy and 47.8% as 4th-line or greater, while 39.5% of the patients in the bosutinib 
arm received bosutinib as 3rd-line and 60.5% as 4th-line or greater.
The study met its primary endpoint. The MMR rate at 24 weeks was 25.5% in the asciminib 
arm compared to 13.2% in the bosutinib arm. The estimated difference in MMR rates of 
asciminib compared to bosutinib at 24 weeks was clinically meaningful and statistically 

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significant 12.2% (95% CI: 2.19, 22.30, p value: 0.029). At the Week 96 cut-off, the clinical 
superiority of asciminib versus bosutinib increased compared to the primary analysis, the MMR 
rate in the asciminib arm 37.58% (95% CI: 29.99, 45.65) compared to 15.79 % (95% CI: 8.43, 
25.96) in the bosutinib arm. This corresponded to a common treatment difference (after 
adjusting for baseline MCyR status) of 21.74% (95% CI: 10.53, 32.95) which was clinically 
relevant and statistically significant (p=0.001) (two-sided Cochrane-Mantel-Haenszel chi-
square test, stratified by the major cytogenetic response status at baseline).
As of the Week 96 cut-off (06-Oct-2021), 99 of the 233 patients (42.5%) were continuing the 
study treatment with 84 patients (53.5%) and 15 patients (19.7%) still ongoing in the asciminib 
and bosutinib arms, respectively. Treatment discontinuations were reported for 45.9% of the 
patients in the asciminib arm and for 80.3% in the bosutinib arm. Lack of efficacy (defined 
according to the response milestones in ELN 2013 recommendations) (24.2% in the asciminib 
arm and 35.5% in the bosutinib arm) remained the most frequently reported reason for treatment 
discontinuation. The median duration of exposure to study treatment was 103.1 weeks in the 
asciminib arm and 30.5 weeks in the bosutinib arm (from start of treatment to last treatment as 
per data cut-off date).
The frequency of AEs was lower in patients on asciminib (91.0%) as compared to bosutinib 
(97.4%), despite the considerably longer exposure to treatment on asciminib vs bosutinib noted 
above. In addition, lower percentage of patients with  
•
Grade ≥ 3 AEs (56.4% vs 68.4%) 
•
AEs leading to treatment discontinuation (7.7% vs 26.3%) 
•
AEs Suspected to be treatment-related: 32.7% vs. 52.6% 
•
Serious AEs: 17.9% vs. 26.3% 
•
SAEs Suspected to be treatment-related: 3.2% vs. 13.2% 
•
AEs leading to dose adjustment and/or interruption: 42.3% vs. 64.5%
were reported in the asciminib group as compared to bosutinib group. The most commonly 
reported AEs in the asciminib and bosutinib treatment group ( ≥ 10% in either arm) included 
the following: thrombocytopenia (23.1% vs. 14.5%, headache (19.9% vs. 15.8%), neutropenia 
(19.2% vs. 17.1%), , fatigue (14.7% vs. 9.2%), hypertension (13.5% vs. 5.3%), arthralgia (12.8% 
vs. 3.9%), diarrhea (12.8% vs. 72.4%), nausea (11.5% vs. 46.1%), and nasopharyngitis (10.9% 
vs. 3.9%) , anemia (10.3% vs. 7.9%), abdominal pain (9.0% vs. 15.8%), rash (9.0% vs. 23.7%), 
vomiting (7.7% vs. 26.3%), aspartate aminotransferase increased (5.8% vs. 21.1%), and alanine 
aminotransferase increased (4.5% vs. 30.3%). Since the primary analysis cut-off, the incidence 
of arthralgia, nasopharyngitis and anemia on asciminib and abdominal pain on bosutinib 
increased to above 10%.
The proportion of patients experiencing myelosuppression was similar in the asciminib (38.5% 
all grades, 26.9% Grade ≥ 3 events) and bosutinib   treatment groups (36.8% all grades, 23.7% 
Grade ≥ 3 events) with the exception of thrombocytopenia which was reported more frequently 
in the asciminib arm than in the bosutinib arm(any grade 23.1% vs. 14.5%). 
The proportion of patients with gastrointestinal toxicity, hepatotoxicity and hypersensitivity 
AESIs were substantially lower in the asciminib treatment group compared to the bosutinib 
treatment group (both all grades and Grade ≥ 3). Comparable proportion of patients with 

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pancreatic enzyme increase was seen without clinical events of pancreatitis in both treatment 
groups. Serious adverse events were reported in a lower proportion of patients in the asciminib 
treatment group (17.9%) compared to the bosutinib treatment group (26.3%). 
Grade ≥ 3 AEs, AEs suspected to be study treatment related, AEs requiring dose interruption, 
dose adjustments, and additional therapies were reported less frequently in the asciminib 
treatment group as compared to the bosutinib treatment group. 
 Three deaths occurred during the study two in the asciminib arm and one in the bosutinib arm. 
The  2 deaths in the asciminib arm were not considered study treatment related by the  
Investigators (causes of death reported as
and 
. The 
death of the one patient in the bosutinib arm was due to
and was considered related 
to study treatment. Please refer to the latest [Asciminib Investigator's Brochure] for more details.
In summary, study CABL001A2301 showed significantly improved efficacy with favorable 
safety and tolerability of asciminib as compared to bosutinib in CML-CP patients treated with 
at least 2 prior TKIs.
Asciminib was granted accelerated approval by the US FDA in Oct-2021 for adult patients with 
Ph+ CML-CP, previously treated with two or more TKIs. The recommended dose of asciminib 
is a total daily dose of 80 mg, taken either as 80 mg QD or 40 mg BID. The FDA also approved 
asciminib for adult patients with Ph+ CML in CP with T315I mutation. The recommended dose 
of asciminib in patients with Ph+ CML in CP with T315I mutation is 200 mg BID.
Asciminib was also approved by the Japan PMDA in Mar-2022, for the treatment CML with 
resistance or intolerance to previous therapy. The posology is 40 mg BID. Novartis did not 
apply for the T315I indication and for the 80 mg QD dose in Japan.
1.2.2.3
Study CABL001E2201
Study CABL001E2201 is a phase II, multi-center, open-label, randomized study of oral 
asciminib added-on to imatinib versus continued imatinib versus single agent nilotinib in 
patients with CML-CP who have been previously treated with imatinib for at least 1 year and 
have not achieved deep molecular response (MR4). The primary endpoint of the study is to 
compare the activity of asciminib at the dose of 40 mg QD and 60 mg QD added-on to imatinib 
versus imatinib continuation and versus switch to nilotinib, assessed by the rate of MR4.5 at 48 
weeks. The MR4.5 rate at 96 weeks is the key secondary endpoint. Secondary endpoints include 
safety and tolerability, PK and additional efficacy endpoints. Approximately 80 eligible patients 
will be randomized in a 1:1:1:1 ratio to receive asciminib 60 mg QD add‑on to imatinib 400 mg 
QD, or asciminib 40 mg QD add-on to imatinib 400 mg QD, or continue imatinib 400 mg QD, 
or switch to nilotinib 300 mg BID.. 
The primary analysis (cut-off date 10-Jan-2022) was conducted when all randomized subjects 
had completed the week 48 visit or discontinued treatment early.
At the data cut-off date (10-Jan-2022), 84 subjects were randomized, eighty-three (98.8%) 
subjects were treated in one of the 4 arms. Out of the 83 subjects, 52 (61.9%) subjects were still 
receiving trial therapy and 31 (36.9%) subjects had discontinued the study.
The median duration of exposure to study drug was longer in the asciminib 40 mg + imatinib 
(104.7 weeks, range 27-160) and asciminib 60 mg + imatinib (94 weeks, range 1-148) arms as 

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compared to monotherapy with nilotinib (78.9 weeks, range 1-146). The median duration of 
exposure in the imatinib arm was 53.4 weeks (range 50-142), subjects in the imatinib arm were 
allowed to cross-over after week 48, if MR4.5 was not achieved by then.
At week 48, there were 4 subjects in the asciminib 40 mg + imatinib arm and 6 subjects in the 
asciminib 60 mg arm + imatinib arm who achieved MR4.5 (BCR::ABL1 ratio of ≤ 0.0032%) 
compared to 0 subjects in the imatinib arm, corresponding to an MR4.5 rate of 19% (90% CI: 
6.8, 38.4) and 28.6% (90% CI: 13.2, 48.7), in the two investigational arms respectively. 
The estimated MR4.5 difference for asciminib 40 mg + imatinib arm was 19.05 (90% CI: 5, 
33.1) and for asciminib 60 mg + imatinib arm was 28.57 (90% CI: 12.4, 44.8).
The most common (≥ 15% subjects in any of the treatment arm) AEs  were: in asciminib 40 mg 
+ imatinib arm: nausea (33.3%), diarrhoea (23.8%), myalgia (23.8%) and pruritus (19%), in 
asciminib 60 mg + imatinib arm: no AEs by PT were observed in ≥ 15 % of subjects, in imatinib 
arm: lipase increased (15%), diarrhoea (15%) and hypophospataemia (15%) and in nilotinib 
arm: alanine aminotransferase increased (23.8%), rash (38.1%) and hypertension (19%).
SAEs were more frequent in nilotinib arm (23.8%) as compared to asciminib 40 mg +imatinib
(14.3%) and asciminib 60 mg + imatinib (14.3%) arm.
AEs leading to discontinuation of study treatment were more frequent in nilotinib (23.8%)
arm compared to asciminib 40 mg + imatinib (4.8%) and asciminib 60 mg + imatinib (14.3%).
No AEs leading to discontinuation of study treatment was observed in imatinib arm.
Please refer to the latest [Asciminib Investigator's Brochure] for more details.
1.2.3
Preliminary pharmacokinetics
The PK profile of asciminib has been evaluated both as single agent in CML patients at a dose 
range between 10 mg to 280 mg BID and 80 mg to 200 mg QD, as well as in healthy subjects. 
Asciminib was rapidly absorbed following single dose and repeated administration with a 
median time to reach maximum plasma concentration (Tmax) of 2 to 3 hours, independent of 
dose. Systemic exposure of asciminib, after oral administration of a single dose and multiple 
doses, as measured by Cmax and area under the curve (AUC), increase in a slightly more than 
dose proportional manner based on statistical analysis. No time-dependent PK was observed. 
The apparent terminal elimination half-life (T1/2) was estimated to be between 7 and 15 hours 
and steady-state was reached by 3 days. With the once-daily dosing regimen there was almost 
no accumulation of asciminib (1.1 to 1.4). Generally, the variability of exposure was low to 
moderate with inter-patient variability (coefficient of variation (CV) %) ranging from 
approximately 25% to 70% for both Cmax and AUClast.
A negative food effect was observed with asciminib. Low-fat and high-fat meals decreased the 
exposure (Cmax and AUC) of asciminib by ~30% and ~60%, respectively, compared to 
asciminib given in the fasted state. The negative food effect may be explained by sequestration 
of asciminib with bile acids when present at high levels in the gastrointestinal tract in vivo.
A 1.56 fold and 1.66 fold increase in AUCinf of asciminib was observed in subjects with severe 
renal impaired function and severe hepatic impaired function, respectively, compared to the 
normal renal function cohort [CABL001A2103, CABL001A2105]. No dose adjustment is 

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2
Objectives, endpoints, and estimands
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
•
The study has multiple primary objectives:
1.
To compare the efficacy of asciminib 
versus Investigator selected TKI, with 
respect to the proportion of participants 
that are in Major Molecular Response 
(MMR) at Week 48.
2.
To compare the efficacy of asciminib 
versus Investigator selected TKI, within 
the stratum of participants with imatinib as 
the pre-randomization selected TKI, with 
respect to the proportion of participants 
that are in MMR at Week 48.
The study will be declared positive if it 
meets either of the two primary objectives 
(i.e. if the null hypothesis associated with either 
of these two objectives is rejected). 
•
The end point associated with both primary 
objectives is:
•
Major Molecular response (MMR) at Week 48 
(Yes/No) 
Secondary objective(s)
Endpoint(s) for secondary objective(s)
•
The study has multiple key secondary 
objectives: 
1.
To compare the efficacy of asciminib 
versus Investigator selected TKI, with 
respect to the proportion of participants 
that are in MMR at Week 96.
2.
To compare the efficacy of asciminib 
versus Investigator selected TKI, within 
the stratum of participants with imatinib as 
the pre-randomization selected TKI, with 
respect to the proportion of participants 
that are in MMR at Week 96.
•
The end point associated with both key secondary 
objectives is:
•
Major Molecular response (MMR) at Week 96 
(Yes/No) 
•
Secondary objective for safety
•
To characterize the safety and tolerability 
profile of asciminib versus 2G TKIs 
(nilotinib, dasatinib, or bosutinib) during 
the course of study treatment.
•
Time to discontinuation of study treatment due to 
AE (TTDAE). 
•
Other secondary objectives for efficacy:
To estimate the efficacy of asciminib versus 
Investigator selected TKI, within the strata of 
participants with a 2G TKI as their pre-
randomization selected TKI, with respect to the 
proportion of participants that are in:
•
MMR at Week 48.
•
MMR at Week 96.
•
The end points associated with the other secondary 
objectives are:
•
Major Molecular response (MMR) at Week 48 
(Yes /No) 
•
Major Molecular response (MMR) at Week 96 
(Yes /No) 
•
Other secondary objectives for efficacy:
•
To compare the efficacy of asciminib 
versus Investigator selected TKI, with 
respect to additional parameters of 
efficacy.
•
To compare the efficacy of asciminib 
versus Investigator selected TKI, within 
the stratum of participants with imatinib as 
•
MMR at all scheduled data collection time 
points (except at Week 48 and at Week 96).
•
MMR by all scheduled data collection time 
points.
•
MR4.0 and MR4.5, at and by all scheduled 
data collection time points.

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2.1
Primary estimands
Primary estimands will be based on the treatment policy and composite approaches as defined 
in this section. Supplementary estimands for the end-point of MMR at Week 48 are defined in 
Section 12. 
The clinical questions of interest are:
1. What is the efficacy of asciminib (80 mg QD) compared to Investigator selected TKI; with 
respect to MMR at Week 48,
2. What is the efficacy of asciminib (80 mg QD) compared to Investigator selected TKI within 
the stratum of participants that have imatinib as their pre-randomization selection of TKI; 
with respect to MMR at Week 48,
without meeting any treatment failure criteria (as per European Leukemia Network (ELN) 
criteria, Hochhaus et al 2020A) and without treatment discontinuation, prior to Week 48, in 
newly diagnosed CML-CP patients; regardless of dose interruptions/reductions/allowed dose 
escalations; regardless of dosing errors, changes on concomitant medication, intake of 
prohibited medication; and regardless of taking a TKI different from their pre-randomization 
selection of TKI in the comparator arm.
 The justification for the primary estimands are that these will capture the effects of the study 
treatments in a manner that reflects their use in practice.
Primary estimands are described by the following attributes:
Population: Newly diagnosed adult Ph+ CML-CP patients, as defined by Inclusion/ Exclusion 
criteria; (1) overall and (2) within the stratum with imatinib as their pre-randomization selection 
of TKI.
Endpoint: the composite end point of MMR at Week 48, without meeting any treatment failure 
criteria prior to Week 48 and without discontinuation due to any reasons prior to Week 48. A 
participant will be counted as being in MMR at Week 48 if he/she meets the MMR criterion 
(BCR-ABL1 transcript level ≤ 0.1% IS) at Week 48. If the participant meets any treatment 
failure criteria prior to Week 48 or discontinues treatment due to any reason prior to Week 48 
the patient is counted as not being in MMR at Week 48.
Intercurrent events (IE):
•
Taking a TKI different from their pre-randomization selection of TKI (i.e. the first dose of 
TKI is different from their pre-randomization selection of TKI): treatment policy strategy 
(ignore)
•
Change on study treatment per protocol (dose reduction/interruption/allowed dose 
escalations): treatment policy strategy (ignore)
•
Dosing errors (e.g., missed dose): treatment policy strategy (ignore)
•
Deviation in any intake of concomitant medications: treatment policy strategy (ignore)
•
Intake of prohibited medications: treatment policy strategy (ignore)
•
Meeting any treatment failure criteria prior to Week 48 or treatment discontinuation due to 
any reason prior to Week 48: composite (consider these as non-response)

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Handling of remaining intercurrent events: no other IE foreseen.
Treatment:
1. The randomized treatment arm (the investigational treatment asciminib 80 mg QD, or the 
Investigator 
selected 
TKI); 
with 
or 
without 
dose 
modifications 
(reductions/interruptions/allowed dose escalations); regardless of dosing errors, deviation 
in any intake of concomitant medications, intake of prohibited medication; and regardless 
of taking or not taking a TKI different from their pre-randomization selection of TKI in the 
comparator arm. Further details about the investigational treatment and control treatments 
are provided in Section 6.
2. The randomized treatment arm (the investigational treatment asciminib 80 mg QD, or the 
Investigator selected TKI), within the stratum of patients that had imatinib as their pre-
randomization 
selection 
of 
TKI; 
with 
or 
without 
dose 
modifications 
(reductions/interruptions/allowed dose escalations); regardless of dosing errors, deviation 
in any intake of concomitant medications, intake of prohibited medication; and regardless 
of taking or not taking a TKI different from their pre-randomization selection of TKI in the 
comparator arm. Further details about the investigational treatment and control treatments 
are provided in Section 6.
The summary measure: stratum adjusted difference in the proportion of participants that are 
in MMR at Week 48 and corresponding 95% CI, between the
1. Randomized treatments (asciminib versus Investigator selected TKI).
2. Randomized treatments (asciminib versus Investigator selected TKI), within the stratum of 
participants that have imatinib as their pre-randomization selection of TKI.
2.2
Secondary estimands
2.2.1
Key Secondary Estimands
Key secondary estimands will be based on the treatment policy and composite approaches as 
defined in this section. Key secondary estimands are similar to the primary estimands, with the 
only difference being that these will be assessed for the end-point of MMR at Week 96. 
Supplementary estimands for the end-point of MMR at Week 96 are defined in Section 12.5. 
Key secondary clinical questions of interest are:
1. What is the efficacy of asciminib (80 mg QD) compared to Investigator selected TKI; with 
respect to MMR at Week 96,
2. What is the efficacy of asciminib (80 mg QD) compared to Investigator selected TKI within 
the stratum of participants that have imatinib as their pre-randomization selection of TKI; 
with respect to MMR at Week 96,
without meeting any treatment failure criteria and without treatment discontinuation, prior to 
Week 
96, 
in 
newly 
diagnosed 
CML-CP 
patients; regardless 
of dose 
interruptions/reductions/allowed dose escalations; regardless of dosing errors, changes on 
concomitant medication, intake of prohibited medication; and regardless of taking a TKI 
different from their pre-randomization selection of TKI in the comparator arm.

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The justification for the key secondary estimands are that these will capture the effects of the 
study drugs in a manner that reflects their use in practice.
Key secondary estimands are described by the following attributes:
•
Population: Newly diagnosed adult Ph+ CML-CP patients, as defined by Inclusion/ 
Exclusion criteria; (1) overall and (2) within the stratum with imatinib as their pre-
randomization selection of TKI.
•
Endpoint: the composite end point of MMR at Week 96, without meeting any treatment 
failure criteria prior to Week 96 and without discontinuation due to any reasons prior to 
Week 96. A participant will be counted as being in MMR at Week 96 if he/she meets the 
MMR criterion (BCR-ABL IS ≤ 0.1%) at Week 96. If the participant meets any treatment 
failure criteria prior to Week 96 or discontinues treatment due to any reason prior to Week 
96 the participant is counted as not being in MMR at Week 96.
•
Intercurrent events (IE): 
•
Taking a TKI different from their pre-randomization selection of TKI (i.e. the first dose 
of TKI is different from pre-randomization selection of TKI): treatment policy strategy 
(ignore)
•
Change on study treatment per protocol (dose reduction/interruption/allowed dose 
escalations): treatment policy strategy (ignore)
•
Dosing errors (e.g., missed dose): treatment policy strategy (ignore)
•
Deviation in any intake of concomitant medications: treatment policy strategy (ignore)
•
Intake of prohibited medications: treatment policy strategy (ignore)
•
Meeting any treatment failure criteria prior to Week 96 or treatment discontinuation 
due to any reason prior to Week 96: composite (consider these as non-response)
•
Handling of remaining intercurrent events: no other IE foreseen.
•
Treatment: 
1. The randomized treatment arm (the investigational treatment asciminib 80 mg QD, or 
the 
Investigator 
selected 
TKI); 
with 
or 
without 
dose 
modifications 
(reductions/interruptions/allowed dose escalations); regardless of dosing errors, 
deviation in any intake of concomitant medications, intake of prohibited medication; 
and regardless of taking or not taking a TKI different from their pre-randomization 
selection of TKI in the comparator arm. Further details about the investigational 
treatment and control treatments are provided in Section 6.
2. The randomized treatment arm (the investigational treatment asciminib 80 mg QD, or 
the Investigator selected TKI), within the stratum of participants that had imatinib as 
their pre-randomization selection of TKI;  with or without dose modifications 
(reductions/interruptions/allowed dose escalations); regardless of dosing errors, 
deviation in any intake of concomitant medications, intake of prohibited medication; 
and regardless of taking or not taking a TKI different from their pre-randomization 
selection of TKI in the comparator arm. Further details about the investigational 
treatment and control treatments are provided in Section 6.
•
The summary measure: stratum adjusted difference in the proportion of participants that 
are in MMR at Week 96 and corresponding 95% CI, between the 

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1. Randomized treatments (asciminib versus Investigator selected TKI).
2. Randomized treatments (asciminib versus Investigator selected TKI), within the 
stratum of participants that have imatinib as their pre-randomization selection of TKI.
2.2.2
Other secondary estimands
The other secondary estimands of interest, for the clinical questions below will be defined in 
the statistical analysis plan (SAP). 
1. A secondary clinical question of interest is: what is the efficacy of asciminib (80 mg QD) 
compared to Investigator selected TKI within the stratum of participants that have a 2G TKI 
as their pre-randomization selection of TKI; with respect to MMR at Week 48, without 
meeting any treatment failure criteria and without treatment discontinuation, prior to Week 
48, in newly diagnosed CML-CP patients; regardless of dose interruptions /reductions 
/allowed dose escalations; regardless of dosing errors, changes on concomitant medication, 
intake of prohibited medication; and regardless of taking a TKI different than the pre-
randomization selection of TKI in the comparator arm.
2. A secondary clinical question of interest is: What is the efficacy of asciminib (80 mg QD) 
compared to Investigator selected TKI within the stratum of participants that have a 
2G TKI as their pre-randomization selection of TKI; with respect to MMR at Week 
96, without meeting any treatment failure criteria and without treatment discontinuation, 
prior to Week 96, in newly diagnosed CML-CP patients; regardless of dose 
interruptions/reductions/allowed dose escalations; regardless of dosing errors, changes on 
concomitant medication, intake of prohibited medication; and regardless of taking a TKI 
different than the pre-randomization selection of TKI in the comparator arm.
3. A secondary clinical question of interest is: What is the safety/tolerability of asciminib 
(80 mg QD) compared to 2G TKIs; with respect to the time to discontinuation of study 
treatment due to AE (TTDAE), where prior treatment discontinuation due to other reasons 
is considered a competing risk event, in newly diagnosed CML-CP patients; regardless 
of dose interruptions/reductions/allowed dose escalations; regardless of dosing errors, 
changes on concomitant medication, intake of prohibited medication.
3
Study design
This study is a phase III, multi-center, open-label, randomized study of oral asciminib 80 mg 
QD versus Investigator selected TKI (imatinib, nilotinib, dasatinib, or bosutinib) in adult 
patients with newly diagnosed Ph+ CML-CP. All comparator TKIs will be made available, 
unless not permitted by local regulations or local Health Authority, or not approved for the 
treatment of CML in the country.
The study is designed to compare the efficacy of asciminib 80 mg QD with Investigator selected 
TKI for the treatment of newly diagnosed, previously untreated patients with Ph+ CML-CP. 
The Investigator selected TKI will be one of the treatment options approved by major Health 
Authorities (FDA/EMA) for first-line treatment of CML-CP - imatinib 400 mg QD or nilotinib 
300 mg BID or dasatinib 100 mg QD or bosutinib 400 mg QD. 
Approximately 402 participants will be randomized in a 1:1 ratio to asciminib or Investigator 
selected TKI.

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Randomization will be stratified based on the following two stratification factors:
•
ELTS score (low versus intermediate versus high)
•
Pre-randomization selected TKI (imatinib versus 2G TKI (nilotinib or dasatinib or 
bosutinib)). 
•
Prior to randomization, the Investigator, in consultation with the patient, considering 
the current treatment paradigm and patient characteristics and comorbidities, will make 
a selection of preference for imatinib or 2G TKI (nilotinib or dasatinib or bosutinib) if 
the patient is randomized to the comparator arm. The selection should be made as close 
as possible to the randomization date once all relevant clinical information becomes 
available.
The stratified randomization based on these two stratification factors will help to achieve a 
balance across the treatment arms for the possible comorbidities and baseline characteristics of 
patients enrolled in the study.
To further ensure that the distribution of participants, between imatinib and 2G TKIs (nilotinib 
or dasatinib or bosutinib), in the Investigator selected TKI arm is reflective of the use of these 
agents in clinical practice, the enrollment into the strata of imatinib versus 2G TKI (nilotinib or 
dasatinib or bosutinib) based on the pre-randomization selection of TKI will be managed by 
Interactive Response Technology (IRT) to be approximately 50% versus 50%.
Figure 3-1
Study design
 
#: either imatinib, or nilotinib, or dasatinib or bosutinib for ≤ 2 weeks is allowed. No other treatment 
with TKIs (tyrosine kinase inhibitors) prior to randomization is permitted. 2G: 2nd generation; CML-CP: 
Chronic Myelogenous Leukemia – Chronic Phase; ELTS: EUTOS Long Term Survival; IMA: imatinib; 
R: randomized; TKI: tyrosine kinase inhibitor
Treatment arms: The study will have 2 treatment arms:
•
Arm 1: Asciminib 80 mg QD under fasting conditions (as described in Section 6.7)
•
Arm 2: Investigator selected TKI that will include one of the below treatments*: 
•
Imatinib 400 mg QD administered with food
•
Nilotinib 300 mg BID (total daily dose of 600 mg) administered under fasting 
conditions (as described in Section 6.7)
•
Dasatinib 100 mg QD administered with or without a meal
•
Bosutinib 400 mg QD administered with food.
*Dose recommendations as per local label should be followed for participants with hepatic 
and renal impairment.

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Dose escalation:
For participants randomized to the asciminib treatment arm, dose escalation beyond 80 mg QD 
for asciminib is not permitted.
In line with the label recommendations (FDA/ EMA approved labels) for the TKIs in the 
Investigator selected TKI arm, dose escalation will be allowed in the Investigator selected TKI 
arm for imatinib, dasatinib and bosutinib. The escalation in dose is not mandatory, but is at the 
discretion of the Investigator, if considered in the participant's best interest, and can only be 
done for participants that meet both the below criteria:
•
Participants who do not experience Grade 3 toxicity
•
Participants who meet the criteria for suboptimal response as per ELN treatment 
recommendation (Hochhaus et al 2020A)
The below dose escalation is allowed*:
•
Imatinib: Dose escalation from a starting dose of 400 mg QD to 600 mg QD
•
Nilotinib: Dose escalation beyond 300 mg BID for nilotinib is not permitted
•
Dasatinib: Dose escalation from a starting dose of 100 mg QD to 140 mg QD
•
Bosutinib: Up to two sequential dose escalations in increments of 100 mg QD from a 
starting dose of 400 mg QD to a maximum of 600 mg QD
*Dose recommendations as per local label should be followed for participants with hepatic and 
renal impairment.
For further details on study treatments refer to Section 6.
No crossover of study treatment across arms and no change of study treatment within the 
Investigator selected TKI will be allowed.
Duration of Study treatment: Participants on the study will continue to receive the assigned 
treatment until the End of Study, or until premature discontinuation due to treatment failure, 
disease progression or intolerance or due to Investigator or participant decision.
Duration of study: The End of Study will occur 5 years from the last participant first treatment 
in the study. Participants who discontinue study treatment prematurely due to any reason, will 
be followed up for survival and progression (to AP/BC) until the End of Study.
At the End of Study, for participants who in the opinion of the Investigator are continuing to 
benefit from the study drug, every effort will be made to continue to provide study treatment. 
The options may include switching to commercial supplies, where applicable.
End-points: In addition to the primary and key secondary end-points based on MMR, the study 
will also investigate secondary endpoints for efficacy, PK of single-agent asciminib, safety 
and tolerability of single-agent asciminib versus that of the Investigator selected TKI, and PRO 
assessment. Exploratory end-points for biomarkers and pharmacokinetics of asciminib will also 
be assessed. 
Analysis time-points:   
•
The primary analysis will be performed when all randomized participants have been treated 
for at least 48 weeks or discontinued from study treatment prior to Week 48.

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•
The key secondary analysis will be performed when all randomized participants have been 
treated for at least 96 weeks or discontinued from study treatment prior to Week 96.
•
The final analysis will be performed once the End of Study (i.e. 5 years from the last 
participant first treatment date in the study) is reached.
4
Rationale
4.1
Rationale for study design
The proposed study CABL001J12301 is a phase III, multi-center, open-label, randomized study 
of oral asciminib versus Investigator selected TKI in adult patients with CML-CP. This patient 
population includes adult participants ≥ 18 years of age with newly diagnosed CML-CP 
enrolled within 3 months of initial diagnosis. The study will include participants with a 
documented 
diagnosis 
of 
CML-CP 
as 
per 
ELN 
treatment 
recommendations 
(Hochhaus et al 2020A). Participants could have received treatment with hydroxyurea and/or 
anagrelide for disease control following initial diagnosis. Treatment with either imatinib, or 
nilotinib, or dasatinib or bosutinib for ≤ 2 weeks is allowed, as this may be initiated around the 
time of diagnosis for emergent disease control prior to randomization and is not expected to 
impact the safety or efficacy endpoints of this study. No other TKI therapy is permitted prior to 
study entry. This is in line with previous investigation of first-line therapy in CML-CP 
(Saglio et al 2010). The inclusion and exclusion criteria are expected to support enrollment of 
a patient population representative of adult patients with newly diagnosed CML-CP, while 
maintaining adequate safeguards for patient safety in view of the experimental nature of the 
study.
To evaluate the efficacy and safety of asciminib in this patient population, the study will have 
an active comparator arm- Investigator selected TKI. Approximately 402 participants will be 
randomized in a 1:1 ratio to receive either asciminib or the comparator arm, Investigator 
selected TKI.
Participants randomized to the Investigator selected TKI arm could be treated with either 
imatinib or 2G TKIs (nilotinib or dasatinib or bosutinib), all of which are treatment options 
approved by major Health Authorities (FDA/ EMA) for newly diagnosed CML-CP patients 
(Hochhaus et al 2020A, NCCN 2020). The TKI in the comparator arm is selected by the 
Investigator in consultation with the patient. Investigator discretion in selection of the TKI in 
comparator arm is allowed as the selection of first line treatment of patients with CML-CP is 
dependent on patient related factors such as age, lifestyle, comorbidities, and disease 
characteristics such as risk score at diagnosis, as well as on the regional treatment paradigm and 
clinical practice. Investigator choice in the selection of TKI for optimal treatment of patients 
with CML-CP in the comparator arm optimizes patient treatment and minimizes the risk of 
exclusion of any group of patients, any adult age group, risk category or patients with specific 
co-morbidity.
The randomized active comparator design, comparing asciminib with recommended treatment 
options in first-line (Hochhaus et al 2020A, NCCN 2020), minimizes the risk of operational 
bias and provides a rigorous tool to appropriately assess the efficacy and safety of asciminib vs 
Investigator selected TKI in this patient population.

