Conditions: Chronic Myelogenous Leukemia - Chronic Phase
Keywords: CML T315I mutation CP Asciminib, BCR-ABL, ABL001, CML-AP, ELN MMR Molecular Response MR4.5 MR4 RQ-PCR AIM4CML, tyrosine Kinase Inhibitor TKI adult
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 56
Healthy volunteers: no

Brief summary:
This study was a multicenter Phase IIIb open-label, three-cohort study of asciminib in patients with CML-CP without T315I mutation who have had at least 2 prior TKIs and CML-CP harboring the T315I mutation with at least 1 prior TKI

Detailed description:
This trial consisted of three periods: screening and baseline for up to 21 days, active treatment for up to 72 weeks and a safety follow up period for 30 days.

One hundred and fifteen (115) patients with chronic myeloid leukemia in chronic phase (CML-CP) without T315I mutation who have had at least 2 prior Tyrosine Kinase Inhibitors (TKIs) and CML-CP with the T315I mutation with at least 1 prior TKI were planned for this study, however the study was finally completed with 56 participants due to enrollment issues.

Informed consent was obtained before any procedures were performed for the study including eligibility assessments. The results of the real time quantitative polymerase chain reaction (RQ-PCR) must be available prior to randomization and first dose of study treatment.

Patients with CML-CP without T315I mutation were randomly assigned to either cohort A or B. Patients with the T315I mutation were enrolled in cohort C. During treatment period asciminib was taken orally: Cohort A was administered 40 mg twice a day, Cohort B was administered 80 mg once a day and Cohort C was administered 200 mg twice a day. The patients were treated up to end of study treatment period defined as up to 72 weeks after the last patient receives the first dose. Patients may have been discontinued from treatment with the study drug at any time due to unacceptable toxicity, disease progression and/or at the discretion of the investigator or the patient.

Arms:
arm 1: 40 mg asciminib orally twice daily (BID) arm 2: 80 mg asciminib orally once daily (QD) arm 3: 200 mg asciminib orally twice daily (BID)

Interventions: intervention 1: ABL001
Intervention descriptions: intervention 1: Asciminib will be supplied as 20 mg or 40 mg strength tablets will be administered orally in accordance with the assigned cohort.

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
ABL001/Asciminib
Clinical Trial Protocol CABL001AUS04 / NCT04666259
An open label, multi-center Phase IIIb study of asciminib 
(ABL001) monotherapy in previously treated patients with 
chronic myeloid leukemia in chronic phase (CML-CP) with 
and without T315I mutation (AIM4CML)
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
Not Applicable
Version number:
03 (clean)
Clinical Trial Phase:
IIIb
Release date:
23-Mar-2022 (content 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 (31-Jan-2020)


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Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................5
List of figures.......................................................................................................................6
List of abbreviations ............................................................................................................7
Glossary of terms...............................................................................................................12
Protocol summary..............................................................................................................21
1
Introduction........................................................................................................................27
1.1
Background............................................................................................................27
1.1.1
Overview of disease pathogenesis, epidemiology and current 
treatment................................................................................................27
1.1.2
Introduction to investigational treatment...............................................28
1.2
Purpose...................................................................................................................34
2
Objectives and endpoints...................................................................................................34
3
Study design.......................................................................................................................35
4
Rationale ............................................................................................................................36
4.1
Rationale for study design......................................................................................36
4.2
Rationale for dose/regimen and duration of treatment...........................................37
4.3
Purpose and timing of interim analyses/design adaptations ..................................39
4.4
Risks and benefits ..................................................................................................40
5
Study Population................................................................................................................40
5.1
Inclusion criteria ....................................................................................................41
5.2
Exclusion criteria ...................................................................................................42
6
Treatment...........................................................................................................................44
6.1
Study treatment ......................................................................................................44
6.1.1
Asciminib Dosing Regimen ..................................................................44
6.1.2
Investigational drugs .............................................................................45
6.1.3
Additional study treatments...................................................................45
6.1.4
Treatment Cohorts.................................................................................45
6.1.5
Guidelines for continuation of treatment...............................................45
6.1.6
Treatment duration ................................................................................46
6.2
Other treatment(s) ..................................................................................................46
6.2.1
Concomitant therapy .............................................................................46
6.2.2
Prohibited medication............................................................................47
6.2.3
Rescue medication.................................................................................48
6.2.4
Other Concomitant medications............................................................48
6.3
Participant numbering, treatment assignment, randomization...............................49