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Randomization will be stratified by EUTOS long-term survival (ELTS) risk group (low versus 
intermediate versus high) and pre-randomization selection of TKI of the control arm (imatinib 
versus 2G TKI [nilotinib or dasatinib or bosutinib]).
•
ELTS score is a predictive and prognostic score used to estimate the risk of progression and 
survival risk in newly diagnosed patients with CML-CP. Similar to the historically used 
Sokal score, ELTS score also uses hematologic data, spleen size, and age, but is focused on 
CML –specific OS by reducing the negative prognostic value of age as applicable to TKI’s. 
The ELTS score has been validated several times for its ability to significantly discriminate 
risk groups regarding long-term survival outcome and has been shown to provide better 
prognostic discrimination than Sokal, Hasford (Euro) or EUTOS score in CML 
(Geelen et al 2018, Pfirrmann et al 2020). The ELN and NCCN treatment guidelines 
recommend the use of the ELTS score as the preferred method to assess baseline CML risk 
and thus to inform the first-line treatment decisions for newly diagnosed patients with CML-
CP (Hochhaus et al 2020A, NCCN 2020).
•
Pre-randomization selection of the control treatment (imatinib vs 2G TKIs): Prior to 
randomization, the Investigator, in consultation with the patient and considering the current 
treatment paradigm and comorbidities presented by the patient, will make a selection of 
preference for one of imatinib, nilotinib, dasatinib or bosutinib, in the event that the patient 
is randomized to the control arm.
The randomization by these stratification factors will help achieve a balance across the 
treatment arms for the possible prognostic factors, comorbidities and baseline disease 
characteristics in the study. Stratification by geographic region is not considered as there is 
expected to be a high degree of overlap/correlation between geographic regions and our 
selected stratification factors; and also in order to limit the total number of strata.
In first line treatment of CML-CP approximately half of the patients are treated with imatinib 
and approximately half with 2G TKIs (Campbell et al 2019). Thus, in order to ensure that the 
distribution of patients between imatinib and 2G TKIs in the Investigator selected TKI arm is 
reflective of the use of these agents in clinical practice, the distribution of pre-randomization 
selection of imatinib versus 2G TKI will be managed by the IRT randomization system to 
be approximately 50% in imatinib and 50% in 2G TKI stratum.
The primary endpoint of the study is the proportion of participants that achieve MMR at Week 
48 (MMR rate at Week 48). Assessment of the efficacy endpoint of MMR by molecular 
monitoring based on BCR-ABL1 levels in International Scale (IS) by RQ-PCR with evidence of 
typical transcript is considered a sensitive and objective measure of response to treatment in 
CML-CP (Hochhaus et al 2020A, [FDA Guidance for Industry 2018], [EMA Anticancer 
guideline 2012]). A Novartis designated laboratory with validated PCR technology that has a 
sensitivity of at least MR4.5 will be used for molecular response assessment in the study.
MMR is predictive of superior long-term clinical outcomes in CML, namely PFS and OS. 
Strong evidence for MMR as a marker for survival comes from the German CML study IV 
where MMR at 12 months was associated with a better PFS (95.3% vs 86.8%) and OS (95.3% 
vs 89.8%) at 5 years (Hehlmann et al 2017). Long-term follow-up from the IRIS study also 
determined that imatinib-treated patients with MMR at 12 months had superior 10-year OS 
(91.1% vs 85.3%) with fewer CML-related deaths (97.8% vs 89.4%) compared with those 
failing this target Hochhaus et al 2017A. MMR is widely used as a surrogate marker of survival 

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in patient care and in clinical trials (Saussele et al 2018, Hochhaus et al 2020A, NCCN 2020). 
The [FDA Guidance for Industry: Hematologic Malignancies (2018)], [EMA Anticancer 
guideline (EMA/CHMP/703715/2012 Rev. 2)] supports the use of MMR as a measure of 
clinical benefit. Treatment guidelines for CML-CP consider achievement of MMR (BCR-ABL1 
levels IS ≤ 0.1% at 12 months (Week 48 of treatment) to be associated with a very low 
probability of subsequent disease progression and consider this an optimal response to treatment 
(Hochhaus et al 2020A, NCCN 2020). Thus, MMR rate at Week 48 of treatment is an objective, 
validated and standardized primary endpoint reflective of clinical benefit to the patient.
The study will be conducted as an open label study. The requirements of dose administration in 
relation to food and frequency of dosing are distinct for the two treatment arms and within the 
comparator arm; asciminib is to be administered once a day under fasting conditions, imatinib 
and bosutinib are to be administered once a day with food, dasatinib is to be administered once 
a day with or without food whereas nilotinib is to be administered twice a day under fasting 
conditions. Blinding of study treatment would be very complex and increase the likelihood of 
dosing errors in the study. Furthermore, as the efficacy endpoints are objectively measured 
standardized laboratory parameters, the open label nature of the study is not expected to 
introduce bias.
The End of Study will occur 5 years from the date the last participant receives the first treatment 
in the study. Participants who discontinue study treatment prematurely due to any reason, will 
be followed up for progression to AP/BC and survival up till the End of Study. The planned 
treatment duration of at least 5 years for all participants will be adequate to address both the 
multiple primary and key secondary objectives of the study, as well as the safety objectives. 
4.2
Rationale for dose/regimen and duration of treatment
The investigational arm of study CABL001J12301 will evaluate asciminib at a continuous dose 
of 80 mg once-daily (QD).
In the FIH dose escalation study CABL001X2101, the MTD for single agent asciminib was not 
reached. Based on PK, safety and efficacy data available from study, a single agent dose of 
asciminib 40 mg BID was determined as the RDE for patients with CML-CP or CML-AP and 
further investigated in study CABL001A2301.
The asciminib dose of 80 mg QD for patients with newly diagnosed CML-CP is based on the 
clinical experience in patients with CML-CP in studies CABL001X2101 and CABL001A2301 
and the PK/Pharmacodynamic (PD) modelling based exposure‑response and exposure-safety 
analyses.
Clinical experience with asciminib single agent 80 mg total daily dose
Study CABL001X2101
The FIH dose escalation study CABL001X2101 evaluated single agent asciminib at a wide 
range of doses (10 mg – 200 mg BID, 80 mg – 200 mg QD). In the dose escalation part of the 
study, the MTD for single agent asciminib was not reached. Testing of escalating doses of 
asciminib showed that the 40 mg BID and the 80 mg QD dose were active and well tolerated in 
this heavily pretreated population of CML-CP patients.  

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significant relationship was found between probability of safety events and increase in exposure 
within the range of dose levels and regimens investigated. For Grade 2 or higher AST increase, 
the increase in the probability of an event due to exposure was very small; for example, the 
increase was from 0.1% to 0.3% in study CABL001A2301 for a 5-fold increase in exposure. 
Regarding dose reduction due to an AE, it was found that the time to first such events was not 
associated with increasing exposure. Finally, analysis of change from baseline in serum 
creatinine was also found to be independent of exposure. In summary, asciminib has a similar 
safety profile across all dose regimens (and associated asciminib exposure) whether at 40 mg 
BID, 80 mg QD or 200 mg BID. The amount of safety data obtained at asciminib 80 mg QD 
may be considered small, however, the small sample size at the 80 mg QD dose (N=18) is more 
than counterbalanced by the total amount of data at 80 mg QD and higher total daily doses 
(N=150) with records collected over several years of treatment. Despite the increase in Cmax 
(by about 60% based on popPK) with the 80 mg QD compared to that of the 40 mg BID, in 
view of the lack of association between the chance of AEs with increasing exposure (by 5-fold), 
the 80 mg QD regimen was considered to have a similar safety profile to that of 40 mg BID.
To characterize the exposure-response relationship based on data from the two studies, semi-
mechanistic drug response models for the effect of asciminib on %BCR-ABL1 levels were 
developed. The exposure response efficacy analyses included data of 303 CML-CP participants 
from study CABL001A2301 (n=154) and study CABL001X2101 (n=149).  A total of 267 
participants received twice-daily (BID.) dosing, while 36 participants received once-daily (QD) 
dosing. At baseline, majority of the patients had >10% BCR-ABL1 transcript levels. The 
exposure-response models in efficacy highlighted the existence of a slightly positive exposure-
efficacy relationship, which did not translate into clinically meaningful difference in median 
predicted MMR rates across the doses tested. Direct comparisons provided evidence that the 
efficacy is similar between asciminib 80 mg QD and 40 mg BID.
The totality of evidence from the various exposure response models indicate a similar efficacy 
between 80 mg QD and 40 mg BID. In the light of the good safety profile of asciminib, and 
lack of association between the probability of AEs and increase in asciminib exposure, e.g. 
Cmax, the 80 mg QD is considered to offer an alternative dosage regimen option. Given the 
food effect of asciminib and its consequent fasting restrictions, the dose regimen of 80 mg QD 
provides a convenient regimen that may improve adherence to treatment.
Participant benefit
In the study CABL001J12301, in view of decreasing participant burden and increasing 
compliance in the first line setting, a once-daily dose (QD) of asciminib 80 mg will be evaluated. 
As presented above, the safety and efficacy of 80 mg QD is not expected to differ from the 40 
mg BID dose that was tested in study CABL001A2301 in patients with CML-CP who received 
at least 2 prior ATP-binding site TKIs.
Requiring participants to take asciminib twice-daily in fasting conditions poses practical 
challenges for many participants with regard to managing their daily meals and schedules, and 
it may impact treatment adherence and long-term compliance. According to Geissler et al 2017, 
35.8% of patients taking their medication once-daily were highly adherent, whereas patients 
taking their medication twice-daily were highly adherent only in 24.9% of patients and 26.7% 

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were in the low adherence group. Consequently, QD dosing is likely to be associated with better 
adherence and patient convenience.
In conclusion, based on the current efficacy and safety data available and safety-exposure and 
efficacy–exposure analyses, asciminib 80 mg QD has been selected as the dose and regimen to 
be used in this phase III study in newly diagnosed patients with CML-CP. Additionally, the 
once daily regimen is patient-centric and is likely to support better patient adherence to 
treatment in this patient population.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Rationale for choice of comparator
The comparator arm for this study is defined as Investigator selected TKI. For participants 
randomized to the Investigator selected TKI arm, the Investigator can choose to treat with either 
imatinib 400 mg QD treatment, or a 2G TKI (i.e. either nilotinib 300 mg BID, or dasatinib 100 
mg QD, or bosutinib 400 mg QD). Ponatinib is not included as a TKI option in the comparator 
arm, as it is not approved for first-line use and would therefore not be reflective of current 
clinical practice. 
Therefore, it is clinically relevant to compare asciminib with the proposed options of 
Investigator selected TKI, which is a comparator reflective of the current treatment paradigm. 
Moreover, imatinib remains the primary choice of first line treatment for many patients and its 
use is further boosted by its availability as a generic drug (Hochhaus et al 2020A). Additionally 
imatinib also served as the control arm in the pivotal studies (ENESTnd: Saglio et al 2010, 
DASISION: Kantarjian et al 2010B, BFORE: Cortes 2018) which were the basis of approval 
for the use of nilotinib, dasatinib and bosutinib, respectively, for treatment of patients with 
newly diagnosed CML-CP. Therefore, it is also important to compare asciminib versus imatinib 
(i.e. compare asciminib versus Investigator selected TKI, within the stratum of patients with 
imatinib as their pre-randomization selection of TKI).
In the Investigator selected TKI arm, dose escalation will be allowed, by Investigator decision, 
for imatinib, dasatinib and bosutinib for patients who do not have AEs of Grade 3 or higher and 
who meet the criteria for suboptimal response as per ELN 2020 treatment recommendation 
(Hochhaus et al 2020A).
For patients being treated with imatinib, dose escalation to imatinib 600 mg QD and for those 
being treated with dasatinib, dose escalation to dasatinib 140 mg QD is allowed. Similarly, for 
patients being treated with bosutinib, up to two sequential dose escalations in increments of 
100 mg QD to a maximum of bosutinib 600 mg QD is allowed. No dose escalation beyond 
300 mg BID is permitted for patients being treated with nilotinib. Escalation of dose for these 
TKIs is based on approved labels (FDA/EMA) of the respective TKI and is reflective of the 
management of patients with CML-CP in clinical practice. Locally applicable approved 
prescribing information should be consulted prior to any dose escalation.
To ensure that the distribution of patients between imatinib and 2G TKIs (nilotinib or dasatinib 
or bosutinib) in the Investigator selected TKI arm is reflective of the use of these agents in 
clinical practice, the patients’ enrollment in the two strata (based on the pre-randomization 

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selection of imatinib versus a 2G TKI) will be approximately 50% versus 50%. This distribution 
is considered to be reflective of the current treatment paradigm and will allow for analyses 
comparing asciminib versus imatinib (i.e. asciminib versus Investigator selected TKI within the 
stratum of patients with imatinib as their pre-randomization selection of TKI), and asciminib 
versus 2G TKIs (i.e. asciminib versus Investigator selected TKI within the stratum of patients 
with a 2G TKI as their pre-randomization selection of TKI).
The treatment selection for newly diagnosed adult patients with CML-CP is complex and 
guided by several factors including age, risk score, comorbidities and treatment goals. Imatinib 
has lower rates of efficacy responses as compared to 2G TKIs (nilotinib, dasatinib or bosutinib), 
however imatinib remains a widely used treatment option with a very favorable safety and 
tolerability profile. Thus an additional sub-population of interest will include the patients with 
newly diagnosed CML-CP within the stratum of patients with imatinib as the pre-randomization 
selection of TKI. 
4.4
Purpose and timing of interim analyses/design adaptations
No formal interim analysis is planned in the study. Safety outputs will be prepared for the data 
monitoring committee (DMC) as outlined in Section 10.2.3.
4.5
Risks and benefits
Appropriate eligibility criteria, as well as specific dose modification and stopping rules in the 
event of expected toxicities, are included in this protocol. Recommended guidelines for 
prophylactic or supportive treatment for expected toxicities; including management of study 
drug induced AEs, are provided in Section 6.5.
Overall, asciminib (as monotherapy or in combination with other TKIs) has shown a favorable 
benefit-risk profile in two independent clinical studies. Results from the phase I study 
([CABL001X2101]) showed positive responses with asciminib in a heavily pretreated 
population who had resistance to or unacceptable side effects from TKIs. In the ASCEMBL 
study ([CABL001A2301]) asciminib demonstrated superiority in the molecular response over 
bosutinib in participants treated with two prior TKIs (Hochhaus et al 2020B).
In the current protocol asciminib will be a first line treatment and this will allow for a population 
with a newly diagnosed condition and lower risk of progression to enter the trial, who may 
potentially benefit from a better response to asciminib. In addition, the tolerability of asciminib 
may allow for a more long-standing treatment with less side effects and lower risk of treatment 
discontinuation in this population.
Efficacy of the drug is assessed through molecular monitoring in central lab standardized to the 
international scale. With the exception of the bone marrow assessment required in the case of 
treatment failure, the protocol does not include invasive examination. Participant visits are 
aligned with the safety monitoring requirements as well as with current treatment 
recommendations and represent a common schedule that is also required in clinical practice 
outside of the study. It is therefore anticipated that the protocol will take every precaution to 
allow for the best possible safety of the patients while at the same time carefully managing the 
additional burden of the trial to patients.

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Management of side effects represent a significant challenge with TKIs, in particular as patients 
may achieve a normal life expectancy. Data from ASCEMBL Hochhaus et al 2020B support a 
more favorable safety profile of asciminib compared with bosutinib. Patients may benefit from 
the treatment with asciminib and the improved quality of life. The most frequently reported AEs 
in both the clinical studies (CABL001X2101 and CABL001A2301) are listed in Section 1.2.2.
In this trial, the risks are managed through detailed information provided in the [Asciminib 
Investigator's Brochure] and requirements delineated in the study protocol. Other risks to 
subjects in this trial will be minimized by compliance with the eligibility criteria and study 
procedures, close clinical monitoring, and adherence to dose modification and interruption 
guidance provided in the protocol.
Recommended guidelines for prophylactic or supportive treatment for expected toxicities; 
including management of study drug induced AEs are provided in Section 6.5. Moreover, close 
follow up for evidence of efficacy, based on molecular response data, will permit rapid decision 
making, and discontinuation of therapy if necessary (see Section 9.1.1 data analysis).
Female participants of child bearing potential must be informed that taking the study treatment 
may involve risks to the fetus if pregnancy were to occur during the study, and agree that in 
order to participate in the study they must adhere to the contraception requirements outlined in 
the exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study.
The local labels for imatinib, bosutinib, dasatinib and nilotinib characterize both efficacy and 
safety of each compound and provide guidance to maximize the efficacy and minimize the risks 
to patients.
There may be unforeseen risks with asciminib which could be serious. Refer to the latest 
[Asciminib Investigator’s Brochure] for additional details.
This study carries no requirement for patients to be tested for SARS-CoV-2. Based on the 
known mechanism of action, asciminib is not expected to negatively impact known immune 
mechanisms involved in clearing SARS-CoV-2 infection. However, no studies were conducted 
to assess whether asciminib may possess an additional risk in case of exposure to SARS-CoV-
2. Subjects treated with asciminib should be informed there could be unknown side effects that 
may lead to complications of COVID-19.
4.6
Rationale for Public Health Emergency mitigation procedures
During a public health emergency as declared by local or regional authorities e.g., pandemic, 
epidemic, or natural disaster, mitigation procedures to ensure participant safety and trial 
integrity may be implemented. Notification of the public health emergency as declared by local 
or regional authorities should be discussed among investigators and Novartis. All procedures 
adapted to the situation must be submitted, if required as per local regulations, through a 
protocol amendment for approval by local or regional Health Authorities and Ethics 
Committees prior to implementation of mitigation procedures. At the Investigator's discretion 
and based on benefit-risk considerations of the participant's clinical condition, qualifying 
participants may be offered the option to have certain clinical trial assessment/procedures 
according to Table 8-1 Assessment schedule performed at a remote location. 
Assessment/procedures will be performed remotely under the oversight of the Investigator, who 

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retains accountability for the oversight. The Investigator retains accountability for all efficacy 
and safety decisions with delegation of tasks to an off-site healthcare professional. The off-site 
healthcare professionals will be provided by a third-party vendor sourced by Novartis. Where 
a site wishes to use off-site healthcare professionals that are not provided by Novartis this must 
be agreed with Novartis before use. 
In addition to procedures performed by the off-site healthcare professional, the on-site staff 
might perform certain procedures remotely using tele-visits.
5
Study Population
The study CABL001J12301 will randomize approximately 402 adult participants (≥ 18 years 
of age) with newly diagnosed CML-CP (diagnosed within 3 months prior to enrollment) in a 
1:1 fashion to receive either asciminib or Investigator selected TKI (imatinib, nilotinib, 
dasatinib or bosutinib). 
Participants could have received treatment with hydroxyurea and/or anagrelide for disease 
control following initial diagnosis. Continuation of hydroxyurea which had been administered 
for urgent control of high cell counts prior to randomization is allowed during the first two 
weeks of study, and should be tapered. Treatment with any TKIs prior to randomization is not 
allowed, except for a period of ≤ 2 weeks of either imatinib, or nilotinib, or dasatinib or 
bosutinib. No TKI other than the study treatment should be used post-randomization. The 
definition of CML-CP will be according to the European Leukemia Network (ELN) criteria 
(Hochhaus et al 2020A), and is outlined below in the inclusion criteria.
The Investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Male or female participants ≥ 18 years of age.
2. Participants with CML-CP within 3 months of diagnosis.
3a. Diagnosis of CML-CP (ELN 2020 criteria) with cytogenetic confirmation of the 
Philadelphia chromosome
•
Documented 
chronic 
phase 
CML 
will 
meet 
all 
the 
below 
criteria 
(Hochhaus et al 2020A): 
•
< 15% blasts in peripheral blood and bone marrow,
•
< 30% blasts plus promyelocytes in peripheral blood and bone marrow,
•
< 20% basophils in the peripheral blood,
•
PLT count ≥ 100 x 109/L (≥ 100,000/mm3),
•
No evidence of extramedullary leukemic involvement, with the exception of 
hepatosplenomegaly.
4. ECOG performance status of 0, or 1.
5. Adequate end organ function as defined by: 
•
Total bilirubin (TBL) < 3 x ULN; participants with Gilbert’s syndrome may only be 
included if TBL ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN

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•
CrCl ≥ 30 mL/min as calculated using Cockcroft-Gault formula,
•
Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value must be 
considered not clinically significant and not associated with risk factors for acute 
pancreatitis
6a. Participants must have the following laboratory values within normal limits or corrected to 
within normal limits with supplements prior to randomization: 
•
Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with 
CrCl* ≥ 90 mL/min)
•
Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 
3.1 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min)
•
Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with 
CrCl* ≥ 90 mL/min)
•
For participants with mild to moderate renal impairment (CrCl* ≥ 30 mL/min and < 90 
mL/min) - potassium, total calcium (corrected for serum albumin) and magnesium 
should be ≥ LLN or corrected to within normal limits with supplements prior to 
randomization. 
*CrCl as calculated using Cockcroft-Gault formula
7. Signed informed consent must be obtained prior to any study related screening procedures 
being performed.
8. Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of screening 
which are amenable to standardized RQ-PCR quantification.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1a. Previous treatment of CML with any other anticancer agents including chemotherapy 
and/or biologic agents or prior stem cell transplant, with the exception of hydroxyurea 
and/or anagrelide. Treatment with either imatinib, or nilotinib, or dasatinib or bosutinib 
for ≤ 2 weeks is allowed. No treatment with other tyrosine kinase inhibitors prior to 
randomization is permitted.
2. Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS 
involvement, lumbar puncture not required).
3. Impaired cardiac function or cardiac repolarization abnormality including but not limited to 
any one of the following: 
•
History within 6 months prior to starting study treatment of myocardial infarction (MI), 
angina pectoris, coronary artery bypass graft (CABG).
•
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).
•
QTc ≥ 450 ms (male participants), ≥460 ms (female participants) on the average of 
three serial baseline ECG (using the QTcF formula) as determined by central reading. 
If QTcF ≥ 450 ms and electrolytes are not within normal ranges, electrolytes should be 
corrected and then the participant re-screened for QTc.

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•
Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome, or any of the following: 
•
Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia.
•
Concomitant medication(s) with a “Known risk of Torsades de Pointes” per 
//.crediblemeds.org/ that cannot be discontinued or replaced 7 days prior to starting 
study drug by safe alternative medication.
•
Inability to determine the QTcF interval.
4. Severe and/or uncontrolled concurrent medical disease that in the opinion of the Investigator 
could cause unacceptable safety risks or compromise compliance with the protocol (e.g. 
uncontrolled diabetes, active or uncontrolled infection; uncontrolled arterial or pulmonary 
hypertension, uncontrolled clinically significant hyperlipidemia). 
5. History of significant congenital or acquired bleeding disorder unrelated to cancer.
6. Major surgery within 4 weeks prior to study entry or who have not recovered from prior 
surgery.
7. History of other active malignancy within 3 years prior to study entry with the exception of 
previous or concomitant basal cell skin cancer and previous carcinoma in situ treated 
curatively.
8. History of acute pancreatitis within 1 year prior to randomization or medical history of 
chronic pancreatitis.
9. History of chronic liver disease leading to severe hepatic impairment, or ongoing acute liver 
disease.
10a Known history of chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) infection. 
Testing for Hepatitis B surface antigen (HBs Ag) and Hepatitis B core antibody (HBc 
Ab/anti 
HBc) 
will 
be 
performed 
at 
screening.  
If 
anti-HBc 
is 
positive, 
HBV-DNA evaluation must be carried out at screening. Patients having positive HBV-
DNA must not be enrolled in the study. Also, patients with positive HBsAg must not be 
enrolled in the study. For details on the criteria see Appendix 16.4.
11. History of Human Immunodeficiency Virus (HIV) unless well-controlled on a stable dose 
of anti-retroviral therapy at the time of screening.
12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, small bowel resection, or gastric bypass surgery).
13. Participation in a prior investigational study within 30 days prior to randomization or within 
5 half-lives of the investigational product, whichever is longer.
14a.If local regulations deviate from the contraception methods listed below to prevent 
pregnancy, local regulations apply and will be described in the ICF.
i. Pregnant or nursing (lactating) women
ii. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and for a period of time after stopping study medication. For asciminib, 
this period of time is 3 days after the last dose; if local regulations or locally approved 

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prescribing information differ from the protocol required duration of contraception, the longer 
duration must be followed and the same requirements will be described in the ICF. Participants 
taking Investigator selected TKI should be willing to follow contraception requirements in the 
locally-applicable prescribing information for the TKI received in the study.
Highly effective contraception methods include:
•
Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.
•
Female bilateral tubal ligation, female sterilization (have had surgical bilateral 
oophorectomy (with or without hysterectomy), or total hysterectomy at least six 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 partner's sterilization (at least 6 months prior to screening): the vasectomized male 
partner should be the sole partner for that participant.
•
Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate < 1%), for example hormone 
vaginal ring or transdermal hormone contraception. In case of use of oral contraception 
women should have been stable on the same pill for a minimum of 3 months before taking 
study treatment.
•
Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history 
of vasomotor symptoms). Women are considered not of child bearing potential if they are 
post-menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before taking 
study medication. In the case of oophorectomy alone, women are considered post-
menopausal and not of child bearing potential only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment.
iii. Sexually active males taking Investigator selected TKI should be willing to follow 
contraception requirements in the locally-applicable prescribing information for the TKI 
received in the study. Sexually active males taking asciminib do not require contraception. 
15. Known hypersensitivity to the study treatment.
6
Treatment
6.1
Study treatment
The investigational treatments in this study includes asciminib (80 mg QD) and an Investigator 
selected TKI that include imatinib (400 mg QD); nilotinib (300 mg BID); dasatinib (100 mg 
QD) and bosutinib (400 mg QD).
The term "investigational drug" refers to the Novartis investigational drug, asciminib.

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The "Investigator selected TKIs" could be considered as Investigational Medicinal Product 
(IMP) as well depending on local regulations. Dose recommendations as per local label should 
be followed for participants with hepatic and renal impairment.
For any component of the investigational treatment, all dosages prescribed and administered to 
the subject and all dose changes during the study (including the reason for change) must be 
recorded on the appropriate electronic Case Report Form (eCRF).
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drugs*
Investigational/ Control Drug 
(Name and Strength)
Treatment form 
or 
Pharmaceutical 
Dosage Form
Route of 
Administration
Presentation
Sponsor (global 
or local)
Asciminib (ABL001) 40 mg
Tablet
Oral use
Open label
Sponsor (global)
Imatinib 400 mg
Tablet
Oral use
Open label
Locally sourced
Imatinib 100 mg
Tablet
Oral use
Open label
Locally sourced
Dasatinib 100 mg
Tablet
Oral use
Open label
Locally sourced
Dasatinib 70 mg
Tablet
Oral use
Open label
Locally sourced
Dasatinib 50 mg
Tablet
Oral use
Open label
Locally sourced
Dasatinib 20 mg
Tablet
Oral use
Open label
Locally sourced
Nilotinib 150 mg
Capsule
Oral use
Open label
Locally sourced
Nilotinib 200 mg
Capsule
Oral use
Open label
Locally sourced
Bosutinib 400 mg
Tablet
Oral use
Open label
Locally sourced
Bosutinib 100 mg
Tablet
Oral use
Open label
Locally sourced
*Please note: Locally available generic equivalents or strength are permitted for all TKIs included in the 
comparator arm. Investigator will select from the locally available appropriate TKIs option.
Refer to Section 6.7 for preparation and dispensation.
Dose recommendations as per local label should be followed for participants with hepatic and 
renal impairment.
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Supply of study treatment
Novartis Global Clinical Supplies will supply asciminib to the investigational site as 40 mg 
tablets. Medication will be packaged as open label, with a 2 part label (base plus peel-off or 
tear-off). A unique medication number will be added on the label.
Investigator selected TKIs (nilotinib, dasatinib, bosutinib, imatinib) will be provided locally by 
the study site, subsidiary or designee as commercially available unless not permitted by local 
regulations or local Health Authority; or not approved for the treatment of CML in the country.
6.1.4
Treatment arms/group
Arm 1: Asciminib 80 mg QD under fasting conditions (as described in Section 6.7)

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Arm 2: Investigator selected TKI that will include one of the below treatments as per the pre-
randomized selection of TKI (imatinib or the 2G TKI (nilotinib or dasatinib or bosutinib))*.
•
Imatinib 400 mg QD administered with food 
•
Nilotinib 300 mg BID (total daily dose of 600 mg) administered under fasting conditions (as 
described in Section 6.7)
•
Dasatinib 100 mg QD administered with or without meal 
•
Bosutinib 400 mg QD administered with food
*Dose recommendations as per local label should be followed for participants with hepatic and 
renal impairment.
6.1.5
Post-trial access to treatment
Participants who complete participation in this trial and continue to derive clinical benefit from 
the treatment based on the Investigator’s evaluation will receive post-trial access based on the 
criteria for post-trial access being satisfied.
Post Trial Access (PTA) means the provision of treatment to trial participants following 
their completion of trial participation. PTA will be provided until one of the following is met: 
participant no longer derives clinical benefit, Investigator discontinues treatment, launch 
or reimbursement (where applicable), treatment fails to achieve registration in the 
trial participant’s country, or the clinical program is discontinued for any other reason.
Mechanisms for provision of PTA may include an extension phase to this study, a 
separate extension protocol, a rollover protocol, provision of the Novartis/Sponsor 
investigational product in a non-trial setting (known as post-study drug supply [PSDS]) when 
no further safety or efficacy data are required, or any other mechanism appropriate for the 
country.
The PTA mechanism must comply with local laws and regulations in the participating 
trial countries. If Novartis/Sponsor discontinues the PTA for this trial, Novartis/Sponsor will 
work with Investigators to transition participants into locally available alternative treatment, or 
standard of care.
6.1.6
Treatment duration
There is no fixed duration of treatment planned per participant. The participants are treated in 
the study up to end of study treatment period (defined as 5 years from the randomization date 
the last participant received the first treatment in the study), unless participants have 
discontinued treatment earlier. Participants may be discontinued from treatment with the study 
drug at any time due to unacceptable toxicity, disease progression, treatment failure and/or at 
the discretion of the Investigator or the participant. Participants who discontinue study treatment 
prematurely due to any reason, will be followed up for progression to AP/BC and survival up 
till End of Study. 
6.1.6.1
Treatment beyond disease progression
Should a disease progression occur during study, the participant must be discontinued and will 
be treated at Investigator’s discretion outside of the study.

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6.2
Other treatment(s)
Anti-emetics
Use of anti-emetics is allowed. Prophylactic anti-emetics should be started only once the 
participant experiences nausea or vomiting, at the discretion of the Investigator. It is 
recommended that participants use drugs that do not cause QT prolongation. Please note that 
some anti-emetics have a known risk for Torsade de Pointes and should be used with caution 
(refer to Section 6.2.1.1 and Section 16.1).
Contraceptives
Hormonal contraceptives are allowed as contraception methods. 
Anticoagulation agents
All anticoagulants or anti-aggregation agents may be administered under the discretion of the 
Investigator.
Therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative 
anticoagulants should be used with caution and fully avoided whenever possible because of its 
known interaction with many commonly used medications and certain foods. As warfarin has 
a narrow therapeutic range, and asciminib is a weak inhibitor of CYP2C9, the major 
metabolizing enzyme of S-warfarin (R-warfarin is metabolized by multiple CYP enzymes), 
warfarin should be carefully monitored whenever used.
Caution is also advised when asciminib is co-administered with anti-PLT pro-drugs such as 
clopidogrel, ticlopidine and prasugrel, which require metabolic activation by CYP3A4 and 
CYP2C9. Participants using anti-PLT pro-drugs should still be carefully monitored.
Direct Thrombin inhibitors (DTIs) and Factor Xa inhibitors are allowed as anticoagulants. 
Individual medications from each of the classes should be checked if they are not prohibited 
due to other drug-drug-interactions with asciminib. Alternatively, therapeutic anticoagulation 
may be accomplished using low-molecular weight heparin.
Drugs that affect gastric pH
Drugs that elevate gastric pH do not affect asciminib absorption. All acid reducing agents are 
allowed.
6.2.1
Concomitant therapy
The participant must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug and including 
over-the-counter treatment and nutritional or vitamin supplements and vaccines) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the “Concomitant 
Medications/Significant nondrug therapies” section of the eCRF. Each concomitant drug must 
be individually assessed against all exclusion criteria/prohibited medication. If in doubt, the 
Investigator should contact the Novartis medical monitor before randomizing a participant or 

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allowing a new medication to be started. If the participant is already enrolled, contact Novartis 
to determine if the participant should continue participation in the study.’
Chronic medication should be maintained at the same dose and schedule throughout the study 
period, as medically feasible.
All prior antineoplastic surgery, chemotherapy, biologic, immunologic and radiation therapy 
must be recorded in the “Prior antineoplastic therapy” section of the eCRF.
In general, concomitant medications and therapies deemed necessary for the supportive care 
and safety of the participant are allowed, provided their use is documented in the participant 
records and on the appropriate case report form, including the medication’s duration (start and 
end dates or if continuing at final exam). These include blood and PLT transfusions for 
participants with anemia and with thrombocytopenia. Concomitant use of hydroxyurea for 
urgent control of high cell counts during the first 2 weeks of study treatments is allowed.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
For participants treated with asciminib:
Following drugs should be used with caution (see Table 16-1 for examples):
•
CYP3A4/5 substrates with narrow therapeutic index
•
CYP2C9 substrates with narrow therapeutic index
•
Strong CYP3A4 inducers
•
Substrates of OATP1B, BCRP or both transporters, including, but not limited to 
sulfasalazine, methotrexate, pravastatin, atorvastatin, pitavastatin, rosuvastatin and 
simvastatin. Refer to OATP1B and BCRP substrates’ dose reductions, as recommended in 
their prescribing information. As far as possible avoid co-administering rosuvastatin and 
consider alternative statins. If during the study co-administration of rosuvastatin is required, 
then the dose of rosuvastatin should be reduced, as recommended in its prescribing 
information (ABL001 IB v10 – Section 1.4.2). As far as possible avoid co-administering 
drugs with a "Known", "Possible" or "Conditional" risk of Torsades de Pointes/QT 
prolongation (per Table 16-1) during the course of the study.
If during the course of the study, concomitant administration of a drug with "Known risk", 
"Possible risk" or "Conditional risk of Torsades de Pointes" is required, based on the 
Investigator assessment and clinical need, study treatment may be continued under close ECG 
monitoring to ensure participant safety.
A list of drugs associated with QT prolongation and/or Torsades de Pointes is available online 
at //.crediblemeds.org/.
For participants treated with the Investigator selected TKI:  
The Investigator must follow the respective local label for specific directions regarding 
restrictions in the use of concomitant therapy for each of the comparator TKIs.
6.2.1.2
Use of bisphosphonates
The use of bisphosphonates regardless of indication is allowed.

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6.2.2
Prohibited medication
For all participants in the study:
Other anticancer agents
The administration of any other anticancer agents including chemotherapy and biologic agents 
is not permitted except for anti-cancer treatments of newly diagnosed solid cancers (e.g. prostate 
cancer) that would not impact the level of minimal residual disease of participants. These 
participants may remain in the current study after consultation with Novartis. The 
administration of other tyrosine kinase inhibitors indicated for treatment of CML is not allowed.
Use of hydroxyurea for urgent control of high cell counts during the first 2 weeks of study 
treatments is allowed.
For participants treated with the Investigator selected TKI:
The Investigator must follow the respective local label for specific directions regarding other 
drugs that are contraindicated with the assigned study treatment.
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a subject Number (subject No.) that is assigned 
when the participant is first enrolled for screening and is retained as the primary identifier for 
the participant throughout his/her entire participation in the trial.
The subject No. consists of the Center Number (Center No.) (as assigned by Novartis to the 
investigative site) with a sequential subject number suffixed to it, so that each participant is 
numbered uniquely across the entire database. Upon signing the informed consent form (ICF), 
the site will use the electronic data capture (EDC) system to assign the participant the next 
sequential subject No. 
Once assigned, the subject No. must not be reused for any other participant and the subject No. 
for that individual must not be changed even if the participant is rescreened.
Re-screening is allowed once for participants that were initially screen failures for reasons 
which are amenable to correction, such as abnormal laboratory values and/ or concurrent 
medical conditions after reaching an adequate level of control. If a patient is a screen failure 
due to not meeting the laboratory levels for electrolytes under Inclusion criterion 6a, and 
rescreened after correction of these levels, the time since diagnosis could exceed 3 months, 
provided all other inclusion/ exclusion criteria continue to be met. All eligibility criteria must 
be re-checked and met prior to enrollment of the participant into the study. A new ICF will need 
to be signed if the Investigator chooses to re-screen the participant.
If the participant fails to be randomized or start treatment for any reason, the reason will be 
entered into the appropriate eCRF page, and the Interactive Response Technology (IRT) system 
should be notified as soon as possible that the participant was not randomized.

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6.3.2
Treatment assignment, randomization
In this randomized, open label trial, participants will be randomized in a 1:1 ratio to one of the 
two treatment arms. Randomization will be stratified into 6 groups based on the two 
stratification factors at screening:
•
The participants ELTS score (low versus intermediate versus high) – the score based on 
the values recorded at diagnosis will be recorded at screening. The score will be calculated 
using the European LeukemiaNet calculator available at: leukemia-
net.org/leukemias/cml/elts_score/
•
The pre-randomization selection of TKI (imatinib versus 2G TKI) 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the Interactive Response Technology (IRT) 
provider using a validated system that automates the random assignment of participant numbers 
to randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication list will be 
produced by or under the responsibility of Novartis Global Clinical Supply (GCS) using a 
validated system that automates the random assignment of medication numbers to medication 
packs containing only the study treatments packaged and labelled under global sponsor. 
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The Investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign 
a randomization number to the participant, which will be used to link the participant to a 
treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the participant. The randomization number will not be 
communicated to the caller (i.e. the Investigator or his/her delegate).
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
This study is a randomized open label study. Treatment will be open to participants, investigator 
staff, persons performing the assessments, and the Novartis Clinical Trial Team (CTT).
However, in order to minimize the potential impact of the knowledge of treatments, the 
randomization list will be kept strictly confidential. No aggregate statistical analyses by 
treatment arm shall be performed prior to the database lock. 
6.5
Dose escalation and dose modification
Asciminib:
The investigational arm of study CABL001J12301 will evaluate asciminib at a dose of 80 mg 
once-daily (QD). Dose escalation beyond 80 mg QD for asciminib is not permitted.

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Investigator selected TKI:
Dose escalation will be allowed in the Investigator selected TKI arm for imatinib, dasatinib and 
bosutinib in participants who do not experience Grade 3 toxicity and who meet the criteria for 
suboptimal response as per ELN 2020 treatment recommendation (Hochhaus et al 2020A)
Imatinib: Dose escalation from a starting dose of 400 mg QD to 600 mg QD
Dasatinib: Dose escalation from a starting dose of 100 mg QD to 140 mg QD
Bosutinib: Up to two sequential dose escalations in increments of 100 mg QD from a starting 
dose of 400 mg QD to a maximum of 600 mg QD.
Nilotinib: Dose escalation beyond 300 mg BID for nilotinib is not permitted.
Dose recommendations as per local label should be followed for participants with hepatic and 
renal impairment.
No crossover of study treatment across arms and no change of study treatment within the 
Investigator selected TKI will be allowed.
6.5.1
Dose modifications
In both treatment arms, if a participant requires a dose interruption more than 28 days for a non-
hematologic toxicity, then the participant must be discontinued from the study treatment. If a 
hematologic toxicity (cytopenia Grade 3 or 4) lasts for more than 42 days without recovery to 
at least a Grade 2, despite the study treatment interruption and adequate management (including 
hematopoietic growth factors), then the participant must be discontinued from the study 
treatment.
For participants treated with asciminib
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions, 
and/or reductions are either recommended or mandated in order to allow participants to continue 
the study treatment.
Dose modifications for asciminib are summarized in Table 6-2. The dose reduction indicated 
as "recommendations" are provided to assist Investigators in the event the participant 
experiences toxicity. However, deviations from "mandatory" dose interruptions and/or 
reductions are not allowed and mandatory interruptions or reductions must be strictly followed. 
Re-escalation to asciminib 80 mg QD is permitted if a change in the participant's individual 
benefit/risk assessment at the lower dose level is seen. Re-escalation will be allowed only once 
for any participant for any specific event per protocol. Further re-escalation to a maximum of 
80 mg QD may be allowed in case the event is considered to be significantly different than the 
one(s) experienced previously and must be based on discussion with and approval by the 
Novartis medical monitor. Permanent treatment discontinuation is mandatory for specific 
events indicated as such in Table 6-2.
These dose changes must be recorded on the appropriate eCRF (Dosage Administration Record 
eCRF).
A participant must discontinue treatment with asciminib if, after treatment is resumed at a lower 
dose level, the toxicity recurs with the same or worse severity, except for recurrence of 

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cytopenias (Table 6-2). If a participant requires a dose interruption more than 28 days for a non-
hematologic toxicity, then the participant must be discontinued from the study treatment. If a 
hematologic toxicity (cytopenia Grade 3 or 4) lasts for more than 42 days without recovery to 
at least a Grade 2, despite the study treatment interruption and adequate management (including 
hematopoietic growth factors), then the participant must be discontinued from the study 
treatment.
Table 6-2
Criteria for dose reduction / interruption and re-initiation of 
asciminib treatment for adverse drug reactions.
Dose modifications for asciminib 
Worst toxicity
CTCAE Grade (version 5)
Asciminib
Investigations (Hematologic) If a hematologic toxicity (cytopenia Grade 3 or 4) lasts for more than 42 
days without recovery to at least a Grade 2, despite the study treatment interruption and adequate 
management (including hematopoietic growth factors), then the participant must be discontinued from 
the study treatment.
Neutropenia (ANC)
Grade 1 (ANC < LLN - 1.5 x 109/L)
Recommendation: Maintain dose level
Grade 2 (ANC < 1.5 - 1.0 x 109/L)
Recommendation: Maintain dose level
Grade 3 (ANC < 1.0 - 0.5 x 109/L)
Mandatory: Omit dose until resolved to ≤ Grade 2, 
(recheck Complete Blood Count (CBC) 2x/week), 
then:
if resolved in ≤ 14 days, then maintain dose level 
If resolved in > 14 days, then reduce dose ↓1 dose 
level
Grade 4 (ANC < 0.5 x 109/L)
Mandatory: Omit dose until resolved to ≤ Grade 2,
(recheck CBC 2x/week), then:
if resolved in ≤ 14 days, then maintain dose level 
If resolved in > 14 days, then reduce dose ↓1 dose 
level
Febrile neutropenia (ANC < 1.0 x 109/L, fever ≥ 
38.5°C)
Mandatory: Omit dose until resolved, then ↓ 1 dose 
level
Thrombocytopenia
Grade 1 (PLT < LLN - 75 x 109/L)
Recommendation: maintain dose level
Grade 2 (PLT < 75- 50 x 109/L)
Recommendation: maintain dose level
Grade 3 (PLT < 50 - 25 x 109/L)
Mandatory: Omit dose until resolved to ≤ Grade 2,
(recheck CBC 2x/week), then:
if resolved in ≤ 14 days, then maintain dose level 
If resolved in > 14 days, then reduce dose ↓1 dose 
level
Grade 4 (PLT < 25 x 109/L)
Mandatory: Omit dose until resolved to ≤ Grade 2,
(recheck CBC 2x/week), then:
if resolved in ≤ 14 days, then maintain dose level 
If resolved in > 14 days, then reduce dose ↓1 dose 
level
Recurrence of all cytopenias
Recommendation: Omit dose until resolved to ≤ 
Grade 2, then maintain current dose level.
For recurrent Grade 3-4 cytopenias
Non-hematologic adverse reactions except where further specified in individual sections
Grade 1
Recommendation: Maintain dose level

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Dose modifications for asciminib 
Grade 2
Recommendation: Omit dose until resolved to ≤ 
Grade 1, then maintain dose level
Grade 3
Mandatory: Omit dose until resolved to ≤ Grade 1, 
then reduce dose ↓ 1 dose level
Grade 4
Mandatory: Permanently discontinue participant from 
study drug treatment
Investigations (Renal)
Serum creatinine
>ULN - 1.5 x ULN
Recommendation: maintain dose level
>1.5 - 3.0 x baseline; > 1.5 - 3.0 x ULN
Recommendation: Omit dose until resolved to ≤ 1.5 x 
ULN or baseline, then maintain dose level
>3.0 x baseline; > 3.0 - 6.0 x ULN)
Mandatory: Permanently discontinue participant from 
study drug treatment
> 6.0 x ULN
Mandatory: Permanently discontinue participant from 
study drug treatment
Investigations (Hepatic) 
Isolated TBL elevation
> ULN – 1.5 x ULN irrespective of baseline levels 
Recommendation: Maintain dose level
> 1.5 - 3.0 x ULN irrespective of baseline levels
Recommendation: Omit dose. Repeat liver testsb 
within 48-72 hours then monitor weekly, or more 
frequently if clinically indicated, until resolved to ≤ 1.5 
x ULN or baseline:
if resolved in ≤ 14 days, then maintain dose level 
if resolved in > 14 days, then reduce dose ↓1 dose 
level
> 3.0 - 10.0 x ULN irrespective of baseline levels 
Mandatory: Omit dose. Repeat liver testsb within 48-
72 hours then monitor weekly, or more frequently if 
clinically indicated, until resolved to ≤ 1.5 x ULN or 
baseline: 
if resolved in ≤ 14 days, then reduce dose ↓1 dose 
level
if resolved in > 14 days, then discontinue participant 
from study drug treatment. 
The participant should be monitored weekly (including 
liver testsb), or more frequently if clinically indicated, 
until TBL have resolved to baseline or stabilization 
over 4 weeks
> 10.0 x ULN irrespective of baseline levels 
Mandatory: Permanently discontinue participant from 
study drug treatment. The participant should be 
monitored weekly (including liver testsb), or more 
frequently if clinically indicated, until TBL have 
resolved to baseline or stabilization over 4 weeks
Isolated Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) elevation 
If normal at baseline
> ULN - 3.0 x ULN 
Recommendation: Maintain dose level
> 3.0 - 5.0 x ULN 
 
Recommendation: Maintain dose level. Repeat liver 
testsb as soon as possible, preferably within 48-72 
hours from awareness of the abnormal results; 

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Dose modifications for asciminib 
if abnormal lab values are confirmed upon the repeat 
test, then monitor Lliver testsb weekly, or more 
frequently if clinically indicated, until resolved to ≤ 3.0 
x ULN 
> 5.0 - 10.0 x ULN 
Mandatory: Omit dose. Repeat liver testsb as soon as 
possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor liver testsb 
weekly, or more frequently if clinically indicated, until 
resolved to ≤ 3.0 x ULN
If resolved in ≤ 14 days resume at prior dose level If 
resolved in > 14 days, resume with reduced dose ↓1 
dose level
> 10.0 - 20.0 x ULN 
Mandatory: Omit dose. Repeat liver testsb as soon as 
possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor liver testsb 
weekly, or more frequently if clinically indicated, until 
resolved to ≤ 3.0 x ULN Then resume with reduced 
dose ↓1 dose level.
> 20.0 x ULN 
Mandatory: Permanently discontinue 
If elevated at baseline:
> Baseline - 3.0 x Baseline AND < 
5 x ULN
Recommendation: Maintain dose level
> 3.0 x Baseline AND > 5.0 x ULN 
(duration less than 2 weeks)
Recommendation: Maintain dose level. Repeat liver testsb as soon as 
possible, preferably within 48-72 hours from awareness of the abnormal 
results; if abnormal lab values are confirmed upon the repeat test, then 
monitor liver testsb weekly, or more frequently if clinically indicated, until 
resolved to ≤ ULN or baseline
> 3.0 x Baseline AND > 5.0 x ULN 
(duration more than 2 weeks):
Mandatory: Omit dose. Repeat liver testsb as soon as possible, 
preferably within 48-72 hours from awareness of the abnormal results; if 
abnormal lab values are confirmed upon the repeat test, then monitor 
liver testsb weekly, or more frequently if clinically indicated, until resolved 
to ≤ ULN or baseline. If resolved, resume with reduced ↓ 1 dose level.
> 5.0 x Baseline AND > 8.0 x ULN 
(irrespective of the duration):
Mandatory: Omit dose. Repeat liver testsb as soon as possible, 
preferably within 48-72 hours from awareness of the abnormal results; if 
abnormal lab values are confirmed upon the repeat test, then monitor 
liver testsb weekly, or more frequently if clinically indicated, until resolved 
to ≤ ULN or baseline. If resolved, resume with reduced ↓ 1 dose level.
> 20.0 x ULN
Permanently discontinue
Combined c elevations of AST or ALT and TBL
For participants with normal baseline ALT and AST 
and TBL value:
AST or ALT >3.0xULN combined with TBL >2.0 x 
ULN without evidence of cholestasisd
For participants with elevated baseline AST or ALT or 
TBL value
AST or ALT> 3 x baseline OR [> 8.0 x ULN], 
whichever is lower, combined with TBL >2x baseline 
AND >2.0 x ULN
**Note: For participants with Gilbert’s syndrome, at 
least 2-fold increase in direct bilirubin.
Mandatory: Interrupt treatment and adjudicate for 
DILI:
Repeat as soon as possible, preferably within 48 
hours from awareness of the abnormal results, then 
with weekly monitoring of liver testsb, or more 
frequently if clinically indicated, until AST, ALT, or 
bilirubin have resolved to baseline or stabilization over 
4 weeks. Refer to Section 6.5.2.1 for additional follow-
up evaluations as applicable.
Mandatory: If causality assessment indicates DILI is 
probable: Permanently discontinue participant from 
treatment.
If not DILI: Treat the identified cause according to 
institutional guidelines. Once resolved, reduce by one 
dose level if cause is treatment related.

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Investigation (metabolic)
Asymptomatic amylase and/or lipase elevation
> ULN - 1.5 x ULN
Recommendation: Maintain dose level, measure 
2x week
> 1.5 - 5.0 x ULN
Recommendation: Maintain dose level, measure 
2x week
>5.0 x ULN
Mandatory: Omit dose until resolved to ≤ 1.5 x ULN 
or baseline, then:
If resolved in ≤ 7 days, then reduce dose ↓1 dose 
level
If resolved in > 7 days, then discontinue treatment and 
obtain appropriate imaging (i.e., Magnetic resonance 
imaging (MRI), CT scan or ultrasound).
> 5.0 x ULN and with signs or symptoms
Mandatory: Permanently discontinue participant from 
study drug treatment. Obtain appropriate imaging (i.e., 
MRI, Computed tomography (CT) scan or ultrasound).
Vascular disorders
Hypertension
Systolic BP 140-159 mm Hg or Diastolic BP 90-99 
mm Hg
Recommendation: Maintain dose level. Initiate 
antihypertensive drug/ increase the dose of existing 
antihypertensive drug or change treatment plan as per 
Investigator's assessment
Systolic BP ≥160 mm Hg or Diastolic BP ≥100 mm Hg
Mandatory: Omit dose until resolved ≤ Grade 
1/baseline, then reduce dose ↓ 1 dose level. Initiate 
anti-hypertensive drug/ increase the dose of existing 
anti-hypertensive drug or change treatment plan as 
per Investigator's assessment
CTCAE Grade 4
Mandatory: Permanently discontinue 
participant from study drug treatment
Gastro intestinal
Pancreatitis
Grade 2 (enzyme elevations with radiologic findings 
for pancreatitis as per CTCAE v5.0.. For 
isolated increased enzymes please see table for 
asymptomatic amylase and/or lipase elevation)
Mandatory: If radiologic findings, hold treatment until 
resolved to ≤ Grade 1 or baseline. 
If treatment delay is ≤ 21 days, then reduce dose ↓ 1 
dose level. 
If treatment delay > 21 days, discontinue 
treatment and keep monitoring with appropriate 
imaging (i.e., MRI, CT scan or ultrasound)**.
Grade ≥ 3
Mandatory: 
Permanently discontinue participant from study 
drug treatment. Obtain appropriate imaging (i.e., MRI, 
CT scan or ultrasound).
Diarrhea***
Grade 1
Recommendation: Maintain dose level but, initiate 
anti-diarrhea treatment
Grade 2
Recommendation: Omit dose until resolved (initiate 
anti-diarrhea treatment) to ≤ grade 1, then maintain 
dose level.
If diarrhea returns as ≥ grade 2, then omit dose until 
resolved to ≤ grade 1, then reduce dose ↓ 1 dose 
level
Grade 3
Recommendation: Omit dose, initiate anti-diarrhea 
treatment and discontinue participant from study drug 
treatment

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Grade 4
Mandatory: Initiate anti- diarrhea treatment and 
permanently discontinue participant from study drug 
treatment
Nausea/vomiting
Grade 1
Recommendation: Maintain dose level but, may 
initiate anti-nausea treatment
Grade 2
Recommendation: Omit dose until resolved (initiate 
anti-nausea and other supportive treatment) to ≤ 
grade 1, then maintain dose level. If nausea/vomiting 
returns as ≥ grade 2, then omit dose until resolved to 
≤ grade 1, then reduce dose ↓ 1 dose level
Grade 3
Mandatory: Omit dose until resolved ( initiate anti-
nausea and other supportive treatment) to ≤ grade 1, 
then reduce dose ↓ 1 dose level.
Recommendation: Omit dose for ≥ grade 3 vomiting 
or grade 3 nausea only if the vomiting or nausea 
cannot be controlled with optimal antiemetic (as per 
local practice)
Grade 4
Mandatory: Permanently discontinue participant from 
study drug treatment.
Skin and subcutaneous tissue disorders
Rash/photosensitivity
Grade 1
Recommendation: Maintain dose level. Consider to 
initiate appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids and low-dose 
systemic corticosteroids)
Grade 2
Recommendation: Maintain dose level, but 
initiate/intensify appropriate skin toxicity therapy (such 
as antihistamines, topical corticosteroids and low-
dose systemic corticosteroids)
Grade 3, despite skin toxicity therapy
Recommendation: Omit dose until resolved to Grade 
≤ 1, then:
If resolved in ≤ 7 days, reduce dose ↓ 1 dose level
If resolved in > 7 days (despite appropriate skin 
toxicity therapy), then discontinue participant from 
study drug treatment
Grade 4, despite skin toxicity therapy
Mandatory: Permanently discontinue participant from 
study drug treatment
General disorders and administration site conditions
Fatigue/ Asthenia (General disorders and administration site conditions)
Grade 1 or 2
Recommendation: Maintain dose level
Grade 3
Recommendation: Omit dose until resolved to ≤ 
grade 1, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then reduce dose ↓ 1 dose 
level
All dose modifications should be based on the worst preceding toxicity.
a Common Toxicity Criteria for AEs (CTCAE Version 5.0).
b Core liver tests consist of ALT, AST, TBL (fractionated [direct and indirect], if TBL > 2.0 x ULN), and alkaline 
phosphatase (fractionated [quantification of isoforms], if alkaline phosphatase > 2.0 x ULN).
c “Combined” defined as TBL increase to the defined threshold concurrently with ALT/AST increase to the 
defined threshold.
If combined elevations of AST or ALT and TBL do not meet the defined thresholds, please follow the 
instructions for isolated elevation of TBL and isolated elevation of AST/ALT, and take a conservative action 
based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is needed for 
one parameter and discontinue treatment is required for another parameter). After all elevations resolve to the 

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defined thresholds that allow treatment re-initiation, re-start the treatment either at the same dose or at one 
dose lower if meeting a criterion for dose reduction.
d “Cholestasis” defined as Alkaline Phosphatase (ALP) elevation (>2.0 x ULN and R value <2 ) in participants 
without bone metastasis or elevation of ALP liver fraction in participants with bone metastasis.
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It 
denotes whether the relative pattern of ALT and/or ALP elevation is due to cholestatic (R ≤ 2), hepatocellular 
(R ≥ 5), or mixed (R >2 and < 5) liver injury.
* Note: If TBL > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as the 
etiology has been ruled out as per institutional guidelines (e.g. review of peripheral blood smear and 
haptoglobin determination), then ↓ 1 dose level and continue treatment at the discretion of the Investigator.
** Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed 
within 1 week of the first occurrence of any ≥ Grade 3 of amylase and/or lipase. If asymptomatic Grade 2 
elevations of lipase and/or amylase occur again at the reduced dose, participants will be discontinued 
permanently from study treatment.
*** Note: Antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools, or 
overt diarrhea.
Table 6-3
Dose reduction steps for asciminib 
Dose reduction* 
Starting dose level – 0
Dose level – 1
Asciminib
Two 40 mg tablet QD (once daily) 
(total daily dose 80 mg)
One 40 mg tablet QD (total 
daily dose 40 mg)
*Dose reduction should be based on the worst toxicity demonstrated at the last dose.
Asciminib dose reduction below a total daily dose of 40 mg is not allowed. 
For participants treated with the Investigator selected TKI:  
Dose modifications of the Investigator selected TKI are at Investigator's discretion and in 
accordance with institutional practice and local labels.
The Investigator must follow the respective local label for specific directions regarding dose 
modifications.
If a participant requires a dose interruption more than 28 days for a non-hematologic toxicity, 
then the participant must be discontinued from the study treatment. If a hematologic toxicity 
(cytopenia Grade 3 or 4) lasts for more than 42 days without recovery to at least a Grade 2, 
despite the study treatment interruption and adequate management (including hematopoietic 
growth factors), then the participant must be discontinued from the study treatment.
6.5.1.1
Dose adjustments for QTcF prolongation
In case of QTcF >500 ms (or QTcF prolongation >60 ms from baseline)
If QTcF >500 ms or QTcF prolongation >60 ms from baseline is observed at any point during 
asciminib treatment, and confirmed, the below guidance must be followed:
•
Assess the quality of the ECG recording and the QT value and repeat if needed
•
Interrupt asciminib treatment until confirmed resolution of QTcF and as per dose reduction 
guidelines for non-hematological AEs.
•
Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming asciminib treatment.
•
Review concomitant medication associated with QT prolongation, including drugs with a 
"Known", "Possible", or "Conditional risk of Torsades de Pointes" (refer to Table 16-1), 

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and drugs with the potential to increase the risk of study drug exposure related QT 
prolongation.
•
Check the dosing schedule and treatment compliance.
After confirming ECG reading at site, if QTcF > 500 ms
•
Interrupt asciminib treatment
•
Repeat ECG and confirm ECG diagnosis by a cardiologist or central ECG lab
•
If QTcF confirmed > 500 ms: 
•
Correct electrolytes, eliminate culprit concomitant treatments, and identify and address 
clinical conditions that could potentially prolong the QT as per the ECG and QTc 
Clinical Safety Standards Guidelines.
•
Consult with a cardiologist (or qualified specialist)
•
Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 480 ms.
•
After resolution to ≤ 480 ms, consider re-introducing treatment of asciminib at reduced dose, 
and increase ECG monitoring for the next treatment(s), (e.g. pre-dose and 2 hours post 
dose after one week and two weeks of treatment re-introduction): 
•
If QTcF remains ≤ 500 ms after dose reduction, continue planned ECG monitoring 
during subsequent treatment
•
If QTcF recurs > 500 ms after dose reduction, discontinue participant from trial.
6.5.2
Follow-up for toxicities
Participants whose treatment is permanently discontinued due to a study drug related adverse 
event or clinically significant laboratory value should be followed up at least once a week for 4 
weeks, until resolution or stabilization of the event, whichever comes first. Appropriate clinical 
experts such as ophthalmologist, endocrinologist, dermatologist, psychiatrists etc. should be 
consulted as deemed necessary. All participants must be followed up for AEs and SAEs for 30 
days following the last dose of study treatment.
6.5.2.1
Follow up on potential drug-induced liver injury (DILI) cases
Transaminase increase combined with TBL increase may be indicative of potentially severe 
Drug-induced liver injury (DILI), and should be considered as clinically important events and 
assessed appropriately to establish the diagnosis. The required clinical information, as detailed 
below, should be sought to obtain the medical diagnosis of the most likely cause of the observed 
laboratory abnormalities.
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and TBL 
value; participants meeting any of the following criteria will require further follow-up as 
outlined below:
•
For participants with normal ALT and AST and TBL value at baseline: AST or ALT > 3.0 
x ULN combined with TBL > 2.0 x ULN
•
For participants with elevated AST or ALT or TBL value at baseline: [AST or ALT >3.0 x 
baseline] OR [ALT or AST > 8.0 x ULN], whichever occurs first, combined with [TBL > 
2.0 x baseline AND > 2.0 x ULN]

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As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury.
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected.
Laboratory tests should include ALT, AST, TBL, direct and indirect bilirubin, GGT, 
prothrombin time (PT)/INR, alkaline phosphatase, albumin, and creatine kinase. If available, 
testing of Glutamate Dehydrogenase (GLDH) is additionally recommended.
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion – e.g. using CT, 
MRI, or duplex sonography.
Perform 
relevant 
examinations 
(Ultrasound 
or 
MRI, 
Endoscopic 
retrograde 
cholangiopancreatography (ERCP)) as appropriate, to rule out an extrahepatic cause of 
cholestasis. Cholestasis (is defined as an Alkaline Phosphatase (ALP) elevation > 2.0 x ULN 
with R value < 2 in participants without bone metastasis, or elevation of the liver-specific ALP 
isoenzyme in participants with bone metastasis).
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT 
can be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, 
since GGT can also be elevated by enzyme induction or by ethanol consumption. It is more 
sensitive than ALP for detecting bile duct injury.
Table 6-4 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed Liver test abnormalities.
Table 6-4
Clinical and diagnostic assessments to rule out possible alternative 
causes of observed Liver Test abnormalities.
Disease
Assessment
Hepatitis A, B, C, E
•
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, HCV 
Ribonucleic acid (RNA), IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection
•
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis
•
Antinuclear Antibodies (ANA) & Anti-Smooth Muscle Antibody (ASMA) 
titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis
•
Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis
•
Ultrasound or MRI
Hypoxic/ischemic hepatopathy
•
Medical history: acute or chronic congestive heart failure, hypotension, 
hypoxia, hepatic venous occlusion. Ultrasound or MRI.
Biliary tract disease
•
Ultrasound or MRI, ERCP as appropriate.
Wilson disease (if <40 yrs old)
•
Caeruloplasmin
Hemochromatosis
•
Ferritin, transferrin
Alpha-1-antitrypsin deficiency
•
Alpha-1-antitrypsin
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic 
hepatitis – ECG, prior hypotensive episodes; Type 1 diabetes / glycogenic hepatitis).