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6.3.1
Participant numbering ...........................................................................49
6.3.2
Treatment assignment............................................................................49
6.4
Treatment blinding.................................................................................................49
6.5
Dose escalation and dose modification..................................................................50
6.5.1
Dose escalation guidelines ....................................................................50
6.5.2
Dose modifications................................................................................50
6.5.3
Follow-up for toxicities.........................................................................59
6.6
Additional treatment guidance...............................................................................60
6.6.1
Treatment compliance ...........................................................................60
6.6.2
Emergency breaking of assigned treatment code ..................................61
6.6.3
Special Considerations for COVID-19 infection ..................................61
6.7
Preparation and dispensation .................................................................................61
6.7.1
Handling of study treatment and additional treatment ..........................61
6.7.2
Instruction for prescribing and taking study treatment..........................62
7
Informed consent procedures.............................................................................................62
8
Visit schedule and assessments..........................................................................................63
8.1
Screening................................................................................................................72
8.1.1
Eligibility screening...............................................................................72
8.1.2
Information to be collected on screening failures .................................73
8.1.3
Treatment Period ...................................................................................73
8.1.4
Visit Windows.......................................................................................73
8.2
Participant demographics/other baseline characteristics........................................73
8.3
Safety and tolerability............................................................................................74
8.3.1
Laboratory Evaluations .........................................................................75
8.3.2
Cardiac Assessments .............................................................................77
8.3.3
Pregnancy and assessments of fertility..................................................79
8.3.4
Other safety evaluations ........................................................................80
8.3.5
Appropriateness of safety measurements ..............................................80
8.4
Efficacy..................................................................................................................80
8.4.1
Molecular Response ..............................................................................80
8.4.2
Hematologic Response..........................................................................82
8.5
Additional assessments ..........................................................................................83
83
83
8.5.3
Biomarkers ............................................................................................84
8.5.4
Imaging..................................................................................................85


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85
9
Study discontinuation and completion...............................................................................86
9.1
Discontinuation and completion ............................................................................86
9.1.1
Study treatment discontinuation and study discontinuation..................86
9.1.2
Withdrawal of informed consent...........................................................87
9.1.3
Lost to follow-up...................................................................................88
9.1.4
Early study termination by the sponsor.................................................88
9.2
Study completion and post-study treatment...........................................................88
10 Safety monitoring and reporting........................................................................................89
10.1
Definition of adverse events and reporting requirements......................................89
10.1.1
Adverse events.......................................................................................89
10.1.2
Serious adverse events...........................................................................91
10.1.3
SAE reporting........................................................................................92
10.1.4
Pregnancy reporting...............................................................................92
10.1.5
Reporting of study treatment errors including misuse/abuse ................93
10.2
Additional Safety Monitoring................................................................................93
10.2.1
Data Monitoring Committee..................................................................93
10.2.2
Steering Committee...............................................................................94
10.2.3
Adjudication committee ........................................................................94
11 Data Collection and Database management ......................................................................94
11.1
Data collection .......................................................................................................94
11.2
Database management and quality control ............................................................94
11.3
Site monitoring.......................................................................................................95
12 Data analysis and statistical methods.................................................................................96
12.1
Analysis sets...........................................................................................................96
12.1.1
Full Analysis Set (FAS).........................................................................96
12.1.2
Safety Set (SS).......................................................................................96
12.1.3
Per-Protocol Set (PPS) ..........................................................................96
96
12.1.5
Other analysis sets.................................................................................97
12.1.6
Efficacy/evaluable set............................................................................97
12.2
Participant demographics and other baseline characteristics.................................97
12.3
Treatments..............................................................................................................97
12.4
Primary objective / analysis of the primary endpoint(s)........................................97
12.4.1
Statistical hypothesis, model, and method of analysis ..........................97
12.4.2
Handling of missing values/censoring/discontinuations .......................97