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Obtain PK sample to determine exposure to study treatment and metabolites.
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for liver tests abnormalities identified, should be considered as 
“medically significant,” and thus, meet the definition of SAE and should be reported as SAE 
using the term “potential treatment-induced liver injury.” All events should be followed up with 
the outcome clearly documented.
6.5.3
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria, as well as specific dose modification and stopping rules are 
included in this protocol. Recommended guidelines for prophylactic or supportive treatment for 
expected toxicities, including management of study-drug induced AEs, i.e., hematological, 
hepatic, renal, metabolic, vascular, gastrointestinal, skin toxicity and general disorders are 
provided in Table 6-2. Refer to preclinical toxicity and or clinical data found in the current 
[Asciminib Investigator’s Brochure] or locally applicable (imatinib, nilotinib, dasatinib, and 
bosutinib labels).
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The Investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
Investigator if he/she is unable for any reason to take the study treatment as prescribed. 
Compliance will be assessed by the Investigator and/or study personnel at each visit using 
tablets counts (if applicable at the visit) and information provided by the participant. This 
information should be captured in the source document at each visit. All study treatment 
dispensed and returned must be recorded in the Drug Accountability Log. Total daily dose of 
study treatment administered with start and end date will be collected on the dedicated eCRF 
page.
Remote treatment administration compliance will be assessed by the off-site healthcare 
professional, and information provided to the Investigator and/or study personnel (as per 
Section 4.6).
6.6.2
Emergency breaking of assigned treatment code
Not applicable as this is an open-label study.

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6.7
Preparation and dispensation
Asciminib (investigational drug):
The Investigator or responsible site personnel must instruct the participant or caregiver to take 
the study drug as per protocol. Study drug will be dispensed to the participant by authorized site 
personnel only. All dosages prescribed to the participant and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF.
The investigational drug, asciminib, will be provided as global clinical open-label supply and 
will be packed and labeled under the responsibility of Novartis, Drug Supply Management.
A unique medication number is printed on the label of the investigational drug. Investigator 
staff will identify the investigational drug kits to administer to the participant by contacting the 
IRT and obtaining the medication number(s). The investigational drug has a 2-part label (base 
plus tear-off label), immediately before administering the medication kit to the participant, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document. 
Other study drugs (imatinib, nilotinib, dasatinib, bosutinib):
The other study drugs (imatinib, nilotinib, dasatinib, bosutinib) will be supplied locally as 
commercially available by the site pharmacy or by Novartis, if so, the drugs will be labeled 
accordingly to comply with the country legal requirements. Preparation and dispensation should 
follow the locally approved label and local practice.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of investigational treatments directly to a participant’s home may be permitted (if 
allowed by Local or Regional Health Authorities and Ethics Committees as appropriate) in the 
event the Investigator has decided that an on-site visit by the participant is no longer appropriate 
or possible, and that it is in the interest of the participant’s health to administer the study 
treatment even without performing an on-site visit. The dispatch of investigational treatments 
from the site to the participant’s home remains under the accountability of the Investigator. 
Each shipment/provisioning will be for a maximum of 12 weeks supply. In this case, regular 
phone calls or virtual contacts (every 4 weeks until 12 weeks, then every 12 weeks or more 
frequently if needed), will occur between the site and the participant for instructional purposes, 
safety monitoring, drug accountability, investigation of any AEs, ensuring participants continue 
to benefit from treatment and discussion of the participant´s health status until the participants 
can resume visits at the study site. Please refer to Section 10.1.1 and Section 6.5 where 
assessment of suitability for continued investigational treatments administration may be needed.
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 

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instructions specified on the medication labels and in the (Asciminib 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 Country Organization Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number.
The Investigator or designated site staff 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 and at the completion of the trial. If study 
treatment is administered at home e.g. oral medication, participants will be asked to return all 
unused study treatment and packaging and at the end of the study or at the time of 
discontinuation of study treatment.
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, 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 treatment for remote administration will be shipped from the pharmacy to the participants' 
home in accordance with the local practice.
6.7.2
Instruction for prescribing and taking study treatment
Study treatment (asciminib) will be provided as global clinical open-label supply and will be 
packed and labeled under the responsibility of Novartis, Global Clinical Supply.
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions and a unique medication number (corresponding to study treatment and 
strength).
Dose and treatment schedule are described in Table 6-5 and Table 6-1 and all the information 
about the administration of the investigational drug are described in the  Section 6.1.3 and 
Section 6.1.4. Dose reductions can be performed as described in  Table 6-3. Dose escalation 
information can be found in Section 6.5.
Table 6-5
Dose and treatment schedule*
Dose
Frequency 
Investigational Drug
Asciminib (ABL001)
80 mg
once daily
Other Study Drugs
Imatinib
400 mg
once daily
Nilotinib
300 mg (total daily dose of 600 
mg)
twice daily
Dasatinib
100 mg
once daily
Bosutinib
400 mg
once daily
* Dose recommendations as per local label should be followed for participants with hepatic and renal 
impairment.

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At baseline visit (Week 1) the participants will be randomized into one of the 2 treatment arms 
(stratified by pre-randomization selection of TKI and ELTS score), and the responsible site 
personnel will identify the study treatment package(s) to dispense by the medication number(s) 
assigned by IRT to the participant.
Asciminib arm:
Asciminib two 40 mg tablets will be administered orally daily on a continuous schedule (i.e. 80 
mg QD). Asciminib should be ingested as follows:
•
Participants should take asciminib daily at approximately the same time each day in the 
morning.
•
Participants should take asciminib under fasting conditions (on an empty stomach). No food 
should be consumed for two hours before and at least one hour after the dose is taken. Each 
dose may be taken with a glass of water, approximately 240 mL (8 ounces) of water.
•
On days that PK samples are obtained, the participant should take asciminib during the 
clinic visit after the pre-dose PK samples, when instructed by the study staff.
•
Participants should be instructed to swallow whole tablets and not to chew or to break them.
•
If vomiting occurs during the first hour after taking the drug, re-dosing is allowed before 
the next scheduled dose.
•
If the participant does not take asciminib within 12 hours after the usual dosing time, that 
dose should be skipped and treatment should continue with the next daily dose at the 
prescribed level.
Investigator selected TKI arm:
The Investigator must follow the respective local label for specific directions for the 
administration of imatinib, dasatinib, bosutinib, and nilotinib. For all drugs taken QD, morning 
dosing is required in the study in order to allow compliance with key study requirements such 
as ECG collection. Dose recommendations as per local label should be followed for participants 
with hepatic and renal impairment. 
Dosages for all compounds prescribed and dispensed to the participants and all dose changes 
during the study must be recorded on the Dosage Administration Record eCRF.
All kits of study treatment will be recorded in the IRT system.
7
Informed consent procedures
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the patient and/or their legally authorized representative and answer all 
questions regarding the study. Participants must be informed that their participation is voluntary. 
Participants or their legally authorized representatives will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
privacy and data protection requirements, where applicable, and the IRB/IEC or study center.

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The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative. 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved informed consent.
If applicable, in cases where the participants' representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
Information about common side effects already known about the investigational treatment can 
be found in the Investigator's Brochure (IB). This information will be included in the 
participant informed consent and should be discussed with the participant upon obtaining 
consent and also during the study as needed. Any new information regarding the safety profile 
of the investigational drug that is identified between IB updates will be communicated as 
appropriate, for example, via an Investigator notification or an aggregate safety finding. New 
information might require an update to the informed consent and then must be discussed with 
the participant.
The following informed consents are included in this study:
•
Main study consent, which also includes
•
A subsection that requires a separate signature for the ‘Optional Consent for Additional 
Research’ to allow future research on data/samples collected during this study
•
As applicable, Pregnancy Outcomes Reporting Consent for female participants 
Women of child bearing potential must be informed that taking the study treatment may involve 
potential 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. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that 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 Heath Authority.

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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.).
Moreover, as per Section 4.6, qualifying participants may be offered the option to have certain 
clinical trial procedures performed at a remote location. In this case, informed consent must be 
obtained before conducting any study-specific procedures. The process for obtaining consent 
should be exactly the same as described above for the main informed consent.
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.
8
Visit schedule and assessments
The Assessment Schedule Table 8-1 lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation.
Participants should be seen for all visits/assessments as outlined in the assessment schedule, 
Table 8-1, or as close to the designated day/time as possible. In case unscheduled assessments 
of any type are required, they may be performed as per Investigator’s decision and will be 
recorded in the appropriate eCRF. The visit “Baseline/Week 1” is the day 1 of the study, 
meaning the first day of dosing; all subsequent visits refer to end of the week, meaning for 
example that the visit “Week 2” is performed 2 weeks after the day 1 at day 14 of the study 
(“Week 4” at day 28 and so on). 
The randomization and assessments (see Table 8-1) for the Visit Name “Baseline/Week 1”, 
except for the one specified as pre-dose, can be done with a window of -3 days from first dose 
(study day 1).
For the other visits, a visit window of +/- 3 days will be allowed. For PROs the collection 
window is described in Section 8.5.1, ECG will be performed before the PK sample collections. 
Missed or rescheduled visits should not lead to automatic discontinuation.
Participants who discontinue from study treatment are to return for the end of treatment (EOT) 
visit as soon as possible and attend the follow-up visits as indicated in the Assessment Schedule.
Participants who discontinue from study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications not previously reported must be recorded on the CRF.
The “X” in the table denotes the assessments to be recorded in the clinical database or received 
electronically from a vendor. The “S” in the table denotes the assessments that are only in the 
participant’s source documentation and do not need to be recorded in the clinical database.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the Investigator as 
the situation dictates. If allowed by local Health Authority national and local regulations and 

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depending on operational capabilities, phone calls, virtual contacts (e.g. tele consultation) or 
visits by site staff/off-site healthcare professional(s) staff to the participant´s home, can replace 
certain protocol assessments, 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.
Where multiple assessments are required to be performed at the same time point, and where the 
order of assessments is important for the evaluation of data, the order is based on study priorities 
and assessment needs. PRO measure(s) must be completed before any clinical assessments are 
performed at any given visit. PK sampling is prioritized, and other assessments are arranged 
around the collection of this sample.

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Table 8-1
Assessment Schedule
Period
Screening4
Treatment*
End of 
Treatment
30 
Days 
Safety 
follow-
up
Survival 
follow-
up 
Phase 
(Every 
12 
weeks)
Visit Name
Screening
Baselin
e/ 
Week 1 
Week 2 Week 4 Week 6 Week 8 Week 
10
Week 
12
Week 
24
Week 
36
Week 
48
Every 
12 
weeks 
to EOT
EOT/ Early 
Discontinua
tion
30 
Days 
Safety 
follow-
up
Survival 
follow- 
up 
Visit 
Numbers1
1
110
120
130
140
150
160
170
180
190
200
210
220
230
240
Days (+/- 3 
days, when 
applicable 
as per 
Section 8)
-21 to -1
1
14
28
42
56
70
84
168
252
336
420
-
-
-
Pre-
randomizatio
n selection 
discussion
S
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain 
Informed 
consent
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IWRS/IRT 
Registration
X
X5
X
X
X
X
X
X
X
X
X
X
X
 
 
Pre-
randomizatio
n selection of 
TKI
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizati
on
 
X5
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol No. CABL001J12301
Period
Screening4
Treatment*
End of 
Treatment
30 
Days 
Safety 
follow-
up
Survival 
follow-
up 
Phase 
(Every 
12 
weeks)
Visit Name
Screening
Baselin
e/ 
Week 1 
Week 2 Week 4 Week 6 Week 8 Week 
10
Week 
12
Week 
24
Week 
36
Week 
48
Every 
12 
weeks 
to EOT
EOT/ Early 
Discontinua
tion
30 
Days 
Safety 
follow-
up
Survival 
follow- 
up 
Visit 
Numbers1
1
110
120
130
140
150
160
170
180
190
200
210
220
230
240
Days (+/- 3 
days, when 
applicable 
as per 
Section 8)
-21 to -1
1
14
28
42
56
70
84
168
252
336
420
-
-
-
Review 
eligibility
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion 
criteria
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history/curren
t medical 
conditions
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking 
History
X
Charlson 
Comorbidity 
Index (CCI)
X
Disease 
History
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol No. CABL001J12301
Period
Screening4
Treatment*
End of 
Treatment
30 
Days 
Safety 
follow-
up
Survival 
follow-
up 
Phase 
(Every 
12 
weeks)
Visit Name
Screening
Baselin
e/ 
Week 1 
Week 2 Week 4 Week 6 Week 8 Week 
10
Week 
12
Week 
24
Week 
36
Week 
48
Every 
12 
weeks 
to EOT
EOT/ Early 
Discontinua
tion
30 
Days 
Safety 
follow-
up
Survival 
follow- 
up 
Visit 
Numbers1
1
110
120
130
140
150
160
170
180
190
200
210
220
230
240
Days (+/- 3 
days, when 
applicable 
as per 
Section 8)
-21 to -1
1
14
28
42
56
70
84
168
252
336
420
-
-
-
Prior 
Antineoplasti
c Therapy
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Conco
mitant 
Medications 
X
Ongoing basis 
 X
 
Physical 
Examination
S
 
 
Extramedulla
ry 
involvement
X
X5
X
X
X
X
X
X
X
X
X
X
X
 
 
Vital Signs
X
X5
X
X
X
X
X
X
X
X
X
X
X
 
 
ECOG 
Performance 
status
X
 
 
Body Height
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight
X
X5
X
X
X
X
X
X
X
X
X
X
X
 
 

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Protocol No. CABL001J12301
Period
Screening4
Treatment*
End of 
Treatment
30 
Days 
Safety 
follow-
up
Survival 
follow-
up 
Phase 
(Every 
12 
weeks)
Visit Name
Screening
Baselin
e/ 
Week 1 
Week 2 Week 4 Week 6 Week 8 Week 
10
Week 
12
Week 
24
Week 
36
Week 
48
Every 
12 
weeks 
to EOT
EOT/ Early 
Discontinua
tion
30 
Days 
Safety 
follow-
up
Survival 
follow- 
up 
Visit 
Numbers1
1
110
120
130
140
150
160
170
180
190
200
210
220
230
240
Days (+/- 3 
days, when 
applicable 
as per 
Section 8)
-21 to -1
1
14
28
42
56
70
84
168
252
336
420
-
-
-
Blood 
collection for 
BCR-ABL1 
quantification 
by RQ-PCR
X
 
 
X
 
X
 
X
X
X
X
X
X
 
 
Bone marrow 
assessment 
for 
cytogenetic 
assessment
If no previous 
result <3 months 
old available
 
if clinically indicated 
 
 
PK sampling 
(asciminib 
arm only)
 
 
X (as 
per 
Table 
8-6)
X (as 
per 
Table 
8-6)
 
 
 
X (as 
per 
Table 
8-6)
X (as 
per 
Table 
8-6)
 
X (as 
per 
Table 
8-6)
 
 
 
 

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Amended Protocol Version 02 (Clean)
Protocol No. CABL001J12301
Period
Screening4
Treatment*
End of 
Treatment
30 
Days 
Safety 
follow-
up
Survival 
follow-
up 
Phase 
(Every 
12 
weeks)
Visit Name
Screening
Baselin
e/ 
Week 1 
Week 2 Week 4 Week 6 Week 8 Week 
10
Week 
12
Week 
24
Week 
36
Week 
48
Every 
12 
weeks 
to EOT
EOT/ Early 
Discontinua
tion
30 
Days 
Safety 
follow-
up
Survival 
follow- 
up 
Visit 
Numbers1
1
110
120
130
140
150
160
170
180
190
200
210
220
230
240
Days (+/- 3 
days, when 
applicable 
as per 
Section 8)
-21 to -1
1
14
28
42
56
70
84
168
252
336
420
-
-
-
Hematology
X
X5
X
X
X
X
X
X
X
X
X
X
X
 
 
Clinical 
Chemistry
X
X5
X
X
X
X
X
X
X
X
X
X
X
 
 
HbA1c
X
 
 
 
 
 
 
X
X
X
X
X
X
 
 
Coagulation 
X
if clinically indicated 
 
 
Other 
Hepatic 
Tests for 
suspected 
DILI
 
If clinically indicated 
 
 
 

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Amended Protocol Version 02 (Clean)
Protocol No. CABL001J12301
Period
Screening4
Treatment*
End of 
Treatment
30 
Days 
Safety 
follow-
up
Survival 
follow-
up 
Phase 
(Every 
12 
weeks)
Visit Name
Screening
Baselin
e/ 
Week 1 
Week 2 Week 4 Week 6 Week 8 Week 
10
Week 
12
Week 
24
Week 
36
Week 
48
Every 
12 
weeks 
to EOT
EOT/ Early 
Discontinua
tion
30 
Days 
Safety 
follow-
up
Survival 
follow- 
up 
Visit 
Numbers1
1
110
120
130
140
150
160
170
180
190
200
210
220
230
240
Days (+/- 3 
days, when 
applicable 
as per 
Section 8)
-21 to -1
1
14
28
42
56
70
84
168
252
336
420
-
-
-
Hepatitis 
screen
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Test (serum)
X
X5
 
X
 
X
 
X
X
X
X
X
X
 
Pregnancy 
Test (urine)
 
S (Every 4 weeks if serum pregnancy test is not performed) 
 
 
Electrocardio
gram (ECG)
X
X
X
X
 
 
 
X
X
 
X
X 
(Week 
96 only)
X
 
 
Adverse 
Events/SAE
Ongoing basis 
X
X2
Study drug 
dispensation
 
S
 
 
 
 
 
S
S
S
S
S
 
 
 
Study drug 
administratio
n
 
Ongoing basis
 
 
 

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Amended Protocol Version 02 (Clean)
Protocol No. CABL001J12301
Period
Screening4
Treatment*
End of 
Treatment
30 
Days 
Safety 
follow-
up
Survival 
follow-
up 
Phase 
(Every 
12 
weeks)
Visit Name
Screening
Baselin
e/ 
Week 1 
Week 2 Week 4 Week 6 Week 8 Week 
10
Week 
12
Week 
24
Week 
36
Week 
48
Every 
12 
weeks 
to EOT
EOT/ Early 
Discontinua
tion
30 
Days 
Safety 
follow-
up
Survival 
follow- 
up 
Visit 
Numbers1
1
110
120
130
140
150
160
170
180
190
200
210
220
230
240
Days (+/- 3 
days, when 
applicable 
as per 
Section 8)
-21 to -1
1
14
28
42
56
70
84
168
252
336
420
-
-
-

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Page 90 of 166
Amended Protocol Version 02 (Clean)
Protocol No. CABL001J12301
Period
Screening4
Treatment*
End of 
Treatment
30 
Days 
Safety 
follow-
up
Survival 
follow-
up 
Phase 
(Every 
12 
weeks)
Visit Name
Screening
Baselin
e/ 
Week 1 
Week 2 Week 4 Week 6 Week 8 Week 
10
Week 
12
Week 
24
Week 
36
Week 
48
Every 
12 
weeks 
to EOT
EOT/ Early 
Discontinua
tion
30 
Days 
Safety 
follow-
up
Survival 
follow- 
up 
Visit 
Numbers1
1
110
120
130
140
150
160
170
180
190
200
210
220
230
240
Days (+/- 3 
days, when 
applicable 
as per 
Section 8)
-21 to -1
1
14
28
42
56
70
84
168
252
336
420
-
-
-
Antineoplasti
c therapies 
since 
discontinuati
on of study 
treatment
 
 
 
 
 
 
 
 
 
 
 
 
 
X
X
Stem Cell 
Transplant 
status
 
 
 
 
 
 
 
 
 
 
 
 
 
X
Progression 
status
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
* “Baseline/Week 1” is the day 1 of the study; all subsequent visits refer to end of the week, meaning for example that the visit “Week 2” is performed 2 weeks after the 
day 1 at day 14 of the study
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Source document
1 Visit structure given for internal programming purpose only

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Amended Protocol Version 02 (Clean)
Protocol No. CABL001J12301
Period
Screening4
Treatment*
End of 
Treatment
30 
Days 
Safety 
follow-
up
Survival 
follow-
up 
Phase 
(Every 
12 
weeks)
Visit Name
Screening
Baselin
e/ 
Week 1 
Week 2 Week 4 Week 6 Week 8 Week 
10
Week 
12
Week 
24
Week 
36
Week 
48
Every 
12 
weeks 
to EOT
EOT/ Early 
Discontinua
tion
30 
Days 
Safety 
follow-
up
Survival 
follow- 
up 
Visit 
Numbers1
1
110
120
130
140
150
160
170
180
190
200
210
220
230
240
Days (+/- 3 
days, when 
applicable 
as per 
Section 8)
-21 to -1
1
14
28
42
56
70
84
168
252
336
420
-
-
-
2 Any SAEs experienced after the 30 day safety FU should be reported to Novartis Safety if the Investigator suspects a causal relationship to study treatment unless 
otherwise specified by local law/regulations
3 The selection should be made as close as possible to the randomization date once all relevant clinical information is available
4 The central reading of the screening ECGs as well as the results of the BCR-ABL1 RQ-PCR, hematology, chemistry and hepatitis screen must be available prior to 
randomization to evaluate eligibility
5 Baseline assessments that can be done with a - 3 days window. The other assessments should be done on day 1
6 TFQ is not considered study data and will be received electronically outside the clinical database 

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Amended Protocol Version 02 (Clean)
Protocol No. CABL001J12301
8.1
Screening
Written informed consent must be obtained before any study specific medical procedures are 
performed.
All screening assessments should occur within 21 days before randomization.
Screening assessments include: physical examination, extramedullary involvement, vital signs, 
body height and weight, ECG, laboratory (hematology, biochemistry, coagulation, hemoglobin 
A1c (HbA1c), Hepatitis screen, serum pregnancy test, peripheral blood collection for BCR-
ABL1 RQ-PCR for evidence of typical transcripts), evaluation of all relevant medical history 
including smoking history and other cardiovascular risk factors and other comorbidities 
including an assessment of the Charlson comorbidity index (CCI), CML disease history, 
including prior TKI therapy, antineoplastic medication, prior and concomitant medication and 
must be performed prior to randomization. ELTS score should be based on the variables 
recorded at the time of initial diagnosis of CML. The score will be calculated using the 
European LeukemiaNet calculator available at //.leukemia-net.org/leukemias/cml/elts_score/ 
For details of assessments required during screening please refer to  Table 8-1.
During the screening visit, inclusion and exclusion criteria will be assessed. Screening 
assessments to confirm eligibility must be performed prior to randomization.
Participants with potassium, and/or magnesium and/or total calcium levels that are < LLN at 
screening, must have their potassium, and/or magnesium, and/or calcium replenished through 
supplementation and the levels must be within normal limits prior to randomization. 
The central reading of the screening ECGs as well as the results of the BCR-ABL1 RQ-PCR, 
hematology, chemistry and hepatitis screen must be available prior to randomization to evaluate 
eligibility.
A participant who has a laboratory test (peripheral blood test) or ECG results that do not satisfy 
the entrance criteria may have the tests repeated. These tests may be repeated as soon as the 
Investigator believes the re-test results are likely to be within the acceptable range to satisfy the 
entrance criteria, but should be completed within the 21 day screening period. In this case, the 
participant will not be required to sign another ICF, and the original participant identification 
(ID) number assigned by the Investigator will be used.
In the event that the laboratory tests cannot be performed within the screening visit window, or 
the re-tests do not meet the entrance criteria, or other eligibility criteria have changed and are 
not met anymore, the participant is considered a screen failure, and must be discontinued from 
the study. A new ICF will need to be signed if the Investigator chooses to re-screen the 
participant after a participant has screen failed. All required screening activities must be 
performed when the participant is re-screened for participation in the study. An individual 
participant may only be re-screened once for the study. Once the number of participants 
screened and enrolled is likely to ensure target enrollment, the Sponsor may close the study to 
further screening. In this case, the participants who screen failed will not be permitted to re-
screen.

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Protocol No. CABL001J12301
8.1.1
Eligibility screening
Following registering in the IRT for screening, participant eligibility check will be embedded 
in the IRT system by an eligibility transaction. The eligibility will be confirmed in the IRT after 
screening procedures and prior to randomization visit. Please refer and comply with detailed 
guidelines in the IRT manual.
8.1.2
Information to be collected on screening failures
Participants who sign an informed consent and are subsequently are found to be ineligible prior 
to randomization will be considered as screen failures. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a SAE during the screening period (see SAE Section 10.1.3 
for reporting details). If the participant fails to be randomized, the IRT must be notified within 
2 days of the screen fail that the participant was not randomized. Data and samples collected 
from participants prior to screen failure may still be analyzed. The reason for screen failure 
should be recorded on the appropriate Case Report Form.
8.2
Participant demographics/other baseline characteristics
Participant demographic and baseline characteristic data to be collected on all participants 
include: age, gender, race, ethnicity, height, weight, relevant medical history/current medical 
condition present before signing informed consent where possible, CML disease history, and 
prior and concomitant medication including prior TKI therapy and antineoplastic medication.
Participant race and ethnicity are collected and analyzed to identify variations in safety or 
efficacy due to these factors as well as to assess the diversity of the study population as required 
by Health Authorities. The collection of race and ethnicity is performed to enable the Sponsor 
to evaluate the potential influence of baseline factors such as age, race/ethnicity, risk group (eg: 
ELTS), cytogenetic response at baseline etc. on the effect of asciminib with respect to the study 
endpoints. Country-specific regulations should be considered for the collection of demographic 
and baseline characteristics in alignment with CRF.
Physical examination including extramedullary involvement, performance status, vital signs, 
ECGs, and laboratory assessments will be performed.
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever, in their judgment, the test abnormality occurred prior to the informed consent 
signature. Significant new findings that begin or worsen after informed consent must be 
recorded on the AE page of the participant’s eCRF.
8.3
Efficacy
8.3.1
Molecular response
•
Molecular response (MR) will be assessed in all participants. Peripheral blood samples will 
be collected from all participants at screening and at every 4 weeks until Week 12 and then 
every 12 weeks till end of study treatment for analysis of BCR-ABL1 level via RQ-PCR by 
a Novartis designated laboratory. Levels of BCR-ABL1 transcripts will be determined by 

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Amended Protocol Version 02 (Clean)
Protocol No. CABL001J12301
real-time quantitative PCR (RQ-PCR) testing of peripheral blood. Log reduction in BCR-
ABL1 transcripts levels from the standardized baseline value, or the percent ratio of BCR-
ABL1 transcripts versus control gene (ABL1) transcripts converted to a reference standard, 
international scale Hughes and Branford 2006, will be calculated for each sample. MMR is 
defined as BCR-ABL1 IS ≤0.1%.
MMR and related variables are defined as the following:
•
MMR criteria is defined as a ≥ 3.0 log reduction in BCR-ABL1 transcripts compared to the 
standardized baseline equivalent to ≤ 0.1 % BCR-ABL1/ABL1 % by international scale as 
measured by RQ-PCR, confirmed by duplicate analysis of the same sample
•
MR4.0 criteria is defined as BCR-ABL1 IS levels ≤ 0.01% 
•
MR4.5 criteria is defined as BCR-ABL1 IS levels ≤ 0.0032% 
•
Loss of MMR is defined as BCR-ABL1 IS > 0.1% in association with a ≥ 5-fold rise in BCR-
ABL1 from the lowest value achieved on study treatment and replicated by a second 
analysis of the same sample.
•
Confirmed Loss of MMR is defined as a loss of MMR confirmed by analysis of another 
sample taken after an interval of not less than 4 weeks and not more than 6 weeks unless 
associated with confirmed loss of CHR or loss of CCyR or progression to AP/BC or CML 
related death.
•
Loss of MR4.0 is defined as BCR-ABL1 IS > 0.01% confirmed by subsequent sample 
analysis within 12 weeks showing loss of MR4 associated with a ≥ 5-fold rise in BCR-
ABL1 from the lowest value achieved on study treatment, unless it is associated with 
confirmed loss of CHR or loss of CCyR or progression to AP/BC or CML-related death.
•
Loss of MR4.5 is defined as BCR-ABL1 IS > 0.0032% confirmed by subsequent sample 
analysis within 12 weeks showing loss of MR4.5 associated with a ≥ 5-fold rise in BCR-
ABL1 from the lowest value achieved on study treatment, unless it is associated with 
confirmed loss of CHR or loss of CCyR or progression to AP/BC or CML-related death.
The blood samples will be taken as described in Table 8-2. Additional unscheduled blood 
sample may be taken at the discretion of the Investigator at any time during the study as 
clinically indicated.
For participants who discontinue treatment for reasons other than death, lost to follow-up, or 
withdrawal of consent (WoC)/opposition to use data/biological samples, disease status and 
survival status must continue to be monitored as in Table 8-1.
Participants who discontinue from study treatment for documented disease progression must 
continue to be followed up for survival as outlined within the schedule of assessments 
(Table 8-1).
Table 8-2
Blood samples (Molecular response)
Sample Type
Volume
Visit*
Time Point
Screening
Anytime
Week 4 
Pre-dose
Week 8 
Pre-dose
Week 12 
Pre-dose
Peripheral Blood 
for BCR-ABL1 
RQ-PCR
15 mL
Week 24 
Pre-dose

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Amended Protocol Version 02 (Clean)
Protocol No. CABL001J12301
Sample Type
Volume
Visit*
Time Point
Week 36 
Pre-dose
Week 48 
Pre-dose
Every 12 weeks visits up to EOT
Pre-dose
EOT
Anytime
Confirmed Loss of MMR
Within 4 to 6 weeks 
from detection of loss of 
MMR
Unscheduled sample
Anytime
* As per Section 8, a visit window +/- 3 days might be allowed
8.3.2
Cytogenetic Response
Bone marrow aspirate for cytogenetic analyses will be performed at screening and upon 
treatment failure (for definition of treatment failure, see Section 9.1.1).  These exams will be 
performed and analyzed locally. Fluorescent In-situ hybridization (FISH) analysis will not be 
accepted. The results will be recorded on the Bone Marrow eCRF. 
If results from a recent bone marrow analysis, done in the past 3 months, are available, bone 
marrow aspiration at screening need not be redone and results can be reported on the Bone 
Marrow eCRF.
Cytogenetic analysis of bone marrow should include quantification of the number of 
metaphases assessed, number of metaphases positive for Ph chromosome, additional 
chromosomal abnormalities as well as data from microscopic analysis of percentage of blasts 
and promyelocytes. CCyR is defined as 0% Ph+ metaphases in a review of at least 20 
metaphases. 
8.3.3
Hematological Response
Hematologic response will be assessed by CBC and physical examination at each visit.
Complete Hematological Response (CHR) will be defined as all of the following present for 
≥ 4 weeks:
•
white blood cell(s) (WBC) count < 10 x 10^9/L
•
PLT count < 450 x 10^9/L
•
Basophils < 5%
•
No blasts and promyelocytes in peripheral blood
•
Myelocytes + metamyelocytes < 5% in peripheral blood
•
No evidence of extramedullary disease, including spleen and liver
8.3.4
Appropriateness of efficacy assessments
Assessment of hematologic response is a standard measure of assessing the return of blood 
counts to normal values, in response to treatment for CML (Cortes et al 2011). Regular 
assessment of hematologic response is recommended by treatment guidelines (NCCN 2020). 
Assessing molecular response with RQ-PCR is considered as standard in CML therapy and 
recommended in treatment guidelines (Hochhaus et al 2020A, NCCN 2020). It is 
acknowledged that response can be assessed using only standardized results via International 

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Protocol No. CABL001J12301
Scale (IS) as BCR-ABL%. Mutational testing for treatment decisions can be done at Baseline, 
Week 24, Week 48, Week 96 and EOT, and any additional timepoint on Investigator discretion 
as clinically indicated is required in case of treatment failure. Cytogenetic assessment is 
required in case of treatment failure (Hochhaus et al 2020A, NCCN 2020).
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur if needed for safety monitoring and discussion of the 
participant´s health status until it is safe for the participant to visit the site again. 
Table 8-3
Safety and tolerability assessments
Assessment
Specification
Physical 
examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities, vascular, and neurological.
Information for all physical examinations must be included in the source documentation at 
the study site as unique source data, this information will not be captured in the CRF, with 
the exception of extramedullary involvement as described below, including the spleen size if 
extramedullary involvement is detected. Clinically relevant findings that are present prior to 
signing informed consent must be included in the Medical History part of the CRF. 
Significant findings made after first administration of investigational drug which meet the 
definition of an Adverse Event must be recorded on the Adverse Event section of the CRF.
Physical examination will be evaluated during each performed visit.
Extramedullary 
involvement
Presence of extramedullary leukemic involvement will be checked with each physical 
examination as outlined above. Findings on physical examination consistent with extra-
medullary leukemic involvement will be recorded (e.g. any organ involvement). With 
regards to lymph nodes, only those palpable lymph nodes should be considered to be CML 
related if leukemic blast infiltration has been confirmed via biopsy/histology or by technically 
adequate aspiration cytology. When extramedullary involvement other than of the spleen or 
liver is the only evidence of blast crisis, this finding must be confirmed by technically 
adequate (not contaminated with peripheral blood) aspiration cytology and/or biopsy 
(especially for isolated lymph nodes) and data entered into the extramedullary involvement 
eCRF.
Extramedullary involvement will be evaluated during each performed visit.
Vital signs
Vital signs include systolic and diastolic blood pressure (supine position preferred when 
ECG is collected), pulse rate measurement, and body temperature.
Vital signs will be evaluated during each performed visit.
Height and 
weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes) will be measured.
Body height will be evaluated only during screening visit.
Body weight will be evaluated during each performed visit.
8.4.1
Laboratory evaluations
Central laboratory will be used for analysis of hematology, coagulation, biochemistry, serum 
pregnancy and hepatitis marker specimens collected (safety monitoring). Details on the 
collections, shipment of the samples and reporting of results by the central laboratory are 
provided to Investigators in the [ABL001J12301 laboratory manual]. The time windows 

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granted for laboratory evaluations are identical with the corresponding visit time windows for 
each visit (see Section 8). As per Table 8-4, each sample for the analysis of Glucose and 
Triglycerides needs to be collected under fasting condition: [ideally] 8 hours fasting is required 
with only water being allowed to be consumed.
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 1) they induce clinical signs or symptoms, 2) they are considered clinically 
significant, or 3) they require concomitant therapy or procedures. Clinically significant 
abnormal laboratory values or test results should be identified through a review of values 
outside of normal ranges/clinically notable ranges, significant changes from screening or the 
previous visit.
If at any time a participant has laboratory parameters obtained from a local laboratory due to 
inability to have an on-site visit, Novartis must be provided with a copy of the certification and 
a tabulation of the normal ranges and units for this laboratory. The results of the local laboratory 
will be recorded in the eCRF if any the following criteria are met:
•
A treatment decision was made based on the local results, or
•
There are no concomitant central results available, or
•
Local lab results document an AE not reported by the central lab, or
•
Local lab results document an AE where the severity is worse than the one reported by the 
central lab.
Table 8-4
Laboratory Assessments
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Mean Corpuscular Hemoglobin Concentration (MCHC), Ery Mean 
Corpuscular hemoglobin Concentration, Ery.Mean Corpuscular Volume, PLTs, 
Erythrocytes, Leukocytes, Erythrocyte Cell Morphology, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Bands, Blasts, Promyelocytes, Myelocytes, 
Metamyelocytes,)
Coagulation
International normalized ratio (INR) and Activated Partial Thromboplastin Time 
(APTT)
Chemistry
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), Lactate 
dehydrogenase (LDH), Bicarbonate, Total Calcium, Magnesium, Phosphate, Chloride, 
Sodium, Potassium, Creatinine, Creatine kinase, Direct Bilirubin, Indirect Bilirubin, Total 
Bilirubin (TBL), Total Cholesterol, Low Density Lipoprotein (LDL Cholesterol), High Density 
Lipoprotein (HDL Cholesterol), Total Protein, Triglycerides (fasting), Urea Nitrogen or Urea, 
Uric Acid, Amylase, Lipase, Glucose (fasting), Hemoglobin A1c
Hepatitis 
markers
Hepatitis B Virus DNA, Hepatitis B Virus Surface Antigen, Hepatitis B Virus Surface 
Antibody, Hepatitis B Virus Core Antibody, Hepatitis C Virus RNA
Pregnancy Test*
Serum / Urine pregnancy test
* For details on pregnancy testing, please refer to Section 8.4.3
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
if participants cannot visit the site for protocol specified safety lab assessments conducted 
through central labs, an alternative lab (local) collection site may be used.

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8.4.2
Electrocardiogram (ECG)
ECGs should be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. The Fridericia QT correction formula (QTcF) 
should be used for clinical decisions, e.g., at the Screening and/or Baseline visit(s) (as 
applicable) to assess eligibility. The Investigator must calculate QTcF if it is not auto-calculated 
by the ECG machine.
Three serial ECGs (triplicate) should be performed half an hour prior to dosing for pre-dose 
assessment and prior to any PK blood draws scheduled for the visit. The serial ECGs should be 
taken approximately 5 minutes apart. After the participant has rested approximately 10 minutes 
in a supine position, three sequential standard 12-lead ECGs (triplicate) must be obtained with 
a recommended minimal interval of 5 minutes between each ECG at the time points specified 
in  Table 8-1 , for details please refer to Table 8-5 and Table 8-6.
These three sequential 12-lead ECGs are to be collected with ECG machines supplied by the 
central ECG laboratory and all three ECGs for each time point should be sent to central 
reading. All ECGs performed will be independently reviewed. Instructions for the collection 
and transmission of these ECGs to the independent central reader will be provided in the 
[CABL001J12301 ECG Manual].
Dose adjustments in case of QT prolongation should be performed per Section 6.5.1 (Refer to 
section Dose adjustments in case of QTcF prolongation).
Readings for QTc prolongation will be based on the average seen in the scans for each time 
point. The enrollment of participants has to be based on centrally assessed QTcF time. If one of 
the 3 serial ECGs prior to dosing on day 1 shows a QTcF ≥ 450 ms (male) or ≥ 460 ms (female) 
by automated reading, an immediate manual central reading must be requested by calling 
Central cardiac safety reading center IQVIA. The participant may not be dosed if the average 
of the manually read ECGs confirms a QTcF ≥ 450 ms (male) or ≥ 460 ms (female).
In the event that a clinically significant ECG abnormality is identified at the site (e.g. severe 
arrhythmia, conduction abnormality of QTcF > 500 ms), a copy of the assessment is sent to the 
central ECG laboratory for expedited review e, and the ECG is repeated to confirm the diagnosis. 
If the participant is hemodynamically compromised, the Investigator or a medically qualified 
person must initiate appropriate safety procedures without delay (for example cardioversion).
All ECGs, including unscheduled triplicate safety ECGs with clinically relevant findings 
collected during the study needs to be transmitted to the central ECG laboratory for review.
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or AEs as appropriate.
A standard 12 lead ECG will be performed at the following time points.
•
At screening and baseline
•
At Week 2, 4, 12, 24, 48, 96 
•
At the EOT

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Table 8-5
Central ECG collection plan in all randomized arms
Week
Study Day*
Time
ECG Type
Screening
-21 to -1
Anytime
12 Lead, triplicate
Baseline
1
Pre-dose
Post-dose 2 hours
12 Lead, triplicate
Week 2
14
Pre-dose
Post-dose 2 hours, 3 
hours, 4 hours
12 Lead, triplicate
Week 4
28
Pre-dose
12 Lead, triplicate
Week 12
84
Pre-dose
12 Lead, triplicate
Week 24
168
Pre-dose
12 Lead, triplicate
Week 48
336
Pre-dose
12 Lead, triplicate
Weeks 96 
672
Pre-dose
12 Lead, triplicate
EOT
-
Pre-dose
12 Lead, triplicate
Unscheduled sample
-
Anytime
12 Lead, triplicate
* As per Section 8, a visit window +/- 3 days will be allowed
In order to enable ECG evaluation by the central laboratory for eligibility assessment, ECGs 
should be submitted to the ECG core laboratory in adequate time prior to the planned 
randomization date.
In the event that a QTcF value of > 500 ms is observed or if an unscheduled ECG is performed 
for safety reasons, it is recommended to collect a time-matched PK sample and record the time 
and date of the last study drug intake to determine the drug exposure. Dose adjustments in case 
of QT prolongation should be performed per Section 6.5.1.1.
Additional, unscheduled, safety ECGs may be repeated at the discretion of the Investigator at 
any time during the study as clinically indicated. For any ECGs with participant safety concerns, 
two additional ECGs must be performed to confirm the safety finding. Unscheduled ECGs with 
clinically significant findings should be collected in triplicate. Local cardiologist ECG 
assessment may also be performed at any time during the study at the discretion of the 
Investigator.
The results of the centrally assessed ECGs are automatically transferred into the clinical 
database.
8.4.3
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
All women of childbearing potential have to complete a serum pregnancy test (Serum ß-HCG) 
as indicated in Table 8-1 and Table 8-4. Pregnancy testing is not required for participants who 
are determined to be post-menopausal. The time windows granted for pregnancy testing are 
identical with the corresponding visit time windows for each visit.  
Serum pregnancy assessments have to be analyzed by a central laboratory, according to 
Table 8-1 and Table 8-4, during the following time points:
•
Randomized treatment: screening, baseline (Week 1), Week 4 (if applicable), Week 8 (if 
applicable), and at each visit from Week 12 onwards until the EOT.

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Urine pregnancy tests have to be performed at home every 4 weeks if serum pregnancy test is 
not performed. This also includes the timepoints at EOT and 30-days safety follow-up where 
required. Information for urine pregnancy test must be included in the source documentation at 
the study site at the next participant visit as unique source data, this information will not be 
captured in the CRF. If a test result indicates a pregnancy, the participant must contact the 
Investigator immediately to stop the study medication, including Investigator selected TKIs.
All pregnancies of study participants should be recorded on a Clinical Trial Pregnancy Form 
and reported by the Investigator to the Oncology Novartis Drug Safety and Epidemiology 
Department (DS&E).
During the treatment phase of the study, women of childbearing potential should employ the 
use of highly effective contraception. Highly effective contraception methods are defined 
in  Section 5.2 .
A woman is considered of childbearing potential from menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Medical documentation of 
oophorectomy, hysterectomy, or bilateral tubal ligation must be retained as source documents. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile.
In absence of  medical documentation,  confirming permanent sterilization, or if the menopausal 
status is not clear, the Investigator should use his medical judgment to appropriately evaluate 
the fertility state of the woman and document it in the source document.
If participants cannot visit the site to have serum pregnancy tests 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, urine pregnancy test kits may be used. 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. It is important that participants are instructed to perform the urine pregnancy test first and 
only if the test result is negative proceed with the administration of the study treatment. A 
communication process should be established with the participant so that the Site is informed 
and can verify the pregnancy test results (e.g., following country specific measures).
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/participant population.
8.5
Additional assessments
The following additional assessments will be performed on participants entered into this study:
•
Patient Reported Outcomes
•
Pharmacokinetics
•
Biomarkers
•
Resource Utilization

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is not available in a language the participant is familiar with, the PRO questionnaire must be 
omitted. If additional information or further instructions are needed, participants can receive 
additional technical support when they bring the ePRO device to the site during all scheduled 
visits.
In order to minimize missing data, compliance must be checked frequently and early on to 
identify any problems with PRO data reporting.
Participant’s refusal to complete all or any part of a PRO measures should not be captured as a 
protocol deviation.
Participants should be made aware that completed PRO measures are not reviewed for 
AEs by the Investigator/ study personnel and if they experience an AE, they should report 
the event to the Investigator / study personnel.
All questionnaires should be administered in the language most familiar to the participant at the 
beginning of scheduled visit prior to any interaction with the study Investigator including any 
tests, treatments or receipt of results from any tests to avoid biasing the participant’s perspective. 
This is to avoid potentially biasing participants or their responses to study questionnaires.
Study Investigators must follow reporting instructions outlined in Section 10 (AEs section) of 
the study protocol.
PRO assessments have to be performed from all participants during the treatment period and up 
to 12 weeks after EOT.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
COA data may be collected remotely (e.g. web portal, telephone interviews utilizing, a tablet 
provided by a third party vendor) depending on local regulations, technical capabilities, and 
following any applicable training in the required process.
EORTC QLQ-C30 and QLQ-CML24
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30) and the CML specific module, the QLQ-CML24 will be 
used to evaluate patient-reported outcome measures of health-related quality-of-life, 
functioning, colorectal cancer symptoms, treatment-related side effects, and global health status 
(Anderson et al 1993).
The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer 
participants and used frequently in cancer clinical trials. The questionnaire contains 30 items 
and is composed of both multi-item scales and single-item measures based on the participant's 
experience over the past week. These include five functional scales (physical, role, emotional, 
cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), 
six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) 
and a global health status/QoL scale (Anderson et al 1993). All of the scales and single-item 
measures range in score from 0 to 100. A high scale score represents a higher response level. 
Thus a high score for a functional scale represents a high / healthy level of functioning; a high 
score for the global health status / QoL represents a high QoL, but a high score for a symptom 

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scale / item represents a high level of symptomatology/problems. All scoring will follow the 
scoring procedures defined by the EORTC Scoring Manual (Fayers 2001).
The EORTC QLQ-CML24 assesses specific concepts relevant to the experience of participants 
with CML. The QLQ-CML24 has 24 items which assess symptom burden, impact on daily life 
and on worry/mood, body image problems, and satisfaction with care and with social life based 
on the participant's experience over the past week (Efficace et al 2014). The QLQ-CML24 
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Refer to the [CABL001J12301 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK samples.
Plasma samples will be obtained to characterize the disposition of the study drug asciminib after 
oral administration. 
Table 8-6
Pharmacokinetic blood collection log
Week 
Study Day*
Scheduled Time Point
Dose 
Reference ID
PK Sample No
Blood 
Volume (mL)
2
14
0 h (Pre-dose)a
1
1
2
 
14
1 h (± 10 min)b
1
2b
2
 
14
2 h (± 10 min)
1
3
2
 
14
3 h (± 15 min)
1
4
2
 
14
4 h (± 15 min)
1
5
2
 
14
6 h (± 30 min)b
1
6b
2
 
14
8 h (± 60 min)b
1
7b
2
 
14
12 h (± 60 min)b
1
8b
2
4
28
0 h (Pre-dose)a
3
9
2
12
84
0 h (Pre-dose)a
4
10
2
24
168
0 h (Pre-dose)a
5
11
2
48
336
0 h (Pre-dose)a
6
12
2
 
 
Unscheduled
 
2001+
 
a Pre-dose PK sample should be taken immediately prior to the next administration of asciminib.
b Full PK-group only.
* As per Section 8, a visit window +/- 3 days might be allowed
8.5.2.2
Analytical method
Plasma asciminib concentrations will be measured at the designated laboratory using a validated 
high-performance liquid chromatography/tandem mass spectrometry (LC-MS/MS) method 
with a lower limit of quantification (LLOQ) of 1.00 ng/mL.
8.5.2.3
Pharmacogenomics
A 3 mL blood sample will be obtained 
 for pharmacogenomics 
analysis from all study participants allocated to the asciminib treatment arm as specified in 
Table 8-1. Genetic variant analysis of the 
 may be performed 
to investigate the effect of enzyme variations on asciminib exposure. Other genetic analyses on 
genes that are related to the asciminib metabolism and action or disease may also (or instead) 
be performed using these samples. In addition, this sample collection is required on the study. 
It is included in the main consent and is not optional, unless otherwise indicated by local 
IRB/EC or Health Authority requirements.
The sample collection must be captured on appropriate eCRF and requisition form(s).
8.5.3
Biomarkers
Exploratory biomarker analysis will be used for characterizing resistance mechanisms and 
association with kinetics of molecular response (duration of response, time to achieve MR). All 
biomarker analysis will be performed at a Novartis designated laboratory. Mutations in 

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8.5.3.1
Additional biomarker assessments
Optional additional biomarker studies
If the participant agrees, the biological samples collected in this trial (e.g.  blood, plasma, 
serum) may be kept for up to 15 years to be used for additional studies related to the study 
drug(s) or cancer, including research to help develop ways to detect, monitor or treat cancer. A 
decision to perform such exploratory biomarker research studies would be based on outcome 
data from this study or from new scientific findings related to the drug class or disease, as well 
as assay availability
8.5.4
Resource utilization
The measures of HCRU to be collected include: hospitalization (H), emergency room (ER) 
visit, general practitioner (GP) visits, specialist (Sp) visit and urgent care (UC) visit. These 
measures will be used to derive the economic impact of treatment. Hospitalization visits will 
also record the number of days in ward and the type of ward (hospital unit) and the discharge 
status. At each RU collection, the reason for the visit (i.e. related to CML, AE or other reason) 
will be collected in order to quantify the impact of asciminib, Investigator selected TKI and 
imatinib within the stratum of Investigator selected TKI on healthcare resources. The RU 
assessment will be completed at each scheduled clinical trial visit; the RU will be completed by 
the Investigator however information with respect to the number of GP, UC, Sp or ER visits 
will be ascertained from the participant. All attempts to collect as much information from the 
participant as possible should be made in order to minimize selection bias.
9
Discontinuation and completion
The Investigator should discontinue study treatment for a given participant and/or withdraw the 
participant from the study if he/she believes that continuation would be detrimental to the 
participant's well-being, or that the participant is unable or unwilling to comply with protocol 
requirements.

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A participant will be considered to have completed the study when the participant has completed 
the last visit planned in the protocol.
The Investigator and/or referring physician will recommend the appropriate follow-up medical 
care, if needed, for all participants who are prematurely withdrawn from the study.
9.1
Discontinuation from study treatment and from study
Completion of the study will be when the last participant has completed end of study follow up. 
9.1.1
Discontinuation from study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug administration, if any) 
and can be initiated by either the participant or the Investigator.
The Investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. Participants who discontinue 
study treatment should undergo an EOT visit.
Discontinuation from study treatment is required under the following circumstances：
•
Participant/guardian decision
•
Use of prohibited treatment as per recommendations in the prohibited treatment 
Section 6.2.2
•
Any situation in which continued study participation might result in a safety risk to the 
participant
In addition to the general discontinuation criteria, the following study specific criteria will also 
require discontinuation of study treatment:
•
In the event of detection of T315I mutation at any time the participant must be discontinued 
from the study treatment.
•
In the event of confirmed loss of MMR (in 2 consecutive tests, Section 12.7 ) at any time 
during the study treatment the participant must be discontinued from the study treatment.
•
In the event of treatment failure (as per ELN criteria, Hochhaus et al 2020A) the participant 
must be discontinued from the study treatment.The following events will constitute ‘treatment 
failure’ based on ELN criteria (Hochhaus et al 2020A)
•
BCR-ABL1 transcript level > 10% IS at 3 months if confirmed within the next 1–3 
months
•
BCR-ABL1 transcript level > 10% IS at 6 months
•
BCR-ABL1 transcript level > 1% IS at 12 months
•
BCR-ABL1 transcript level >1% IS after 12 months,
•
Detection of a BCR-ABL1 mutation which can potentially cause resistance to study 
treatment (asciminib or Investigator selected TKI) or high-risk additional 
chromosome abnormalities in Ph+ cells at any time after initiation of study treatment. 
[Per ELN treatment recommendations for known mutations resistant to specific TKI 
and high-risk additional chromosome abnormalities Hochhaus et al 2020A].

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•
 In the event of disease progression, the participant must be discontinued from the study 
treatment. 
•
The following events are considered disease progression 
•
CML-related death (any death during treatment or follow-up if the principal cause 
of death is marked as “study indication” in the eCRF by the Investigator, or if the 
death occurred subsequent to documented progression to AP/BC and the cause of 
death is reported as “unknown” or not reported by the Investigator)
•
Accelerated phase (AP) as defined by any of the following: 
•
≥ 15% blasts in the peripheral blood or bone marrow aspirate, but < 30% 
blasts in both the peripheral blood and bone marrow aspirate
•
≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow aspirate
•
≥ 20% basophils in the peripheral blood
•
Thrombocytopenia (< 100 x 109/L) that is unrelated to therapy
•
Blast crisis (BC) as defined by any of the following: 
•
≥ 30% blasts in peripheral blood or bone marrow aspirate
•
 Appearance of extramedullary involvement other than hepatosplenomegaly 
proven by biopsy (i.e., chloroma).
•
Any value of AP or BC within the first 4 weeks of study treatment is not 
considered as progression to AP/BC unless the patient discontinues study 
treatment due to progression or unsatisfactory therapeutic effect within the 
first 8 weeks.
•
In the event of a pregnancy during study, if a participant wants to pursue the pregnancy 
then participant must be discontinued from the study treatment. However, in the event of a 
spontaneous miscarriage or in the event of elective abortion, the participant is permitted 
to continue study treatment.
If discontinuation from study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information.
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table.
Participants who discontinue from study treatment agree to return for the EOT and follow-up 
visits indicated in the Assessment Schedule (refer to Section 8), every effort should be made to 
contact the participant/pre-designated contact as specified in the lost to follow-up section. This 
contact should preferably be done according to the study visit schedule.
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact:
•
New / concomitant treatments

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•
AEs / SAEs
The Investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.
Participants who discontinue from study treatment for reasons other than death, lost to follow-
up, or WoC/opposition to use data/biological samples, must continue to be followed up for 
disease progression and survival as outlined within the schedule of assessments (Table 8-1).
Participants who discontinue from study treatment for documented disease progression must 
continue to be followed up for survival as outlined within the schedule of assessments 
(Table 8-1).
9.1.2
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. If the 
participant agrees, a final evaluation at the time of the participant’s study discontinuation should 
be made as detailed in the assessment table (refer to Section 8).
9.1.3
Withdrawal of informed consent/Opposition to use data/biological 
samples
WoC/opposition to use data/biological samples occurs when a participant:
•
Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples)
and
•
No longer wishes to receive study treatment
and
•
Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the 
source documentation.
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, 
letter) to understand the primary reason for the participant’s decision to withdraw their 
consent/opposition to use data/biological samples and record this information.
Where consent to the use of personal and coded data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their personal data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up.
If the participant agrees, a final evaluation at the time of the participant’s WoC/opposition to 
use data/biological samples should be made as detailed in the assessment table (refer to 
Section 8).

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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 (including biological 
samples) will be collected following WoC/opposition.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the ICF.
For EU and Rest of World (RoW): All biological samples not yet analyzed at the time of 
withdrawal will no longer be used, unless permitted by applicable law. They will be stored 
according to applicable legal requirements.
9.1.4
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the Investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g. 
dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed or until the end of the study.
9.1.5
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.
•
Unexpected, significant, or unacceptable safety risk to participants enrolled in the study
•
Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data
•
Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider the participant's welfare and 
safety. Should early termination be necessary, participants must be seen as soon as possible and 
treated as a participant who discontinued from study treatment. The Investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the participant’s interests. The Investigator or Sponsor depending 
on the local regulation will be responsible for informing IRBs/IECs of the early termination of 
the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last participant finishes his/her Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision (e.g. Each participant will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them).

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Participants on the study will continue to receive the assigned treatment until End of Study, or 
until premature discontinuation due to treatment failure, disease progression or intolerance or 
due to Investigator or participant decision.
The End of Study will occur 5 years from the randomization date of the last participant first 
treatment in the study. Participants who discontinue study treatment prematurely due to any 
reason, will be followed up for survival until the End of Study.
The primary analysis cut-off date will be when all randomized participants have been treated 
for at least 48 weeks or discontinued from study treatment prior to Week 48. Subsequent to this 
analysis, the primary Clinical study report (CSR) will be developed. Following the cut-off date 
for the primary CSR, the study will remain open. Participants who are ongoing at the time of 
the primary analysis will continue to receive the assigned study treatment.
The key secondary analysis cut-off date will be when all randomized participants have been 
treated for at least 96 weeks or discontinued from study treatment prior to Week 96.
The final analysis cut-off date will be once the End of Study (i.e. 5 years from the randomization 
date of the last participant enrolled into the study) is reached.
The end of study treatment analysis will be conducted with a cut-off date 30 days after the end 
of study treatment period to ensure all available treatment data from all participants in the study 
is analyzed and summarized in a CSR.
After the end of the study treatment period the study treatment will be made available to 
participants who in the opinion of the Investigators are still deriving clinical benefit. This may 
be outside of this study through alternative options including, but not limited to participant 
rollover program.
Participants will be followed for survival and progression to AP/BC for up to 5 years from the 
randomization date of the last participant enrolled into the study. Information on subsequent 
treatments will also be collected. An updated analysis of OS and PFS will be performed at the 
end of the follow-up period in the final study CSR.
10
Safety monitoring, reporting and committees
10.1
Definition of adverse events and reporting requirements
During any pandemic such as COVID-19 that limits or prevents on-site study visits regular 
phone calls will occur for safety monitoring and discussion of the participant's health status 
until the participant can again visit the site. This telephone contact should preferably be done 
according to the study visit schedule or more frequently if needed. Please refer to Section 4.6 
for further information.
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 clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.

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The Investigator has the responsibility for managing the safety of individual participant and 
identifying AEs.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. AEs also may be detected when they are volunteered by the participant 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments.
AEs must be recorded in the AEs CRF under the signs, symptoms or diagnosis associated with 
them, accompanied by the following information (as far as possible) (if the event is serious refer 
to  Section 10.1.2):
1. The Common Toxicity Criteria (CTC) AE grade (version 5).
Grade 1 to 5 will be used to characterize the severity of the Adverse Event.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will be 
used.
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported.
4. Whether it constitutes a SAE (see  Section 10.1.2  for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with study treatment.
All AEs must be treated appropriately. Treatment may include one or more of the following:
•
Dose not changed
•
Dose Reduced/increased
•
Drug interrupted/permanently discontinued
6. its outcome 
a. Not recovered/not resolved;
b. Recovered/resolved;
c. Recovered/resolved with sequelae;
d. Fatal; or unknown.
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 AEs 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.

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Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be not recovered/not resolved (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.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, loss of response, progression to AP or BC), should not be reported as a 
serious adverse event.
AEs separate from the progression of malignancy (for example deep vein thrombosis at the time 
of progression or hemoptysis concurrent with finding of disease progression) will be reported 
as per usual guidelines used for such events with proper attribution regarding relatedness to the 
drug.
Information about adverse drug reactions for the investigational drug can be found in the 
[Asciminib Investigator Brochure].
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:
•
They induce clinical signs or symptoms
•
They are considered clinically significant
•
They require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participants 
with the underlying disease.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:
•
Fatal
•
Life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E15D Guidelines).
•
Results in persistent or significant disability/incapacity
•
Constitutes a congenital anomaly/birth defect

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•
Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
•
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition
•
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent
•
Social reasons and respite care in the absence of any deterioration in the participant’s 
general condition
•
Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission
•
Is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room (ER) or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalization or development of dependency or abuse (please refer to the 
ICH-E15D Guidelines).
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered SAE irrespective 
if a clinical event has occurred.
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after participant stopped the study treatment 
must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the event (Note: If more 
stringent, local regulations regarding reporting timelines prevail). The Investigator must 
complete and submit the SAE report form directly in the CRF. 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 eSAE with paper backup 
Serious Adverse Event Report Form; all applicable sections of the form must be completed in 
order to provide a clinically thorough report.
All follow-up information for the SAE including 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 

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receiving the follow-up information (Note: If more stringent, local regulations regarding 
reporting timelines prevail). An SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one should be reported separately as 
a new event.
The following SAE reporting timeframes apply:
1. Screen Failures (e.g. a participant who is screened but is not treated or randomized): SAEs 
occurring after the participant has provided informed consent until the time the participant 
is deemed a Screen Failure must be reported to Novartis.
2. Randomized OR Treated participants: SAEs collected between time participant signs ICF 
until 30 days after the participant has discontinued or stopped study treatment
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a 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, EU Clinical Trial Regulation 536/2014 (once transfer is completed), or as per 
national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day safety evaluation 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 participant safety, each pregnancy occurring after signing the informed 
consent must be reported to Novartis within 24 hours of learning of its occurrence. The 
pregnancy should be followed up 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 of any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.
For all pregnancies with live birth and/or unknown outcome the newborn has to be followed up 
to obtain infant health status and development up to twelve months after delivery.

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10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (definition from European Medicines Agency).
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 eCRF irrespective of whether or not associated with an AE/SAE and (until 
transition to the EU CTR) reported to Safety only if associated with an SAE. Misuse or abuse 
(and upon transition to the EU CTR, also study treatment errors and uses outside of what is 
foreseen in the protocol) 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. 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.1.6
Adverse events of special interest
AEs of special interest (AESI) are defined as events (serious or non-serious) which are ones of 
scientific and medical concern specific to the Sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor may be appropriate. 
Such events may require further investigation in order to characterize and understand them.
AEs of special interest are defined on the basis of an ongoing review of the safety data. AESIs 
are discussed in detail in the [Asciminib Investigator’s Brochure].
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities/AEs have to be considered during the course of 
the study (irrespective of whether classified/reported as AE/SAE):
•
Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter
•
Liver events, which will require close observation, follow-up monitoring 
Please refer to Table 16-2 in Section 16.2 for complete definitions of liver laboratory triggers 
and liver events.
Once a participant is exposed to study treatment, every liver event defined in 
Table 16-1 should be followed up by the Investigator or designated personnel at the trial site, 
as summarized below. Additional details on actions required in case of liver events are outlined 

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in Table 16-3 . Repeat liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and GGT) to 
confirm elevation.
•
These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a local 
laboratory to monitor the safety of the participant. If a liver event is subsequently reported, 
any local liver chemistry tests previously conducted that are associated with this event 
should have results reported on the unplanned local laboratory CRF.
•
If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate.
•
Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate
•
Hospitalization of the participant if appropriate
•
Causality assessment of the liver event
•
Thorough follow-up of the liver event should include 
•
These investigations can include based on Investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
10.2.2
Renal safety monitoring
Every renal laboratory trigger or renal event as defined in Table 16-4 should be followed up by 
the Investigator or designated personnel at the trial site as summarized in Section 16.3.
10.2.3
Data Monitoring Committee
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
Investigators participating in the study. The DMC will be constituted prior to the first participant 
randomization. The DMC will assess the safety data at defined intervals, beginning 
approximately 6 months after the first randomized participant has started treatment. Subsequent 
reviews of the safety data will be conducted approximately every 6 months. Additional meetings 
may be scheduled in the event of unexpected new data or events on an as needed basis (eg. if 
significant safety findings).
This includes but does not limit the role of the DMC to evaluate these data and to provide 
recommendations to the sponsor to continue, modify or stop the study early. The DMC will be 
in place at least until the conduct of the primary analysis. It is expected that the DMC will 
consist at a minimum of two physicians with appropriate disease area qualifications and one 
statistician. There will be a meeting with the DMC describing their roles and responsibilities 
and discussing potential data format and process issues prior to the finalization of DMC charter.
It is envisioned that the DMC may make certain types of recommendations, namely:
•
No safety concerns, ethical to continue the study as planned

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•
Serious safety concerns precluding further study treatment, regardless of efficacy
•
Recommendation to continue the study but proposing an amendment to the protocol (e.g., 
incorporate an additional safety assessments)
If the study is recommended to continue by the DMC, no details about the safety results will be 
revealed.
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC.
10.2.4
Steering Committee
The Steering Committee (SC) will be established comprising Investigators participating in the 
trial, i.e. not being members of the DMC and 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 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 the steering committee charter.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The Investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate
After final database lock, the Investigator will receive copies of the participant data for 
archiving at the investigational site.
Data collected by third parties (hematology, biochemistry, PCR assessments, biomarkers, ECG, 
PK and PROs) will be sent electronically to Novartis.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 

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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 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes 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 (or a designated CRO) at specific timelines.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. eSource DDE or eCRFs) with the Investigators and their staff. During the study, 
Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of participant records, the accuracy of data capture / data entry, the adherence to the protocol 
and to Good Clinical Practice, the progress of enrollment, and to ensure that study treatment is 
being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the field monitor during these visits. Continuous remote monitoring 
of each site’s data may be performed by a centralized Novartis/delegated CRO/CRA 
organization. Additionally, a central analytics organization may analyze data & identify risks 
& trends for site operational parameters, and provide reports to Novartis clinical teams to assist 
with trial oversight.
The Investigator must maintain source documents for 15 years for each participant in the study, 
consisting of case and visit notes (hospital or clinic medical records) containing demographic 
and medical information, laboratory data, electrocardiograms, and the results of any other tests 
or assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The Investigator must also keep the original ICF signed by the participant (a 
signed copy is given to the participant) for 15 years.
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 

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study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed.
12
Data analysis and statistical methods
The primary analysis cut-off date will be when all randomized participants have been treated 
for at least 48 weeks or discontinued from study treatment prior to Week 48.
The key secondary analysis cut-off date will be when all randomized participants have been 
treated for at least 96 weeks or discontinued from study treatment prior to Week 96.
The final analysis cut-off date will be once the End of Study (i.e. 5 years from the randomization 
date of the last participant enrolled into the study) is reached.
Participants who discontinue study treatment prematurely due to any reason (e.g.: treatment 
failure, disease progression or intolerance or due to Investigator or participant decision), will 
be followed up for survival and progression to AP/BC until the End of Study.
The data will be analyzed by Novartis and/or designated CRO. The data from all participating 
centers in this protocol will be combined, so that an adequate number of participants will be 
available for analyses. Study data will be summarized with respect to demographic and baseline 
characteristics, efficacy observations and measurements, safety observations and measurements, 
and all relevant PK and PD measurements. Categorical data will be presented as frequencies 
and percentages. For continuous data, mean, standard deviation (SD), median, minimum, and 
maximum as well as 25th and 75th percentiles will be presented.
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned by randomization. 
The IMA Full Analysis Set (FASIMA) comprises all from the FAS, whose pre-randomization 
selection of TKI is imatinib.
The 2G TKI Full Analysis Set (FAS2GTKI) comprises all participants from the FAS, whose 
pre-randomization selection of TKI is a 2G TKI (nilotinib, dasatinib or bosutinib).
According to the intent to treat principle (reflecting the treatment policy estimands approach), 
participants in the FAS, FASIMA, FAS2GTKI will be analyzed according to the treatment and 
stratum they have been assigned to during the randomization procedure.
The main primary and key secondary estimands that are based on the treatment policy and 
composite approach and will analyze participants according to the treatment and stratum they 
have been assigned to during the randomization procedure. 
As described in Section 12.4.6 and Section 12.5.6; the supplemental estimands based on a 
combination of the treatment policy and hypothetical approach will also analyze participants 
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procedure. The difference will be that that data after occurrence of an intercurrent event will be 
imputed when the hypothetical approach is used. 
The Safety Set comprises all participants who received at least one dose of any study treatment. 
Participants will be analyzed according to the study treatment received, where treatment 
received is defined as the randomized treatment if the participant took at least one dose of that 
treatment, or the first treatment received if the randomized treatment was never received.
The Pharmacokinetic analysis set (PAS) includes all participants who provide at least one 
evaluable asciminib PK concentration. For a concentration to be evaluable, participants are 
required to:
•
Take a dose of asciminib prior to sampling,
•
Take the same dose of asciminib for at least 3 consecutive days without dose interruption 
or dose modification prior to sampling,
•
For post-dose samples, do not vomit within 4 hours after the dosing of asciminib (this is the 
current dose); for pre-dose samples do not vomit within 4 hours after the dosing of asciminib 
prior to sampling (this is the previous dose),
•
Have the pre-dose sample collected before the next dose administration.
Other analysis sets
For duration of MMR, the MMR Responder Set will be used, which comprises the subset of 
participants from the FAS (or FASIMAor FAS2GTKI ) who achieve MMR at any time.
For duration of MR4.0, the MR4.0 Responder Set will be used, which comprises the subset of 
participants from the FAS (or FASIMA or FAS2GTKI ) who achieve MR4.0 at any time.
For duration of MR4.5, the MR4.5 Responder Set will be used, which comprises the subset of 
participants from the FAS (or FASIMA or FAS2GTKI ) who achieve MR4.5 at any time.
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment arm for the FAS, FASIMA and FAS2GTKI. Categorical data will be 
presented as frequencies and percentages. For continuous data, mean, SD, median, minimum, 
and maximum will be presented. For selected parameters, 25th and 75th percentiles will also 
be presented.
Relevant medical histories and current medical conditions at baseline will be summarized, by 
system organ class and preferred term, by treatment arm.
12.3
Treatments
The Safety set will be used for the analyses below.
Categorical data will be summarized as frequencies and percentages. For continuous data, mean, 
SD, median, 25th and 75th percentiles, minimum, and maximum will be presented.
The duration of exposure in days to asciminib and Investigator selected TKI (overall and by 
strata of pre-randomization selection of TKI), as well as the dose intensity (computed as the 
ratio of actual cumulative dose received and actual duration of exposure) and the relative dose 

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intensity (computed as the ratio of dose intensity and planned dose intensity) will be 
summarized by means of descriptive statistics.
The number of participants with dose adjustments (reductions, interruption, or permanent 
discontinuation, allowed dose escalations for comparator arm drugs, dosing errors) and the 
reasons will be summarized by study drug components and by study treatment. All dosing data 
will be listed.
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, by treatment arms.
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, SD, median, 25th and 75th percentiles, 
minimum, and maximum will be presented.
12.4
Analysis of the primary endpoint(s)/estimand(s)
12.4.1
Definition of primary endpoint(s)/estimand(s)
The study has multiple primary objectives which are to compare the efficacy of:
1. Asciminib versus Investigator selected TKI, in participants with newly diagnosed CML-CP, 
with respect to the proportion of participants that are in MMR at Week 48.
2. Asciminib versus that of Investigator selected TKI, within the stratum of participants with 
imatinib as their pre-randomization selection of TKI, in participants with newly diagnosed 
CML-CP, with respect to the proportion of participants that are in MMR at Week 48.
The study will be declared positive if either of the two primary objectives is 
met.
The primary endpoint of the study is defined as the binary outcome (Yes/No) of whether a 
participant meets the criteria for MMR at Week 48. 
Only participants with MMR at Week 48 visit are considered responders. In other words, any 
participant who achieves MMR before Week 48 visit, but is no longer in MMR at Week 48 
visit, will be considered as a non-responder for the primary analyses. A participant will be 
considered to have met the primary endpoint if the result of BCR-ABL1 analysis from the 
Novartis designated laboratory by RQ-PCR meets the MMR criteria (BCR-ABL1 IS levels ≤ 
0.1%) at Week 48. Participants discontinuing the randomized treatment due to any reason (e.g. 
intolerance, death, etc., i.e. having performed an end of study treatment (EOT)) prior to Week 
48, or participants meeting any treatment failure criteria prior to Week 48, will be counted as 
not being in MMR at Week 48. 
The primary estimands corresponding to the multiple primary objectives will address the 
following clinical questions of interest:
1. What is the efficacy of asciminib (80 mg QD) compared to Investigator selected TKI; with 
respect to MMR at Week 48, without meeting any treatment failure criteria and without 
treatment discontinuation prior to Week 48, in participants with newly diagnosed CML-CP; 
regardless of dose interruption/ reduction/ allowed escalations, dosing errors, changes on 

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concomitant medication, intake of prohibited medication , and regardless of taking a TKI 
different from their pre-randomization selection of TKI in the comparator arm.
2. What is the efficacy of asciminib (80 mg QD) compared to Investigator selected TKI within 
the stratum of participants that have imatinib as their pre-randomization selection of TKI; 
with respect to MMR at Week 48, without meeting any treatment failure criteria and without 
treatment discontinuation prior to Week 48, in participants with newly diagnosed CML-CP; 
regardless of dose interruption/ reduction/ allowed escalations, dosing errors, changes on 
concomitant medication, intake of prohibited medication , and regardless of taking a TKI 
different from their pre-randomization selection of TKI in the comparator arm. 
The primary estimands strategy (based on the treatment policy and composite approaches), their 
attributes, handling of intercurrent events are described in detail in Section 2.1.
12.4.2
Statistical model, hypothesis, and method of analysis
The hypotheses corresponding to the multiple primary objectives are as follows: 
•
H1 
•
H10: the proportion of participants that achieve MMR at Week 48 in the asciminib arm 
is less than or equal to the proportion of participants that achieve MMR at Week 48 in 
the Investigator selected TKI arm.
•
H1a: the proportion of participants that achieve MMR at Week 48 in the asciminib arm 
is higher than the proportion of participants that achieve MMR at Week 48 in the 
Investigator selected TKI arm.
•
H2 
•
H20: within the stratum of participants that have imatinib as their pre-randomization 
selection of TKI, the proportion of participants that achieve MMR at Week 48 in the 
asciminib arm is less than or equal to the proportion of participants that achieve MMR 
at Week 48 in the Investigator selected TKI arm.
•
H2a: within the stratum of participants that have imatinib as their pre-randomization 
selection of TKI, the proportion of participants that achieve MMR at Week 48 in the 
asciminib arm is higher than the proportion of participants that achieve MMR at Week 
48 in the Investigator selected TKI arm.
The analyses of the primary endpoints will be performed using the FAS for the comparison of 
asciminib versus the Investigator selected TKI; or the FASIMA for the comparison of asciminib 
versus Investigator selected TKI, within the stratum of participants that have imatinib as their 
pre-randomization selection of TKI. Following the intent to treat principle (which is reflective 
of the primary estimands approach based on the treatment policy and composite strategy), 
participants will be analyzed according to the treatment arm and stratum they were assigned to 
at randomization.
The primary comparisons of proportions of participants that are in MMR at Week 48 for:
1. Asciminib versus Investigator selected TKI, will be performed using a one-sided stratified 
Mantel-Haenszel test, stratified by both randomization stratification factors (ELTS risk 
score and pre-randomization selection of TKI (imatinib versus 2G TKI)).
2. Asciminib versus Investigator selected TKI, within the stratum of participants that have 
imatinib as their pre-randomization selection of TKI, will be performed using a one-sided 

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stratified Mantel-Haenszel test, stratified by only the ELTS risk score randomization 
stratification factor. 
The family wise error rate will be controlled at 2.5% level via the graphical gatekeeping 
procedure which is described Section 12.7 
The study will be considered positive if the null hypothesis for either of the two primary 
objectives can be rejected. 
The response rates and corresponding two sided 95% CIs for the primary endpoints, based on 
the Pearson-Clopper method will be presented by the:
1. Treatment arms (asciminib or Investigator selected TKI).
2. Treatment arms (asciminib or Investigator selected TKI) within the stratum of participants 
that have imatinib as their pre-randomization selection of TKI.
The stratified Mantel-Haenszel estimate of the common risk difference (for the proportion of 
participants that are in MMR at Week 48) between:
1. Asciminib and Investigator selected TKI arm, stratified by randomization stratification 
factors of the ELTS risk score and pre-randomization selection of TKI (imatinib versus 2G 
TKI),
2. Asciminib and Investigator selected TKI arm, within the stratum of participants that have 
imatinib as their pre-randomization selection of TKI, stratified by only randomization 
stratification factor of the ELTS risk score, will be provided, together with the 
corresponding two sided 95% confidence interval.
All the confidence intervals (CIs) reported will be nominal 95% CIs which are unadjusted for 
multiple testing and will be presented for descriptive purposes. 
12.4.3
Handling of remaining intercurrent events of primary estimand
The handling of intercurrent events for the primary estimands are described in detail in 
Section 2.1. No other intercurrent events are foreseen.
12.4.4
Handling of missing values not related to intercurrent event
Only participants with MMR at Week 48 visit are considered responders for the primary 
analyses. In other words, any participant who achieves MMR before Week 48 visit, but is no 
longer in MMR at Week 48 visit, will be considered as a non-responder (as is the case for 
participants who never achieve MMR at or before Week 48 visit).
Handling of missing values/censoring/discontinuations: 
•
Participants discontinuing the randomized treatment due to any reason (e.g. intolerance, 
death, etc., i.e. having performed an EOT) prior to Week 48, or participants meeting any 
treatment failure criteria prior to Week 48, will be counted as not being in MMR at Week 
48.
•
Participants with missing PCR evaluation at Week 48 visit, will be imputed as MMR, if 
they have non-missing PCR evaluations at Week 36 and Week 60 visits, and both of these 
meet the MMR criteria (BCR-ABL1 IS levels ≤ 0.1%). 

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If PCR evaluations are performed at unscheduled visits, these will be mapped to non-
overlapping analysis time windows and will be taken into consideration. The analysis time 
windows will be described in detail in the SAP.
12.4.5
Sensitivity analyses for primary endpoint/estimand
Sensitivity analysis for the primary end-points may be performed and will be described in the 
statistical analyses plan.
12.4.6
Supplementary analysis
Supplemental estimands for the end-point of MMR at Week 48 based on the treatment 
policy, composite and hypothetical strategies as described below will be produced. The 
supplemental estimand differs from the primary estimand in the way in which it handles the 
intercurrent event of taking a TKI different from the pre-randomization selection TKI in the 
comparator arm. These estimands will be presented for descriptive purposes.
Additional supplemental clinical questions of interest are:
1. What is the efficacy of asciminib (80 mg QD) compared to Investigator selected TKI, with 
respect to MMR at Week 48, without meeting any treatment failure criteria prior to Week 
48 or discontinuing treatment due to any reason prior to Week 48, in participants with newly 
diagnosed CML-CP; regardless of dose interruption/reduction/allowed escalations, dosing 
errors, changes on concomitant medication, intake of prohibited medication; if participants 
did not take a TKI different from their pre-randomization selection TKI in the comparator 
arm.
2. What is the efficacy of asciminib (80 mg QD) compared to imatinib as the Investigator 
selected TKI, with respect to MMR at Week 48, without meeting any treatment failure 
criteria prior to Week 48 or discontinuing treatment due to any reason prior to Week 48, in 
participants with newly diagnosed CML-CP, within the stratum of participant that have 
imatinib 
as 
their 
pre-randomization 
selection 
of 
TKI; 
regardless 
of dose 
interruption/reduction/allowed escalations, dosing errors, changes on concomitant 
medication, intake of prohibited medication; if participants did not take a TKI different from 
their pre-randomization selection of imatinib the comparator arm.
The supplemental estimands for the end-point of MMR at Week 48 are described by the 
following attributes:
Population: Newly diagnosed adult Ph+ CML-CP participants, as defined by 
Inclusion/Exclusion criteria; (1) overall and (2) within the stratum with imatinib as their pre-
randomization selection of TKI.
Endpoint: the composite end-point of MMR at Week 48 visit, without meeting any treatment 
failure criteria prior to Week 48 and without discontinuing treatment due to any reason prior to 
Week 48. A participant will be counted as being in MMR at Week 48 visit if he/she meets the 
MMR criterion (BCR-ABL IS ≤ 0.1%) at Week 48 visit, unless the participant met any 
treatment failure criteria prior to Week 48 or discontinued the randomized treatment due to any 
reason prior to Week 48.
Intercurrent events (IE):
•
Set 1 (IE1) 

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•
Taking a TKI different from the pre-randomization selection of TKI (i.e. the first dose 
of TKI is different from pre-randomization selection of TKI): hypothetical strategy 
(impute)
•
Set 2 (IE2) 
•
Change of study treatment per protocol (dose reduction/interruption/allowed dose 
escalations): treatment policy strategy (ignore)
•
Dosing errors (e.g.: missed dose): treatment policy strategy (ignore)
•
Deviation in any intake of concomitant medications: treatment policy strategy (ignore)
•
Intake of prohibited medications : treatment policy strategy (ignore)
•
Set 3 (IE3) 
•
Meeting any treatment failure criteria prior to Week 48 or treatment discontinuation 
due to any reason prior to Week 48: composite (consider this non-response).
•
If a participant only experience IE2s’ these will be handled as per treatment policy 
approach and ignored. If a participant experiences IE1, these are handled as per the 
hypothetical policy approach and the data for MMR after the occurrence of the IE1 will be 
imputed (by hypothetical values from a model based on participants from the comparator 
arm that take a TKI at randomization that is the same as their pre-randomization selection 
of TKI).
•
The IE1 if it occurs, will always occur before any other IE2 events. If a participant 
experiences both IE1 and IE2s, the hypothetical strategy will take precedence over the 
treatment policy strategy and all the data for MMR after the occurrence of IE1 will be 
imputed. 
•
 Further details on the imputation model will be specified in the SAP.
Handling of remaining intercurrent events: no other IE foreseen
Treatment:
1. The randomized treatment arm (the investigational treatment asciminib 80 mg QD, or the 
Investigator 
selected 
TKI); 
with 
or 
without 
dose 
modifications 
(reduction/interruption/allowed escalation), dosing errors, deviation in any intake of 
concomitant medications, intake of prohibited medication, if taking a TKI different from the 
pre-randomization selection of TKI in the comparator arm would not be possible.
2. The randomized treatment arm (the investigational treatment asciminib 80 mg QD, 
or imatinib as the Investigator selected TKI), within the stratum of participants that have 
imatinib as their pre-randomization selection of TKI; with or without dose modifications 
(reduction/interruption/allowed escalation), dosing errors, deviation in any intake of 
concomitant medications, intake of prohibited medication, if taking a TKI different from the 
pre-randomization selection of imatinib in the comparator arm would not be possible.
The summary measure: 
1. stratum adjusted difference in the proportion of participants that are in MMR at Week 48 
and corresponding 95% CI, between the two treatments (asciminib versus Investigator 
selected TKI).

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2. stratum adjusted difference in the proportion of participants that are in MMR at Week 48 
and corresponding 95% CI, between the two treatments (asciminib versus imatinib), within 
the stratum of participants that have imatinib as their pre-randomization selection of TKI.
12.4.7
Supportive analyses
If either of the primary objectives is met, subgroup analyses to assess the homogeneity of the 
treatment effect (for MMR at Week 48) across subgroups (eg: based on demographic and 
baseline disease characteristics, ELTS prognostic categories, geographic regions etc.) will be 
performed.
Details will be provided in the SAP.
12.5
Analysis of the key secondary endpoint(s)/estimand(s)
12.5.1
Definition of key secondary endpoint(s)/estimand(s)
The study has multiple key secondary objectives which are:
1. To compare the efficacy of asciminib versus Investigator selected TKI, in patients with 
newly diagnosed CML-CP, with respect to the proportion of participants that are in MMR 
at Week 96.
2. To compare the efficacy of asciminib versus that of Investigator selected TKI, within the 
stratum of participants with imatinib as their pre-randomization selection of TKI, in patients 
with newly diagnosed CML-CP, with respect to the proportion of participants that are in 
MMR at Week 96.
The two key secondary objectives will be formally tested only if either (i) H10 and H20 are 
both rejected or (ii) if only H20 is rejected, as described in the testing strategy in 
Section 12.7. 
The key secondary endpoint is defined as the binary outcome (Yes/No) of whether a 
participant meets the criteria for MMR at Week 96. 
Only participants with MMR at Week 96 visit are considered responders. In other words, any 
participant who achieves MMR before Week 96 visit, but is no longer in MMR at Week 96 
visit, will be considered as a non-responder for the key secondary analyses. A participant will 
be considered to have met the key secondary endpoint if the result of BCR-ABL1 analysis from 
the Novartis designated laboratory by RQ-PCR meets the MMR criteria (BCR-ABL1 IS levels 
≤ 0.1%) at Week 96. Participants discontinuing the randomized treatment due to any reason 
(e.g. intolerance, death, etc., i.e. having performed an end of study treatment (EOT)) prior to 
Week 96, or participants meeting any treatment failure criteria prior to Week 96, will be counted 
as not having being in MMR at Week 96. 
The key secondary estimands corresponding to the multiple key secondary objectives will 
address the following clinical questions of interest:
1. What is the efficacy of asciminib (80mg QD) compared to Investigator selected TKI; with 
respect to MMR at Week 96, without meeting any treatment failure criteria and without 
treatment discontinuation prior to Week 96, in patients with newly diagnosed CML-CP; 
regardless of dose interruption/ reduction/ allowed escalations, dosing errors, changes on 

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concomitant medication, intake of prohibited medication , and regardless of taking a TKI 
different from their pre-randomization selection of TKI in the comparator arm.
2. What is the efficacy of asciminib (80mg QD) compared to Investigator selected TKI within 
the stratum of participants that have imatinib as their pre-randomization selection of TKI; 
with respect to MMR at Week 96, without meeting any treatment failure criteria and without 
treatment discontinuation prior to Week 96, in patients with newly diagnosed CML-CP; 
regardless of dose interruption/ reduction/ allowed escalations, dosing errors, changes on 
concomitant medication, intake of prohibited medication , and regardless of taking a TKI 
different from their pre-randomization selection of TKI in the comparator arm. 
The key secondary estimands strategy (based on the treatment policy and composite 
approaches), their attributes, handling of intercurrent events are described in detail in 
Section 2.2.1.
12.5.2
Statistical model, hypothesis and methods of analysis
The hypotheses corresponding to the multiple key secondary objectives are as follows: 
•
H3  
•
H30: the proportion of participants that are in MMR at Week 96 in the asciminib arm 
is less than or equal to the proportion of participants that achieve MMR at Week 96 in 
the Investigator selected TKI arm.
•
H3a: the proportion of participants that achieve MMR at Week 96 in the asciminib arm 
is higher than the proportion of participants that are in MMR at Week 96 in the 
Investigator selected TKI arm.
•
H4 
•
H40: within the stratum of participants that have imatinib as their pre-randomization 
selection of TKI, the proportion of participants that are in MMR at Week 96 in the 
asciminib arm is less than or equal to the proportion of participants that achieve MMR 
at Week 96 in the Investigator selected TKI arm.
•
H4a: within the stratum of participants that have imatinib as their pre-randomization 
selection of TKI, the proportion of participants that achieve MMR at Week 96 in the 
asciminib arm is higher than the proportion of participants that are in MMR at Week 
96 in the Investigator selected TKI arm.
The analyses of the key secondary endpoints will be performed using the FAS for the 
comparison of asciminib versus the Investigator selected TKI; or the FASIMA for the comparison 
of asciminib versus Investigator selected TKI, within the stratum of participants that have 
imatinib as their pre-randomization selection of TKI. Following the intent to treat principle 
(which is reflective of the key secondary estimands approach based on the treatment policy and 
composite strategy), participants will be analyzed according to the treatment arm and stratum 
they were assigned to at randomization.
The key secondary comparisons of the proportions of participants are in MMR at Week 96 for:
1. Asciminib versus Investigator selected TKI, will be performed using a one-sided stratified 
Mantel-Haenszel test, stratified by both randomization stratification factors (ELTS risk 
score and pre-randomization selection of TKI (imatinib versus 2G TKI)).

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2. Asciminib versus Investigator selected TKI, within the stratum of participants that have 
imatinib as their pre-randomization selection of TKI, will be performed using a one-sided 
stratified Mantel-Haenszel test, stratified by only the ELTS risk score randomization 
stratification factor. 
The family wise error rate will be controlled at 2.5% level via the graphical gatekeeping 
procedure which is described Section 12.7.
The response rates and corresponding two sided 95% CIs for the key secondary endpoints, 
based on the Pearson-Clopper method will be presented by the:
1. Treatment arms (asciminib or Investigator selected TKI).
2. Treatment arms (asciminib or Investigator selected TKI) within the stratum of participants 
that have imatinib as their pre-randomization selection of TKI.
The stratified Mantel-Haenszel estimate of the common risk difference (in the proportion of 
participants that are in MMR at Week 96) between:
1. Asciminib and Investigator selected TKI arm, stratified by randomization stratification 
factors of the ELTS risk score and pre-randomization selection of TKI (imatinib versus 2G 
TKI),
2. Asciminib and Investigator selected TKI arm, within the stratum of participants that have 
imatinib as their pre-randomization selection of TKI, stratified by only randomization 
stratification factor of the ELTS risk score, will be provided, together with the 
corresponding two sided 95% CI.
All the confidence intervals (CIs) reported will be nominal 95% CIs which are unadjusted for 
multiple testing and will be presented for descriptive purposes. 
12.5.3
Handling of remaining intercurrent events of key secondary estimand
The handling of intercurrent events for the key secondary estimands are described in detail in 
Section 2.2.1. No further intercurrent events are foreseen.
12.5.4
Handling of missing values not related to intercurrent event
Only participants with MMR at Week 96 visit are considered responders for the key Secondary 
analyses. In other words, any participant who achieves MMR before Week 96 visit, but is no 
longer in MMR at Week 96 visit, will be considered as a non-responder.
Handling of missing values/censoring/discontinuations: 
•
Participants discontinuing the randomized treatment due to any reason (e.g. intolerance, 
death, etc., i.e. having performed an EOT) prior to Week 96, or participants meeting any 
treatment failure criteria prior to Week 96, will be counted as not being in MMR at Week 
96.
•
Participants with missing PCR evaluation at Week 96, will be imputed as MMR, if they 
have non-missing PCR evaluations at Week 84 and Week 108, and both of these meet the 
MMR criteria (BCR-ABL1 IS levels ≤ 0.1%). 
If PCR evaluations are performed at unscheduled visits, these will be mapped to non-
overlapping analysis time windows and will be taken into consideration. The analysis time 
windows will be described in detail in the SAP.

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12.5.5
Sensitivity analysis for key secondary endpoint/estimand
Sensitivity analyses for the key secondary end-points may be performed and will be described 
in the SAP.
12.5.6
Supplementary analysis
Supplemental estimands for the end-point of MMR at Week 96 based on the treatment 
policy, composite and hypothetical strategies as described below will be produced. The 
supplemental estimand differs from the key secondary estimand in the way in which it handles 
the intercurrent event of taking a TKI different from the pre-randomization selection TKI in the 
comparator arm. These estimands will be presented for descriptive purposes.
Additional supplemental clinical questions of interest are:
1. What is the efficacy of asciminib (80 mg QD) compared to Investigator selected TKI, with 
respect to MMR at Week 96, without meeting any treatment failure criteria prior to Week 
96 or discontinuing treatment due to any reason prior to Week 96, in patients with newly 
diagnosed CML-CP; regardless of dose interruption/reduction/allowed escalations, dosing 
errors, changes on concomitant medication, intake of prohibited medication; if participants 
did not take a TKI different from their pre-randomization selection TKI in the comparator 
arm.
2. What is the efficacy of asciminib (80 mg QD) compared to imatinib as the Investigator 
selected TKI, with respect to MMR at Week 96, without meeting any treatment failure 
criteria prior to Week 96 or discontinuing treatment due to any reason prior to Week 96, in 
patients with newly diagnosed CML-CP, within the stratum of participant that have imatinib 
as 
their 
pre-randomization 
selection 
of 
TKI; 
regardless 
of dose 
interruption/reduction/allowed escalations, dosing errors, changes on concomitant 
medication, intake of prohibited medication; if participants did not take a TKI different from 
their pre-randomization selection of imatinib the comparator arm.
The supplemental estimands for the end-point of MMR at Week 96 are described by the 
following attributes:
Population: Newly diagnosed adult Ph+ CML-CP participants, as defined by 
Inclusion/Exclusion criteria; (1) overall and (2) within the stratum with imatinib as their pre-
randomization selection of TKI.
Endpoint: the composite end-point of MMR at Week 96 visit, without meeting any treatment 
failure criteria prior to Week 96 and without discontinuing treatment due to any reason prior to 
Week 96. A participant will be counted as being in MMR at Week 96 visit if he/she meets the 
MMR criterion (BCR-ABL IS ≤ 0.1%) at Week 96 visit, unless the participant met any 
treatment failure criteria prior to Week 96 or discontinued the randomized treatment due to any 
reason prior to Week 96.
Intercurrent events (IE):
•
Set 1 (IE1) 
•
Taking a TKI different from the pre-randomization selection of TKI (i.e. the first dose 
of TKI is different from pre-randomization selection of TKI): hypothetical strategy 
(impute)

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•
Set 2 (IE2) 
•
Change of study treatment per protocol (dose reduction/interruption/allowed dose 
escalations): treatment policy strategy (ignore)
•
Dosing errors (e.g.: missed dose): treatment policy strategy (ignore)
•
Deviation in any intake of concomitant medications: treatment policy strategy (ignore)
•
Intake of prohibited medications : treatment policy strategy (ignore)
•
Set 3 (IE3) 
•
Meeting any treatment failure criteria prior to Week 96 or treatment discontinuation 
due to any reason prior to Week 96: composite (consider this non-response).
•
If a participant only experience IE2s’ these will be handled as per treatment policy 
approach and ignored. If a participant experiences IE1, these are handled as per the 
hypothetical policy approach and the data for MMR after the occurrence of the IE1 will be 
imputed (by hypothetical values from a model based on participants from the comparator 
arm that take a TKI at randomization that is the same as their pre-randomization selection 
of TKI). 
•
The IE1 if it occurs, will always occur before any other IE2 events. If a participant 
experiences both IE1 and IE2s, the hypothetical strategy will take precedence over the 
treatment policy strategy and all the data for MMR after the occurrence of IE1 will be 
imputed. 
•
 Further details on the imputation model will be specified in the SAP.
Handling of remaining intercurrent events: no other IE foreseen
Treatment:
1. The randomized treatment (the investigational treatment asciminib 80 mg QD, or the 
Investigator 
selected 
TKI); 
with 
or 
without 
dose 
modifications 
(reduction/interruption/allowed escalation), dosing errors, deviation in any intake of 
concomitant medications, intake of prohibited medication, if taking a TKI different from the 
pre-randomization selection of TKI in the comparator arm would not be possible.
2. The randomized treatment (the investigational treatment asciminib 80 mg QD, or imatinib 
as the Investigator selected TKI), within the stratum of participants that have imatinib as 
their pre-randomization selection of TKI; with or without dose modifications 
(reduction/interruption/allowed escalation), dosing errors, deviation in any intake of 
concomitant medications, intake of prohibited medication, if taking a TKI different from the 
pre-randomization selection of imatinib in the comparator arm would not be possible.
The summary measure: 
1. stratum adjusted difference in the proportion of participants that are in MMR at Week 96 
and corresponding 95% CI, between the two treatments (asciminib versus Investigator 
selected TKI).
2. stratum adjusted difference in the proportion of participants that are in MMR at Week 96 
and corresponding 95% CI, between the two treatments (asciminib versus imatinib), within 
the stratum of participants that have imatinib as their pre-randomization selection of TKI.

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12.5.7
Supportive analyses
If either of the key secondary objectives is met, subgroup analyses to assess the homogeneity 
of the treatment effect (for MMR at Week 96) across subgroups (eg: based on demographic and 
baseline disease characteristics, ELTS prognostic categories, geographic regions etc.) will be 
performed.
Details will be presented in the SAP.
12.6
Analysis of the secondary safety end-point of Time to 
Discontinuation of Study Treatment due to AE (TTDAE)
The study has one secondary safety objective, which will be formally tested at the Week 96 
analysis timepoint.
The secondary safety objective is to compare the safety/tolerability of asciminib versus 2G TKIs, 
in patients with newly diagnosed CML-CP, with respect to the time to discontinuation of study 
treatment due to AE (TTDAE).
This secondary safety objective will be formally tested only if both key secondary 
objectives are met. i.e if H40 and H30 are both rejected, as described in the testing strategy 
in Section 12.7.
The secondary endpoint of TTDAE is defined as the time from the date of first dose of study 
treatment to the date of discontinuation of study treatment due to AE.  For participants ongoing 
without study treatment discontinuation, on or prior to the analysis cut-off date, the time will 
be censored at the at the analysis cut-off date.
The secondary safety objective estimand strategy, its attributes, handling of intercurrent events 
will be described in detail in the SAP. 
Statistical model, hypothesis and methods of analysis
The hypotheses corresponding to the secondary safety objective for TTDAE is as follows: 
H5: 
•
H50: the cause-specific hazard for the event of discontinuation of study treatment due to 
AE, for participants that received asciminib is greater than or equal to that for participants 
that received a 2G TKI.
•
H5a: the cause-specific hazard for the event of discontinuation of study treatment due to 
AE, for participants that received asciminib is less than that for participants that received a 
2G TKI.
Competing risk analysis of TTDAE will be performed using the safety set. The ‘discontinuation 
of study treatment due to AE’ will be considered as the event of interest, while discontinuation 
from study treatment due to other reasons that are not due AEs will be considered as competing 
risk events.
The estimated cumulative incidence rates and 95% CIs at specified scheduled visits will be 
presented for each treatment group (asciminib and the 2G TKI). The cumulative incidence curve 
will be plotted.

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The comparison of TTDAE for asciminib versus the 2G TKIs will be implemented via the log-
rank test of the cause-specific hazard for the event of interest.
The family wise error rate will be controlled at 2.5% level via the graphical gatekeeping 
procedure which is described in Section 12.7. 
Supplementary analysis
The competing risk analysis for the cause-specific hazard for the competing risk events will 
also be performed; as will the analysis via the sub-distribution hazard approach. These 
supplementary analyses will be provided for information purpose only.
12.7
Testing Strategy and Type-I Error Control for the multiple primary 
and key secondary objectives; and for the secondary safety 
objective
The overall family wise type-I error (1-sided level of significance α = 2.5%) control for testing 
the multiple primary and key secondary hypotheses, is achieved through the graphical gate-
keeping multiple testing procedure (Bretz et al 2009, Bretz et al 2011) as shown in in 
Figure 12-1 .
The multiple hypotheses are grouped into three families; those associated with the primary 
objectives (H1, H2), those associated with the key secondary objectives (H3, H4) and those 
associated with the secondary safety objective (H5).
The primary end-point (MMR at Week 48) family of hypotheses F1, are:
•
H10: the proportion of participants that achieve MMR at Week 48 in the asciminib arm is 
less than or equal to the proportion of participants that achieve MMR at Week 48 in the 
Investigator selected TKI arm.
versus
•
H1a: the proportion of participants that achieve MMR at Week 48 in the asciminib arm is 
greater than the proportion of participants that achieve MMR at Week 48 in the Investigator 
selected TKI arm.
and 
•
H20: within the stratum of participants that have imatinib as their pre-randomization 
selection of TKI, the proportion of participants that achieve MMR at Week 48 in the 
asciminib arm is less than or equal to the proportion of participants that achieve MMR at 
Week 48 in the Investigator selected TKI arm.
versus
•
H2a: within the stratum of participants that have imatinib as their pre-randomization 
selection of TKI, the proportion of participants that achieve MMR at Week 48 in the 
asciminib arm is greater than the proportion of participants that achieve MMR at Week 48 
in the Investigator selected TKI arm.
The key secondary end-point (MMR at Week 96) family of hypotheses F2, are:

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•
H30: the proportion of participants that achieve MMR at Week 96 in the asciminib arm is 
less than or equal to the proportion of participants that achieve MMR at Week 96 in the 
Investigator selected TKI arm.
versus
•
H3a: the proportion of participants that achieve MMR at Week 96 in the asciminib arm is 
greater than the proportion of participants that achieve MMR at Week 96 in the Investigator 
selected TKI arm.
and
•
H40: within the stratum of participants that have imatinib as their pre-randomization 
selection of TKI, the proportion of participants that achieve MMR at Week 96 in the 
asciminib arm is less than or equal to the proportion of participants that achieve MMR at 
Week 96 in the Investigator selected TKI arm.
versus
•
H4a: within the stratum of participants that have imatinib as their pre-randomization 
selection of TKI, the proportion of participants that achieve MMR at Week 96 in the 
asciminib arm is greater than the proportion of participants that achieve MMR at Week 96 
in the Investigator selected TKI arm.
The secondary safety end-point (TTDAE) family of hypotheses F3 is:
•
H50: the cause-specific hazard for the event of discontinuation of study treatment due to 
AE, for participants that received asciminib is greater than or equal to that for participants 
that received a 2G TKI.
versus
•
H5a: the cause-specific hazard for the event of discontinuation of study treatment due to 
AE, for participants that received asciminib is less than that for participants that received a 
2G TKI.
The analyses cut-off date for testing H1 and H2 will be when all randomized participants have 
been treated for at least 48 weeks or discontinued from study treatment prior to Week 48.
The analyses cut-off date for testing H3 and H4 will be when all randomized participants have 
been treated for at least 96 weeks or discontinued from study treatment prior to Week 96.
The analyses cut-off date for testing H5 will be when all randomized participants have been 
treated for at least 96 weeks or discontinued from study treatment prior to Week 96.

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Figure 12-1
Testing hierarchy (graphical gatekeeping procedure)
 
The primary and key secondary hypotheses, H1, H2, H3, H4 and H54, are represented by nodes in the graph; with the associated local weights (i.e. 
proportion of total alpha (1- sided α=2.5%) available to test that hypothesis). A directed edge from one hypothesis Hi, to another one Hj, means that when the 
null hypothesis associated with Hi is rejected, its local weight (i.e. the local alpha) can be transferred to Hj. The weight associated with that edge quantifies the 
proportion of the local alpha of Hi that is transferred to Hj. 

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The three families of hypotheses will be tested in the following manner. The null hypotheses in 
family F1 (H1 and H2) will be examined first and tested using the weighted parametric tests 
(Bretz et al 2011); the hypotheses in family F2 (H3 and H4) will be tested using the fixed-
sequence testing approach; followed by the hypothesis in family F3 (H5) will be tested using 
the fixed-sequence testing approach. The null hypotheses in key secondary end-point family 
F2 can be tested if the null hypothesis for H2 (or for both H1 and H2) in the primary end-point 
family F1 is rejected. The null hypotheses in secondary safety end-point family F3 can be tested 
if the null hypothesis for both H4 and H3 in the key secondary end-point family F2 are rejected.
The weighted parametric test for the primary end-points family also exploits the correlation 
between the test statistics for H1 and H2, which arises because the population for testing H2 is 
a stratum from within the population for testing H1. Let T1 and T2 be the test statistics for H1 
and H2 respectively, then the correlation is computed as shown in the figure below:
where n1, n1* are the number of participants in asciminib arm, overall and within the stratum of 
participants with imatinib as their pre-randomization selection of TKI; and n0, n0* are the 
number of participants in Investigator selected TKI arm, overall and within the stratum of 
participants with imatinib as their pre-randomization selection of TKI respectively.
Let α1 =w1*α and α2 =w2*α be primary end-point specific alphas for H1 and H2 respectively, 
let α3 and the α4 be key secondary end-point specific alphas for H3 and H4 respectively, and the 
α5 be secondary safety end-point specific alpha for H5. To begin with, we distribute the overall 
global alpha level (1-sided α=0.025) such that the two primary hypotheses get equal weights 
(i.e. w1=0.5 and w2=0.5), as each of the multiple primary objectives is considered equally 
important. In addition, to begin with, the two key secondary hypotheses are not given any 
weight since achieving these objectives is not relevant if we cannot meet the primary objective 
H2, or meet both H1 and H2. Similarly, the secondary hypothesis H5 is also not given any 
weight to begin with.
Within the primary end-point family F1:
•
The testing of H1 and H2 can be performed simultaneously at the split levels of α1 =w1*α 
and α2 =w2*α respectively. 
•
When using the correlation between the test statistics for H1 and H2, the test of the 
intersection hypothesis H1 and H2 would be done at levels that are slightly larger than 
w1*alpha and w2*alpha (for details please refer to Bretz et al 2011).
•
If H10 is rejected at an alpha of α1, then this w1 is passed on to test H2 which can then be 
tested at the alpha of w1*α+w2*α =α (i.e. H2 can be tested at the full alpha).
•
If H20 is rejected at an alpha of α2, then 0.9 of w2 is passed onto testing H1, which can then 
be tested at an alpha of (w1 + 0.9*w2)*α
Within the key secondary end-point family F2:
•
If only H20 is rejected in the primary family, then H4 can be tested at an alpha of α4= 
0.1*w2*α
•
If both H10 and H20 are rejected in the primary family, then H4 can be tested at the full 
alpha of α4=0.025.
•
If H40 is rejected at an alpha of α4, then this α4 is passed on to test H3 

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•
if only H20 from the primary family and H40 from the key secondary family are rejected, 
then H3 is tested at an alpha level α3=0.1*w2*α
•
if both H10 and H20 from the primary family, and H40 from the key secondary family 
are rejected, then H3 is tested at the full alpha level α3 =0.025.
Within the secondary safety end-point family F3:
•
If both H40 and H30 are rejected in the key secondary family, then H5 can be tested at the 
full alpha of α5=0.025. 
The raw p-value rejection boundaries:
Let p1 and the p2 be the raw p-values for H1 and H2 respectively; let p3 and the p4 be the raw p-
values for H3 and H4 respectively and let p5 be the raw p-values for H5. 
Assuming that the number of participants enrolled into the imatinib stratum based on pre-
randomization selection of TKI is 50% of the total number of participant enrolled into the study, 
the raw p-value rejection boundaries for the primary end-point family F1 are:
H1 and H2 are simultaneously tested, each at local alpha= 0.01469289 (which is greater 
than 0.025/2 due to the positively correlated test statistics with a correlation of sqrt (0.5)). 
•
If p1 > 0.01469289 and p2 > 0.01469289 then H10 is not rejected and H20 is not rejected, and 
testing stops 
•
If p1 ≤ 0.01469289 and p2 ≤ 0.01469289 then H10 is rejected and H20 is rejected 
•
if p1 ≤ 0.01469289 and p2 > 0.01469289 then H10 is rejected and H2 can be retested at the 
local alpha level of 0.025. If 0.01469289 < p2 ≤ 0.025 then we can also reject H20 
•
If p1 > 0.01469289 and p2 ≤ 0.01469289 then H20 is rejected and H1 can be retested at the 
local alpha level of 0.02375 = (1+0.9)*0.0125. If 0.01469289 < p1 ≤ 0.02375 then we can 
also reject H10 
The raw p-value rejection boundaries for the key secondary end-point family 
F2: 
•
If both H10 and H20 are rejected in the primary family, then H4 can be tested at the full 
alpha of 0.025. If p4 ≤ 0.025 then we can reject H40. If H40 is rejected and p3 ≤ 0.025, then 
we can reject H30. 
•
If only H20 is rejected in the primary family, then H4 will be tested at an alpha of 0.00125. 
If p4 ≤ 0.00125 then we can also reject H40. If H40 is rejected and p3 ≤ 0.00125, then we can 
reject H30. 
•
If only H10 is rejected in the primary family, or none of the null hypotheses in the primary 
family are rejected, then the secondary family cannot be tested. 
The raw p-value rejection boundaries for the secondary safety end-point family 
F3: 
If both H40 and H30 are rejected in the key secondary family, then H5 can be tested at the full 
alpha of 0.025. If p5 ≤ 0.025 then we can reject H50.  

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Equivalently, the raw p-values from the Mantel-Haenszel tests (as described in 
Section 12.4.2 and Section 12.5.2) and from the log-rank test (as described in Section 12.6) will 
be adjusted for the multiple testing (alpha control as described in the above graphical 
gatekeeping procedure), to obtain the adjusted p-values, using the “gMCP” package (Rohmeyer 
K, Klinglmueller F (2020))  in R. The adjusted p-values will be used to perform the 1-sided 
2.5% level test for each of the hypotheses. i.e. if the adjusted p-value for a hypothesis is ≤0.025 
we will reject the corresponding null hypothesis. The adjusted p-values for the primary end-
points family will be computed as per the weighted parametric test using the correlation 
estimated from the observed study data.
12.8
Analysis of secondary endpoints/estimands
This section describes the analyses for other secondary end-points related to efficacy, PK, safety 
and tolerability and PROs. No confirmatory statistical testing of other secondary endpoints, that 
are described in this section, will be performed.
12.8.1
Efficacy and/or Pharmacodynamic endpoint(s)
This section describes definitions and the analyses methods for other secondary end-points 
related to efficacy. No confirmatory statistical testing of other secondary efficacy endpoints will 
be performed, however, nominal p-values when presented will be provided for descriptive 
purposes. 
Additional details such as handling of missing values, sensitivity analyses, supportive analyses 
etc. will be described in detail in the SAP. 
12.8.1.1 Other Efficacy Endpoints
The other secondary objectives related to efficacy in this study are:
•
To estimate the efficacy of asciminib versus Investigator selected TKI, within the strata of 
participants with a 2G TKI as their pre-randomization selected TKI, with respect to 
MMR at Week 48.
•
To estimate the efficacy of asciminib versus Investigator selected TKI, within the strata of 
participants with a 2G TKI as their pre-randomization selected TKI, with respect to 
MMR at Week 96.
•
To compare the efficacy of asciminib versus Investigator selected TKI with respect to the 
additional efficacy endpoints listed below.
•
To compare the efficacy of asciminib versus Investigator selected TKI, within the stratum 
of participants with imatinib as their pre-randomization selected TKI, with respect to the 
additional efficacy endpoints listed below.
•
To estimate the efficacy of asciminib versus Investigator selected TKI, within the strata of 
participants with a 2G TKI as their pre-randomization selected TKI, with respect to the 
additional efficacy endpoints listed below.
The other efficacy endpoints are:
•
MMR at all scheduled data collection time points (except Week 48 and Week 96).
•
MMR by all scheduled data collection time points.

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•
MR4.0 and MR4.5 at and by all scheduled data collection time points.
•
BCR-ABL1 ≤1% at and by all scheduled data collection time points.
•
Complete Hematological response (CHR) at and by all scheduled data collection time 
points.
•
Complete Cytogenetic response (CCyR) by Week 48 and Week 96.
•
Time to first MMR, first MR4.0, first MR4.5.
•
Duration of MMR, MR4.0, MR4.5.
•
TTF.
•
FFS.
•
EFS.
•
PFS.
•
OS.
Unless otherwise stated, the analysis of all other secondary efficacy endpoints for the 
comparison of:  
•
Asciminib versus Investigator selected TKI arm will be based on the FAS
•
Asciminib versus Investigator selected TKI, within the strata of participants with imatinib 
as their pre-randomization selected TKI will be based on the FASIMA
•
Asciminib versus Investigator selected TKI, within the strata of participants with a 2G TKI 
as their pre-randomization selected TKI will be based on the FAS2GTKI
The exceptions are using the Molecular Responder Set, MR4.0 Responder Set and MR4.5 
Responder Set for the analysis of durations of MMR, MR4.0 and MR4.5 respectively.
Definitions of MMR/ MR4.0/MR4.5/CHR/CCyR at and by a scheduled visit:
The rates “at” a scheduled visit are defined as the proportion of participants who meet the 
criteria for the end-point (MMR/MR4.0/MR4.5/CHR/CCyR) at the specified visit. Participants 
discontinuing the randomized treatment due to any reason or participants meeting failure 
criteria, prior to the specific visit will be considered as non-responder for the end-point at the 
specified visit. 
I.e. If a participant achieves the end-point earlier, but then loses it at the visit, he/she will be 
classified as a non-responder the end-point at that visit.
For the end-point of MMR and CCyR, an exception to the rule is if the evaluation at the 
specified visit is missing, but both evaluations from the preceding and following scheduled 
visits meet the criteria for the end-point, the assessment at the specified visit is imputed as a 
responder for the end-point (Yes).
If PCR evaluations are performed at unscheduled visits, these will be mapped to non-
overlapping analysis time windows and will be taken into consideration. The analysis time 
windows will be described in detail in the SAP.
The rates “by” scheduled visits are defined as the proportion of participants who meet the 
criteria for having achieved the end-point (MMR/MR4.0/MR4.5/CHR/CCyR) at or before the 
specified visit, i.e. if a participant achieves the end-point, but then loses it before or at the visit, 

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he/she will still be classified as achieving the end-point by that specified visit. Participants 
discontinuing the randomized treatment prior to the specific time point due to any reason or 
participants meeting failure criteria, without having achieved the end-point at or before that 
visit will be considered as not achieving the end-point by the specified visit.
Definitions of Duration of MMR/ MR4.0/MR4.5:
Duration of a specified molecular end-point (MMR/ MR4.0/ MR4.5) is defined as the time 
between the date of the first documented achievement of the specified molecular end-point and 
the earliest date of loss of the specified molecular end-point, treatment failure, progression to 
AP/BC, or CML-related death for participants in the specified molecular end-point Responder 
Set. The duration will be censored at the last molecular assessment (RQ-PCR) date while on 
treatment for participants who have not experienced any of the above events.
In case of duration of MMR, loss of MMR must be a confirmed loss (confirmed by 2 
consecutive tests). 
Confirmed loss of MMR is the loss of MMR that must be confirmed by subsequent sample 
analysis within 4 to 6 weeks showing loss of MMR associated with a ≥ 5-fold rise in BCR-
ABL1 from the lowest value achieved on study treatment, unless it is associated with confirmed 
loss of CHR or loss of CCyR or progression to AP/BC or CML-related death.
Confirmed loss of MR4.0 or MR4.5 is the loss of MR4.0 or MR4.5, respectively, that must be 
confirmed by subsequent sample analysis within 12 weeks showing loss of MR4 or MR4.5 as 
applicable, associated with a ≥ 5-fold rise in BCR-ABL1 from the lowest value achieved on 
study treatment, unless it is associated with confirmed loss of CHR or loss of CCyR or 
progression to AP/BC or CML-related death.
Definitions of Time to first MMR/ MR4.0/ MR4.5:
Time to first specified molecular end-point (MMR/MR4.0/MR4.5) is defined as the time from 
the date of randomization to the date of the first documented occurrence of the end-point. 
In the time to event analysis, time will be censored at the last molecular assessment (RQ-PCR) 
date while on treatment, or the EOT (whichever comes first) for participants who have not 
experienced the event (i.e. not achieved the end-point).
In the competing risk analysis, time to MMR will be censored at the last molecular assessment 
(RQ-PCR) date on treatment, or the EOT (whichever comes first) prior to or at the analysis cut-
off date; for participants who have not experienced an event (MMR/ MR4.0/ MR4.5) or a 
competing risk event (as described in Section 12.8.1.2 ). 
Definitions of Time to Treatment Failure (TTF):
TTF is defined as the time from date of randomization to the first/earliest documented date of 
any of the following events:
•
Treatment failure as defined below based on ELN criteria (Hochhaus et al 2020A),
•
Confirmed loss of MMR (in 2 consecutive tests, Section 12.8.1.1) at any time while on 
study treatment,

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•
Discontinuation from study treatment due to any reason (e.g.: discontinuation due to AE, 
Investigator/participant decision, unsatisfactory treatment response, progression to AP/BC, 
death due to any cause etc.)
For participants that have not experienced an event prior to or at the analysis cut-off date, the 
time will be censored at the last study assessment (RQ-PCR, cytogenetic, hematologic etc.) 
date while on treatment, or the EOT (whichever comes first).
Definitions of Failure Free Survival (FFS):
FFS is defined as the time from the date of randomization to the earliest occurrence of the 
following events:
•
Treatment failure as defined below based on ELN criteria (Hochhaus et al 2020A),
•
confirmed loss of MMR (in 2 consecutive tests, Section 12.8.1.1) at any time while on study 
treatment,
•
progression to AP/BC (including progressions observed during the survival follow-up 
period),
•
death from any cause (including deaths observed during the survival follow-up period).
For participants that have not experienced an event prior to or at the analysis cut-off date, the 
time will be censored at the date of last study treatment assessment (PCR, cytogenetic, 
hematologic or extramedullary) or last post-treatment follow-up.
Definitions of Event Free Survival (EFS):
EFS is defined as the time from the date of randomization to the earliest occurrence of the 
following events:
•
Treatment failure as defined below based on ELN criteria (Hochhaus et al 2020A),
•
confirmed loss of MMR (in 2 consecutive tests, Section 12.8.1.1) at any time while on study 
treatment,
•
discontinuation of study treatment due to AE,
•
progression to AP/BC (including progressions observed during the survival follow-up 
period),
•
death from any cause (including deaths observed during the survival follow-up period).
For participants that have not experienced an event prior to or at the analysis cut-off date, the 
time will be censored at the date of last study treatment assessment (PCR, cytogenetic, 
hematologic or extramedullary) or last post-treatment follow-up.
Definitions of Progression Free Survival (PFS):
PFS is defined as the time from the date of randomization to the earliest occurrence of the 
following events:
•
progression to AP/BC (including progressions observed during the survival follow-up 
period),
•
death from any cause (including deaths observed during the survival follow-up period).

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For participants that have not experienced an event prior to or at the analysis cut-off date, the 
time will be censored at the date of last study treatment assessment (PCR, cytogenetic, 
hematologic or extramedullary) or last post-treatment follow-up. 
Definition of Overall Survival (OS):
OS is defined as the time from the date of randomization to the date of death from any cause 
(including deaths observed during the survival follow-up period). For participants that have not 
experienced an event prior to or at the analysis cut-off date, the time will be censored at the date 
of last contact before the cut-off date.
Molecular Response Criteria:
Please refer to Section 8.3.1
Complete Haematological Response (CHR) Criteria:
Please refer to Section 8.3.3
Complete Cytogenetic Response Criteria
•
Please refer to Section 8.3.2
Treatment Failure Criteria:
The following events will constitute ‘treatment failure’ based on ELN criteria 
(Hochhaus et al 2020A)
•
BCR-ABL1 transcript level > 10% IS at 3 months if confirmed within the next 1–3 months
•
BCR-ABL1 transcript level > 10% IS at 6 months
•
BCR-ABL1 transcript level > 1% IS at 12 months
•
BCR-ABL1 transcript level >1% IS after 12 months,
•
Detection of a BCR-ABL1 mutation which can potentially cause resistance to study 
treatment (asciminib or Investigator selected TKI) at any time after initiation of study 
treatment. [Per ELN treatment recommendations for known mutations resistant to specific 
TKI Hochhaus et al 2020A].
Intolerance is defined as:
•
Non-hematologic intolerance: Participants with grade 3 or 4 toxicity while on therapy, or 
with persistent grade 2 toxicity, unresponsive to optimal management, including dose 
adjustments (unless dose reduction is not considered in the best interest of the participant if 
response is already suboptimal).
•
Hematologic intolerance: Participants with grade 3 or 4 toxicity (absolute neutrophil count 
[ANC] or PLTs) while on therapy that is recurrent after dose reduction to the lowest doses 
recommended by manufacturer.

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12.8.1.2 Statistical hypothesis, models and methods of analyses of other 
efficacy endpoints
Analyses of the other secondary efficacy endpoints will not adjusted for multiple testing and, 
nominal p-values when presented will be provided for descriptive purposes.
Analyses for (MMR/ MR4.0/ MR4.5 / CHR/ CCyR) rates at and by scheduled 
visits:
Frequency and percentage of participants in the molecular response categories will be presented 
for each scheduled visit. For the by visits summary, the within-participant best molecular 
response category up to the specific time points is used to calculate the frequency and 
percentage. The response rate for each endpoint and the associated two sided 95% CI based on 
the Pearson-Clopper method will be presented by the:
•
Treatment arms (asciminib or Investigator selected TKI).
•
Treatment arms (asciminib or Investigator selected TKI) within the stratum of participants 
that have imatinib as their pre-randomization selection of TKI.
•
Treatment arms (asciminib or Investigator selected TKI) within the stratum of participants 
that have a 2G TKI as their pre-randomization selection of TKI.
Comparisons of proportion of participants achieving the end-points (at and by scheduled 
visits) for:
•
Asciminib versus Investigator selected TKI, will be performed using a one-sided stratified 
Mantel-Haenszel test, stratified by both randomization stratification factors (ELTS risk 
score and pre-randomization selection of TKI (imatinib versus 2G TKI)).
•
Asciminib versus Investigator selected TKI, within the stratum of participants that have 
imatinib as their pre-randomization selection of TKI, will be performed using a one-sided 
stratified Mantel-Haenszel test, stratified by only the ELTS risk score randomization 
stratification factor. 
The stratified Mantel-Haenszel estimate of the common risk difference (for the proportion of 
participants achieving the end-point) between:
•
Asciminib and Investigator selected TKI arm, stratified by randomization stratification 
factors of the ELTS risk score and pre-randomization selection of TKI (imatinib versus 2G 
TKI),
•
Asciminib and Investigator selected TKI arm, within the stratum of participants that have 
imatinib as their pre-randomization selection of TKI, stratified by only randomization 
stratification factor of the ELTS risk score,
•
Asciminib and Investigator selected TKI arm, within the stratum of participants that have a 
2G TKI as their pre-randomization selection of TKI, stratified by only randomization 
stratification factor of the ELTS risk score,
will be provided, together with the corresponding two sided 95% CI.
Analyses for Duration of MMR/ MR4.0/ MR4.5
Duration of MMR/ MR4.0/ MR4.5 will be analyzed by Kaplan-Meier (KM) method and 
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Brookmeyer and Crowley 1982 , along with the proportion of participants who are still in still 
responders at specified scheduled visits and the associated 95% CIs, will be presented for each 
treatment arm (overall and within the stratum defined by pre-randomization selection of TKI).
The cumulative incidence of MMR/ MR4.0/ MR4.5 will be graphically displayed by an 
increasing step function. This curve will increase each time (after randomization) at which a 
new responder is observed and thus will increase up to the best observed response rate (e.g. up 
to 50% if half of the participants in the analysis population are able to achieve response).
Analyses for Time to First MMR/ MR4.0/ MR4.5 
Competing risk analysis of time to first MMR/ MR4.0/ MR4.5 will be performed. 
Discontinuation from study treatment due to any reason (treatment failure, death etc.), without 
prior achievement of the end-point (MMR/ MR4.0/ MR4.5) will be considered as competing 
risk. The estimated cumulative incidence rates and 95% CIs at specified scheduled visits will 
be presented for each treatment arm (overall and within the stratum defined by pre-
randomization selection of TKI). The cumulative incidence curve will be plotted. For this 
competing risk analysis, time to first achievement of the end-point (MMR/ MR4.0/ MR4.5) will 
be censored at the last molecular assessment (RQ-PCR) date on treatment, or the 
EOT (whichever comes first) prior to or at the analysis cut-off date, for participants who have 
not experienced an event (MMR/ MR4.0/ MR4.5) or a competing risk event. 
Analyses for Failure Free Survival (FFS) and Event Free Survival (EFS)
Competing risk analysis of FFS and EFS will be performed. The estimated cumulative 
incidence rates and 95% CIs at specified scheduled visits will be presented for each treatment 
arm (overall and within the stratum defined by pre-randomization selection of TKI). The 
cumulative incidence curve will be plotted.
In the analysis of FFS, discontinuation from study treatment due to other reasons that are not 
due to lack/loss of efficacy (e.g.: discontinuations due to: subject/guardian or physician decision, 
loss to follow-up, pregnancy, study termination, AEs) will be considered as competing risks. In 
the analysis of EFS, discontinuation from study treatment for other reasons which are not due 
to AE and not due to lack/loss of efficacy (e.g.: discontinuations due to: subject/guardian or 
physician decision, loss to follow-up, pregnancy, study termination) will be considered as 
competing risks.
Analyses for Time to Event End-points (TTF, PFS, OS) 
For each endpoint the time to event distribution will be estimated using the Kaplan-Meier 
method, and Kaplan-Meier curves, medians and 95% CIs (Brookmeyer and Crowley 1982) of 
the medians, along with the proportion of participants who have not experienced the respective 
events at select scheduled visits (e.g.: 1, 2 and 5 years) and the associated 95% CIs, will be 
presented for each treatment arm (overall and within the stratum defined by pre-randomization 
selection of TKI). The hazard ratio between the two treatments arms (overall and within the 
stratum defined by pre-randomization selection of TKI) will be calculated, along with its 95% 
CI, using a stratified Cox model. The descriptive p-value obtained using a stratified log-rank 
test will be also presented. The stratification will be based on both randomization stratification 
factors (ELTS and pre-randomization selection of TKI) for the overall comparison between 

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arms; and by the stratification factor of ELTS for the comparison between arms, within the 
stratum defined by pre-randomization selection of TKI. 
12.8.2
Safety endpoints
Analysis Set and Grouping
For all safety analyses, the safety set will be used.
All listings and tables will be presented by treatment arm.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of participant’s first informed consent to the day before first 
administration of study treatment.
2. On-treatment period: from day of first administration of study treatment to 30 days after last 
actual administration of the same study treatment (asciminib or Investigator selected TKI 
(imatinib, nilotinib, dasatinib, bosutinib)), including start and stop date.
3. Post-treatment period: starting at day 31 after last administration of any study treatment 
(asciminib or Investigator selected TKI (imatinib, nilotinib, dasatinib, bosutinib)). 
Summary tables for safety data will be presented for the on-treatment period. Comparative 
analysis will be performed only for the on-treatment period. Listings of safety data will include 
pre-treatment, on-treatment, and post-treatment periods, with a flag to indicate data collected 
before or after the on-treatment period.
AEs
All information obtained on AEs will be displayed by treatment arm and participant.
Summary tables for AEs (AEs) will include only AEs that started or worsened during the on-
treatment period. The number (and percentage) of participants with treatment emergent AEs 
will be summarized by primary system organ class, preferred term and maximum severity 
(based on CTCAE grades). A participant with multiple AEs within a primary system organ class 
is only counted once towards the total of the primary system organ class. Separate summaries 
will be provided for study medication related AEs, deaths, serious AEs, AEs leading to 
treatment discontinuation, and AEs leading to dose adjustment. The number (and percentage) 
of participants with AEs will be summarized by treatment arm, primary system organ class, 
preferred term and maximum severity.
The incidence of AEs will be summarized by system organ class and or preferred term, severity 
(based on CTCAE grades), type of adverse event, relation to study treatment. Serious AEs and 
non-serious AEs will be tabulated.
In addition, selected summaries of AEs will be produced for the overall safety period.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths, and serious AEs (including those from the pre and post-treatment periods) will 
be listed and those collected during the pre-treatment, post-treatment period and overall safety 
period will be flagged.

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Clinical laboratory evaluations/abnormalities
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for AEs (CTCAE) v5. The calculation of CTCAE grades will be based 
on the observed laboratory values only, clinical assessments will not be taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
For laboratory tests where grades are not defined by CTCAE v5, results will be categorized as 
low/normal/high based on laboratory normal ranges.
The following listings and summaries will be generated separately for hematology, and 
biochemistry tests:
•
Listing of all laboratory data with values flagged to show the corresponding CTCAE v5 
grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v5:
•
Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant will 
be counted only once for the worst grade observed post-baseline in the on-treatment period.
•
Shift tables using CTCAE grades to compare respective baseline to the worst on-treatment 
value
For laboratory tests where grades are not defined by CTCAE v5:
•
Shift tables using the low/normal/high/ (low and high) classification to compare respective 
baseline to the worst on-treatment value.
Vital signs
All vital signs abnormalities will be summarized by treatment arm and listed, notable values 
will be flagged.
ECG (12-lead)
ECGs (12-lead) including PR, QRS, QT, QTcF, and HR intervals will be obtained for each 
participant during the study. ECG data will be read and interpreted centrally.
Categorical analysis of QT/QTc interval data based on the number of participants meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these participants will be produced by treatment group.
12.8.3
Tolerability
Tolerability of each study treatment will be assessed by summarizing the number of participants 
with dose interruptions and dose reductions. Reasons for dose interruptions and dose reductions 
will be listed by participant and summarized.
12.8.4
Pharmacokinetics
The PK objective is to characterize the PK of asciminib in newly diagnosed CML-CP patients.

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Using PAS, summary statistics (n, mean, SD, coefficient of variation (CV) for mean, geometric 
mean, CV for geometric mean, median, minimum and maximum) will be presented for plasma 
concentration at each scheduled time point. The geometric mean with mean (SD) and individual 
plasma concentration versus time profiles of asciminib will be displayed graphically.
Using Safety set, concentration data will be listed. Concentration values below the limit of 
quantification (BLQ) will be set to zero by the Bioanalyst and displayed in listings as zero with 
a flag. BLQ values will be handled as zero in any calculations of summary statistics, but handled 
as missing for the calculation of the geometric means and CVs.
PK parameters will be determined by non-compartmental method(s) using the PK profile of 
asciminib in participants with full PK sampling on Week 2/Day 14. PK parameters listed in 
Table 12-1 will be derived and reported, when feasible.
Population PK modeling may be performed (using all PK data) and the results may be reported 
in a separate population PK report. Data from this study may be combined with data from other 
studies for this analysis.
Table 12-1
Non compartmental pharmacokinetic parameters in full PK group
AUClast
The area under the plasma concentration-time curve calculated from time zero to the last 
measurable concentration sampling time (tlast) (mass x time x volume-1)
AUC0-tau
The area under the plasma concentration-time curve from time zero to the end of a dosing interval 
(tau=24h) at steady-state (amount x time x volume-1)
Cmax
The maximum (peak) observed plasma drug concentration after dose administration (mass x 
volume-1)
Tmax  
The time to reach maximum (peak) plasma drug concentration after dose administration (time)
CL/F  
The total body clearance of drug from the plasma after oral administration (volume x time-1)
12.8.5
Patient reported outcomes
The respective full analyses sets (FAS, FASIMA, FAS2GTKI) will be used for analyzing PRO data 
unless specified differently. 
The EORTC QLQ-C30 (version 3.0) and the EORTC QLQ-CML24 will be used to assess 
general health related quality of life and impairment related to the patient’s CML (respectively). 
Change from baseline in Overall Scores and individual domains each PRO instruments will be 
summarized using descriptive statistics for each treatment arm (overall and by strata defined by 
pre-randomization selection of TKI). Participants with an evaluable baseline score and at least 
one evaluable post-baseline score during the treatment period will be included in the change 
from baseline analyses. 
All PRO measures require participant’s direct completion and will be administered utilizing 
electronic device for data collection at scheduled time points from screening to EOT.
Missing data items in a scale will be handled according to the manual for each instrument. No 
imputation will be applied if the total or subscale scores are missing at a visit. All measures will 
assess differences between the treatment arms (overall and by strata defined by pre-
randomization selection of TKI).
Additional analyses may be performed if deemed necessary. Such analyses will be defined in 
the SAP.

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Additional details for the analyses, models and missing data handling will be specified in the 
SAP. 
12.9
Analysis of exploratory endpoints
12.9.1
Exploratory Biomarkers
This trial is not designed to address specific biomarkers-related hypotheses, the analysis of the 
data should be viewed as exploratory and hypotheses generating.  There may be circumstances 
when a decision is made to stop a collection, or not to perform or discontinue the analysis of 
samples due to either practical or strategic reasons. Under such circumstances, the sample size 
number may be too small or the quality of the data not sufficient to perform any data analysis 
and the available data will be only listed.
Additional analyses that may be performed after the completion of the end-of-study CSR will 
be documented in separate reports. These analyses may include but are not limited to the meta-
analysis of data from this study combined with data from other studies or the analysis of 
biomarkers generated from samples collected during the study but analyzed after the database 
lock and completion of the CSR. The data analysis will be described in a stand-alone analysis 
plan document.
Data transformations, such as base 2 logarithms, may be used to summarize and adequately 
analyze the data and will be described in detail in the SAPs.
Data analysis principles 
Analysis sets
Unless otherwise mentioned, the Full Analysis Set is used to describe biomarkers; Safety Set is 
used to assess the relationship between biomarkers and selected safety endpoints, while the PK 
Set is used to assess the relationship between PK parameters and biomarkers. Since no 
imputation is usually planned, the number of participants included in a given analysis will 
reflect the number of participants in the chosen analysis set which have valid biomarker 
assessments.
Basic tables, figures and listings
Unless otherwise specified, analysis will be performed by treatment arm and overall. Analysis 
may also be presented by each stratum based on pre-randomization selection of TKI separately.
The exploratory biomarker objectives in this study are 
•
To characterize 
 and their 
association with molecular response. 
•
To conduct gene expression analysis in peripheral blood to predict treatment response. 
•
To explore the impact of the immune landscape of peripheral blood on treatment response.
Continuous biomarkers (e.g.: gene expression) will be summarized using means, medians, SDs, 
minimums, and maximums, by visit. Both level and change from baseline levels (absolute, 

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percent and fold changes) will be summarized for biomarker that also have assessments at post-
baseline visits.
Categorical biomarkers (e.g.: % cells for immune microenvironment markers, BCR-ABL1 
mutation status etc.) will be summarized using frequency counts and percentages.  
Associations between biomarker levels/change from baseline levels (e.g.: expression profile) 
and clinical end-points (e.g. MMR, TTF, OS etc.) will be explored through suitable figures. 
Associations between continuous biomarkers levels/change from baseline levels and 
categorical end-points (e.g. MMR) will be explored through box-plots/strip-plots showing the 
biomarker levels (or change from baseline levels) versus categories of response. Associations 
between biomarkers levels/change from baseline levels (suitably categorized) and time to event 
end-points (e.g. TTF, OS etc.) will be explored through KM plots. Details will be provided in 
the SAPs and may be reported separately.
If sample size is limited then the biomarker data will be listed. For large panels, selected sets of 
relevant markers will be chosen for the listing.
12.9.2
Pharmacogenomics
The impact of baseline genetic variants of the 
 genes on asciminib 
exposure will be explored. Using PAS, summary statistics for plasma concentration at 
scheduled time points and/or selected PK parameters (e.g. AUC, Cmax) will be summarized by 
genetic variant groups. These analyses may be reported separately. 
In addition or instead of the 
pharmacogenomics analysis, other genetic 
analyses on the impact of genes that are thought to be related to the asciminib metabolism and 
action or disease may be performed.
12.9.3
Exploratory Efficacy
Subgroup analyses will be performed to evaluate the influence of factors such as ELTS scores, 
pre-randomization selection of TKI, gender, race and age on the primary and key secondary 
efficacy endpoints (i.e. MMR at Week 48 and MMR at Week 96 respectively).
In addition, a multivariate logistic regression analysis will incorporate the key baseline variables 
into the model to further evaluate the impact of these variables on these endpoints and to provide 
a treatment effect estimates which are adjusted for these variables. Adjusted odds ratios for the 
treatment effects with associated 95% CIs will be presented. Mantel- Haenszel estimates of the 
common odds ratios and the corresponding 95% CIs will also be provided. 
12.9.4
Exploratory Patient Reported Outcomes
Data from PROs measures collected in the study as exploratory study endpoints using the 
will also be assessed. 
will be presented descriptively by treatment 
group with summary statistics and graphical presentations. Responses to the 
 
questions will be characterized descriptively with summary statistics by visit and by treatment 
group.

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MMR rate 
at/by* 48 
weeks (n)
MMR rate 
by 96 weeks (n)
Study 
Acronym
Investigational 
Drug
Imatinib Arm 
(400mg QD)
Investigational 
Drug 
Arm
Imatinib Arm 
(400mg QD)
Investigational 
Drug 
Arm
BELA
Bosutinib 500 
mg QD
0.27 (n=252)
0.41 (n=250)
0.49 (n=252)
0.59 (n=250)
DASISION
Dasatinib 100 
mg QD
0.28* (n=260)
0.46* (n=259)
0.47 (n=260)
0.65 (n=259)
ENESTND  
Nilotinib 300 mg 
BID
0.22 (n=281)
0.44 (n=283)
0.44 (n=281)
0.71 (n=283)
BFORE: Cortes et al 2018
BELA: Cortes et al 2012
DASISION: Kantarjian et al 2010A
ENESTND: Saglio et al 2010
Random effects meta-analyses are performed using the historical published data and is 
implemented in R 3.4.3 using the package ‘Meta’ Balduzzi et al 2019 .
A random effects meta-analysis of MMR at/by Week 48 from the published data gives us 
estimated proportions (95% CI) of participants that are in MMR at Week 48 for imatinib of 0.28 
(0.23, 0.34), and for 2G TKIs of 0.44 (0.41, 0.48).
The assumption on the MMR rate at Week 48 for asciminib is based on extrapolation of data 
from the FIH CABL001X2101 study and the data from the pivotal CABL001A2301 study in 
third line patients, to the first line setting.
The proportions of participants that will achieve the primary endpoint of being in MMR at 
Week 48 are thus assumed to be:
•
0.525 for asciminib
•
0.28 for imatinib
•
0.45 for any 2G TKI
A random effects meta-analysis of MMR by Week 96 from the published data gives us 
estimated proportions (95% CI) of participants that are in MMR by Week 96 for imatinib of 
0.49 (0.44, 0.55), and for 2G TKIs of 0.66 (0.61, 0.71). A random effects meta-analysis of the 
difference in rate of MMR by Week 96 and MMR at/by Week 48, from the published data gives 
us estimated proportions (95% CI) for imatinib of 0.21 (0.17, 0.25), and for 2G TKIs of 
0.21(0.17, 0.26). Based on internal data for ENESTnd the difference between MMR by Week 
96 and MMR at week 48 is approximately 6% for imatinib and approximately 9% for nilotinib.
The proportions of participants that will achieve the secondary endpoint of MMR at Week 96 
are thus assumed to be:
•
0.635 for asciminib
•
0.43 for imatinib
•
0.56 for any 2G TKI
The study design plans for a 50% versus 50% enrollment of imatinib versus the 2G TKIs into 
the control arm.

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Therefore the proportion of participants that will achieve the primary endpoint of MMR at Week 
48 is assumed to be 0.365 for the Investigator selected TKI arm. This proportion is calculated 
as a weighted average of the 50% of participants on imatinib with the assumed proportion being 
in MMR at Week 48 of 0.28, and 50% participants on a 2G TKI with the assumed proportion 
being in MMR at Week 48 of 0.45.
Similarly the proportion of participants that will achieve the primary endpoint of MMR at Week 
96 is assumed to be 0.495 for the Investigator selected TKI arm. This proportion is calculated 
as a weighted average of the 50% of participants on imatinib with the assumed proportion being 
in MMR at Week 96 of 0.43, and 50% participants on a 2G TKI with the assumed proportion 
being in MMR at Week 96 of 0.56.
Adjustment for dropouts is not made since any participant that discontinues study treatment 
prior to Week 48 will be considered a non-responder for the end-point of MMR at Week 48; 
and any participant that discontinues study treatment prior to Week 96 will be considered a non-
responder for the end-point of MMR at Week 96.
The power for rejecting at least one of the two multiple primary hypotheses, tested according 
to the graphical gatekeeping strategy described in Section 12.7  is computed via simulations in 
R version 3.6.1 using the package “gMCP” Rohmeyer and Klinglmueller F 2020. The 
underlying distribution of test statistics in power simulations is assumed to be multivariate 
normal with the correlation matrix that is a block diagonal matrix (with correlation between the 
test statistics for H1 and H2=√0.5 and correlation between the test statistic for H3 and H4=√0.5). 
The non-centrality parameters are the standardized test statistics computed under the alternative 
assumptions.
Based on a 1-sided 2.5% level of significance, with 402 participants and 1:1 randomization 
ratio between arms (i.e. 201 participants in the asciminib arm and 201 participants in the 
Investigator selected TKI arm) we have 94.6% power to reject at least one of the null 
hypotheses from the primary family (F1={H1, H2}). At this sample size, the local power to 
reject the null hypothesis for H1 is 88.5% and local power to reject the null hypothesis for H2 
is 92.7%.
This sample size is based on 10000 simulations and from the non-centrality parameters 
computed from the assumptions that:
•
Asciminib leads to an increase over Investigator selected TKI, in the proportion of 
participants that are in MMR rate at Week 48, from 0.365 to 0.525, which corresponds to 
an odds ratio of 1.92 (for asciminib versus Investigator selected TKI).
•
Asciminib leads to an increase over imatinib, in the proportion of participants that are in 
MMR at Week 48, from 0.28 to 0.525 which corresponds to an odds ratio of 2.84 (for 
asciminib versus imatinib).
•
Asciminib leads to an increase over Investigator selected TKI, in the proportion of 
participants that are in MMR rate at Week 96, from 0.495 to 0.635, which corresponds to 
an odds ratio of 1.77 (for asciminib versus Investigator selected TKI).
•
Asciminib leads to an increase over imatinib, in the proportion of participants that are in 
MMR at Week 96, from 0.43 to 0.635 which corresponds to an odds ratio of 2.31 (for 
asciminib versus imatinib).

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The secondary end-point of Time to discontinuation due to AE will be assessed based on the 
sample size as defined for the primary endpoints. The graphical gatekeeping procedure 
described in Section 12.7 ensures preservation of the overall one-sided type I error at 0.025.
Table 12-3
Sensitivity of power to changes in the MMR assumptions (N=402)
MMR at Week 48
MMR at Week 96
Asc.
Inv. 
selec
ted 
TKI
2G 
TKIs
Ima.
Asc.
Inv. 
selec
ted 
TKI
2G 
TKIs
Ima.
Powe
r 
to rej
ect 
at lea
st 
one o
f H1 
or H2
Local
 
powe
r 
to 
reject 
H1
Local
 
powe
r
to 
reject 
H2
Local
 
powe
r
to 
reject 
H3
Local
 
powe
r
to 
reject 
H4
0.525
0.365
0.450
0.280
0.635
0.495
0.560
0.430
94.56
%
88.46
%
92.73
%
65.70
%
74.43
%
0.525
0.400
0.520
0.280
0.635
0.530
0.630
0.430
92.13
%
69.72
%
91.69
%
41.60
%
67.52
%
0.480
0.365
0.450
0.280
0.590
0.495
0.560
0.430
80.61
%
62.13
%
78.53
%
26.59
%
41.30
%
0.500
0.365
0.450
0.280
0.610
0.495
0.560
0.430
88.26
%
75.96
%
86.11
%
43.76
%
57.20
%
Asc.=asciminib; Inv.=Investigator; 2G TKIs = second generation TKIs (nilotinib/ dasatinib/ bosutinib); 
Ima.=imatinib
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, EU Clinical Trial Regulation 
536/2014 once transfer is completed, US CFR 21), and with the ethical principles laid down in 
the Declaration of Helsinki.
13.2
Responsibilities of the Investigator and IRB/IEC
Before initiating a trial, the Investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written ICF, consent form updates, participant recruitment procedures (e.g., advertisements) 
and any other written information to be provided to participants. 
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 study participants. 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 study participants.
The Investigator will be responsible for the following:

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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.
Providing oversight of the conduct of the study at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations.
Informing Novartis immediately if an inspection of the clinical site is requested by a regulatory 
authority.
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 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 once transfer to EU Clinical Trial 
Regulation 536/2014 is completed, 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/Sponsor before publication or presentation.
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Participant 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.

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Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
13.5
Data Protection
Participants will be assigned a unique identifier by Novartis/Sponsor. Any participant records 
or datasets that are transferred to Novartis/Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by 
Novartis/Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to be used 
as described in the informed consent.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis/Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Novartis/Sponsor has appropriate processes and policies in place to handle personal data 
breaches according to applicable privacy laws.
13.6
Participant Engagement
The following participant engagement initiatives are included but not limited in this study and 
will be provided, as available, for distribution to study participants at the timepoints indicated.
If compliance is impacted by cultural norms or local laws and regulations, sites may discuss 
modifications to these requirements with Novartis.
•
Thank You letter
•
Trial Feedback Questionnaires (TFQ)
•
Plain language trial summary-after CSR publication
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the Investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented.

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14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.

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Cross NC, White HE, Müller MC, et al (2012) Standardized definitions of molecular response 
in chronic myeloid leukemia. Leukemia; 26:2172-5.
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Chronic Myeloid Leukemia: Efficacy and Safety. Front Oncol; 9(603):1-10.
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16
Appendices
16.1
Appendix 1: Concomitant Medications. Prohibited medication 
and medication to be used with caution
In general, the use of any concomitant medication deemed necessary for the care of the 
participant is permitted in this study, except as specifically prohibited in Section 6.2.2 for 
participants.
The following lists are based on the internal [Pharmacokinetic Sciences memorandum on Drug-
Drug Interaction] (release date: Apr-2021), which was compiled from the Indiana University 
School of Medicine's "Clinically Relevant" Table and supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies - Study Design, Data Analysis, and 
Implications for Dosing and Labeling (2017), and the University of Washington's Drug 
Interaction Database (2017). These lists are not comprehensive and are only meant to be used 
as a guide. Please contact the medical monitor with any question. 
Table 16-1
Concomitant medications to be used with caution
Category
Drug Names
Torsade de pointe (TdP) 
TdP/QT risk: Known
amiodarone, anagrelide, arsenic trioxide, astemizole (off us mkt), azithromycin, 
bepridil (off us mkt), chloroquine, chlorpromazine, cilostazol, cisapride (off us 
mkt), citalopram, clarithromycin, cocaine, disopyramide, dofetilide, domperidone 
(not on us mkt), donepezil, dronedarone, droperidol, erythromycin, 
escitalopram, flecainide, fluconazole, grepafloxacin (off market worldwide), 
halofantrine, haloperidol, ibutilide, levofloxacin, levomethadyl (off mkt 
worldwide), mesoridazine (off mkt worldwide), methadone, moxifloxacin, 
ondansetron, oxaliplatin, papaverine HCl, pentamidine, pimozide, probucol (off 
mkt worldwide), procainamide (oral off us mkt), propofol, quinidine, sevoflurane, 
sotalol, sparfloxacin (off us mkt), sulpiride (not on us mkt), terfenadine (off us 
mkt), thioridazine, vandetanib
TdP/QT risk: Possible1
alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine, asenapine, 
bedaquiline, bortezomib, buprenorphine, capecitabine, ceritinib, clomipramine, 
clozapine, crizotinib, cyamemazine (cyamepromazine) (Only on Non US 
Market), dabrafenib, dasatinib, degarilix, delamanid (off US mkt), desipramine, 
dexmedetomidine, dolasetron, eribulin, ezogabine, famotidine, felbamate, 
fingolimod, foscarnet, gemifloxacin, granisetron, hydrocodone extended-
release, iloperidone, imipramine (melipramine), isradipine, lapatinib, lenvatinib, 
leuprolide, lithium, mifepristone, mirabegron, mirtazapine, moexipril/hctz, 
nicardipine, nilotinib, norfloxacin, nortriptyline, ofloxacin, olanzapine, 
osimertinib, oxytocin, paliperidone, panabinostat, pasireotide, pazopanib, 
perflutren lipid microspheres, pipamperone (not on us mkt), promethazine, 
quetiapine, ranolazine, rilpivirine, risperidone, roxithromycin (on non us mkt), 
saquinavir, sertindole (on non us mkt), sorafenib, sunitinib, tacrolimus, 
tamoxifen, telavancin, telithromycin, tetrabenazine  
(orphan drug in us), tizanidine, tolterodine, toremifene, trimipramine, vardenafil, 
vemurafenib, venlafaxine, vorinostat, zotepine
TdP/QT risk: 
Conditional1
amantadine, amisulpride, amitriptyline, atazanavir, chloral hydrate, 
diphenhydramine, doxepin, fluoxetine, furosemide (frusemide), galantamine, 
hydrochlorothiazide, hydroxyzine, hydroxychloroquine, indapamide, 
itraconazole, ivabradine (on non us mkt), ketoconazole, loperamide, 
metoclopramide, metronidazole, nelfinavir, pantoprazole, paroxetine, 
posaconazole, quinine sulfate, ritonavir, sertraline, solifenacin, telaprevir, 
torsemide, trazodone, voriconazole, ziprasidone 
Strong inducers of 
CYP3A4/5
carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, 
rifabutin, rifampicin, St. John’s wort (Hypericum perforatum)

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Category
Drug Names
Narrow Therapeutic 
index substrates of 
CYP2C9
phenytoin, warfarin (also sensitive)
Narrow Therapeutic 
index substrates of 
CYP3A4/5
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus, 
terfanadine,
OATP1B substrates
aliskiren, ambrisentan, anacetrapib, atenolol, asunaprevir, atogepant, atorvastatin, 
bosentan, bromocriptine, caspofungin, celiprolol, danoprevir, digoxin, docetaxel, 
eliglustat, empangliflozin, ezetimibe, fimasartan, fexofenadine, fluvastatin, 
glyburide, ibrexafungerp, maraviroc, methotrexate, montelukast, nateglinide, 
olmesartan, paclitaxel, pirataprevir, pitavastatin, pravastatin, repaglinide, 
revefenacin, rifampicin, rosuvastatin, saquinavir, simvastatin, telmisartan, 
tezacaftor, ticlopidine, valsartan
BCRP substrates
alpelisib, atorvastatin, baricitinib, daunorubicin, dolutegravir, doxorubicin, 
hematoporphyrin, imatinib, methotrexate, mitoxantrone, ozanimod, paritaprevir, 
pitavastatin, rimegepant, rosuvastatin, irinotecan, ethinyl estradiol, simvastatin, 
sofosbuvir, sulfasalazine, tenofovir, tezacaftor, topotecan, ubrogepant, venetoclax
1Check: crediblemeds.org/healthcare-providers/drug-list for the most updated list. This list gets updated periodically. 
Kindly refer to the above links for latest information.
16.2
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements
Table 16-2
Liver event and laboratory trigger definitions
 
Definition/ threshold
Liver laboratory 
triggers
If ALT, AST and 
total bilirubin normal 
at baseline:
•
ALT or AST > 5 × ULN
•
ALP > 2 × ULN (in the absence of known bone pathology)
•
TBL > 3 × ULN (in the absence of known Gilbert syndrome)
•
ALT or AST > 3 × ULN and INR > 1.5
•
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBL > 2 × ULN 
[mainly conjugated fraction] without notable increase in ALP to > 2 × ULN)
•
Any clinical event of jaundice (or equivalent term)
•
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia
•
Any adverse event potentially indicative of a liver toxicity
If ALT or AST 
abnormal at 
baseline:
•
ALT or AST > 3x baseline or > 300 U/L (whichever occurs first)
Table 16-3
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia
Criteria
Actions required
Follow-up monitoring
Total Bilirubin (isolated)
 
 
>1.5 – 3.0 ULN
•
Maintain treatment
•
Repeat liver tests within 48-72 hours
Monitor liver tests weekly until 
resolution to ≤ Grade 1 or to 
baseline
> 3 - 10 × ULN (in the 
absence of known Gilbert 
syndrome)
•
Interrupt treatment
•
Repeat liver tests within 48-72 hours
•
Hospitalize if clinically appropriate
•
Establish causality
Monitor liver tests weekly until 
resolution to ≤ Grade 1 or to 
baseline (ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT)

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Criteria
Actions required
Follow-up monitoring
•
Record the AE and contributing 
factors (e.g. conmeds, med hx, lab) in 
the appropriate CRF
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 10 x ULN
•
Discontinue the study treatment 
immediately
•
Hospitalize the participant
•
Establish causality
•
Record the AE and contributing 
factors(e.g. conmeds, med hx, lab)in 
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolution 
(frequency at Investigator 
discretion)
Any AE potentially 
indicative of a liver toxicity
•
Consider study treatment interruption 
or discontinuation
•
Hospitalization if clinically appropriate
•
Establish causality
•
Record the AE and contributing 
factors(e.g., conmeds, med hx, lab)in 
the appropriate CRF
Based on Investigator’s discretion 
investigation(s) for contributing 
factors for the liver event can 
include: Serology tests, imaging 
and pathology assessments, 
hepatologist’s consultancy; 
obtaining more detailed history of 
symptoms and prior or concurrent 
diseases, history of concomitant 
drug use, exclusion of underlying 
liver disease.

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16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-4
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase 25 – 49% compared to 
baseline
Confirm 25% increase after 24-48h
Follow up within 2-5 days
Acute Kidney Injury: Serum creatinine increase ≥ 
50%+ compared to baseline
Follow up within 24-48h if possible
Consider study treatment interruption
Consider participant hospitalization /specialized 
treatment
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed
Monitor participant regularly (frequency at Investigator’s discretion) until either:
Event resolution: sCr within 10% of baseline, or
Event stabilization: sCr level with ±10% variability over last 6 months
+ Corresponds to KDIGO criteria for Acute Kidney Injury
16.4
Appendix 4: Eligibility based on serologic markers for hepatitis B 
and C
Table 16-5
Eligibility based on serologic marker for hepatitis B and C 
Test
Result
HBsAg
+
-
-
-
-
HBcAb
Any
+
-
+
-
HBsAb
Any
-
+
+
-
HCV Ab
Any
Any
-
-
-
Eligibility
Not Eligible
Indeterminate
Eligible
Eligible
Eligible
If indeterminate results are obtained, viral DNA (hepatitis B) or RNA (hepatitis C)
should be measured to confirm negative viral status.
HBsAg positive: Indicates active infection and risk for reactivation with fulminant hepatitis. 
These subjects are not eligible for the trial.
HBcAb positive: As a standalone marker it can indicate four possibilities: Resolved infection 
(Immune due to natural infection), false-positive anti-HBc (susceptible for infection), low level 
chronic infection and resolving acute infection
HBV-DNA should be performed if only HBcAb is positive at screening and if positive then 
the subjects are not eligible for the trial. Even if HBV-DNA is negative suggesting resolved 
infection, there is still a risk for HBV reactivation. In these cases, HBV-DNA should be 
monitored on a monthly basis to detect HBV reactivation.
Both HBcAb and HBsAg are positive Indicates active infection and risk for reactivation with 
fulminant hepatitis. These subjects are not eligible for the trial. Hence HBV-DNA testing is not 
necessary. 

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HBsAb positive: As a standalone marker, it indicates successful vaccination or previous 
infection that has been successfully resolved if the only positive finding. These subjects are 
eligible for the trial.
HBsAg negative, HBcAb positive, HBsAb positive: Resolved or latent infection. These
subjects are eligible for this trial, however, they are at risk for viral reactivation 
HCV Ab positive: Indicates active infection and risk for reactivation. These subjects are not 
eligible for the trial.
All markers negative: No prior exposure or vaccination to hepatitis B and no prior exposure 
to Hepatitis C. Subjects are eligible for the trial.