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12.4.3
Supportive analyses...............................................................................97
12.5
Secondary objectives / analysis of secondary endpoints .......................................98
12.5.1
Secondary objective(s) ..........................................................................98
12.5.2
Secondary objectives.............................................................................98
100
100
101
12.7
Safety objectives ..................................................................................................101
12.7.1
Analysis set and grouping for the analyses .........................................101
12.7.2
Adverse events (AEs)..........................................................................101
12.7.3
Laboratory abnormalities.....................................................................102
12.7.4
Other safety data..................................................................................102
102
103
12.8
Interim analysis....................................................................................................103
12.9
Sample size calculation........................................................................................103
13 Ethical considerations and administrative procedures.....................................................104
13.1
Regulatory and ethical compliance......................................................................104
13.2
Responsibilities of the investigator and IRB/IEC................................................104
13.3
Publication of study protocol and results.............................................................104
13.4
Quality Control and Quality Assurance...............................................................105
14 Protocol adherence...........................................................................................................105
14.1
Protocol amendments...........................................................................................105
15 References........................................................................................................................106
16 Appendices.......................................................................................................................109
16.1
Appendix 1 List of concomitant medications for patients on asciminib..............109
List of tables
Table 6-1
Investigational and control drug............................................................45
Table 6-2
Criteria for dose reduction / interruption and re-initiation of 
asciminib treatment for adverse drug reactions.....................................50
Table 6-3
Dose reduction steps for asciminib........................................................58
Table 6-8 
Provides guidance on specific clinical and diagnostic assessments 
that can be performed to rule out possible alternative causes of 
observed LFT abnormalities..................................................................60
Table 8-1
Assessment schedule .............................................................................64
Table 8-2
ECG collection plan ..............................................................................77


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Table 8-3
Blood samples (efficacy secondary endpoint).......................................82
Table 8-4
Assessments...........................................................................................74
Table 8-5
Table ECOG Performance Status Scale ................................................75
Table 8-6 
Clinical laboratory parameters collection plan......................................76
84
85
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse..........................................................................................93
Table 16-1
Prohibited concomitant medications for asciminib.............................109
Table 16-2
Concomitant medications to be used with caution..............................110
List of figures
Figure 1-1
KCL-22 CML Xenograft.......................................................................29
Figure 3-1
Study design ..........................................................................................36
Figure 4-1
Pharmacokinetic data of 40 mg BID and 80 mg QD.............................38
Figure 4-2
Comparison of the effects of Asciminib with those of ATP-
competitive BCR-ABL inhibitors approved for the treatment of 
CML on Luc-Ba/F3 cells engineered to express drug-resistant 
BCR-ABL mutants................................................................................39


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
List of abbreviations
ABL
Abelson proto-oncogene
ADME
Absorption, Distribution, Metabolism, and Excretion
AE
Adverse Event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute neutrophil count
AP
Accelerated phase
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATP
Adenosine triphosphate
AUC
Area under the curve
AV
block Atrioventricular block
b.i.d.
bis in die/twice a day
BC
Blast crisis
BCR
Breakpoint Cluster Region gene
BCR-ABL
BCR-ABL fusion gene (also called the Philadelphia chromosome)
BCRP
Breast Cancer Resistant Protein
BID
bis in diem/twice a day
BLRM
Bayesian Logistic Regression Model
BMA
Bone marrow aspirate
BMI
Body Mass Index
BUN
Blood urea nitrogen
CBC
Complete Blood Count
CCA
Clonal chromosome abnormalities
CCyR
Complete Cytogenetic Response
CD34
Cluster of differentiation 34
CD8
Cluster of differentiation 8
CDP
Clinical Development Plan
CDS
Core Data Sheet
CHR
Complete Hematological Response
CI
Confidence Interval
CK
Creatinine Kinase
ClinRO
Clinician Reported Outcomes
CML
Chronic Myelogenous Leukemia
CML-AP
Chronic Myelogenous Leukemia-Accelerated Phase
CMO&PS 
Chief Medical Office and Patient Safety
CO
Country Organization
CO2
carbon dioxide


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CP
Chronic phase
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSP
Clinical study protocol
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
CYP3A4
Cytochrome P450 3A4
DBP
Diastolic Blood Pressure
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DIN
Drug Inducted Nephrotoxicity
DLCO
Carbon monoxide diffusing capacity
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DQF
Data Query Form
DS&E
Drug Safety and Epidemiology
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCOA
Electronic Clinical Outcome Assessment
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic data capture
ELISA
Enzyme-linked immunosorbent assay
ELN
European Leukemia Network
EOI
End of Infusion
EOT
End of Treatment
ERT
Electronic Research Technology, Inc
eSAE
Electronic Serious Adverse Event
eSource
Electronic Source
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
FIH
First In Human
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GDPR
General Data Protection Regulation
GFR
Glomerular Filtration Rate
GGT
Gamma-glutamyl transferase


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h
Hour
hADME
Human ADME study (Absorption, Distribution, Metabolism and Excretion)
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDL
High density lipoprotein
HED
Human Equivalent Dose
HEOR
Health Economics & Outcomes Research 
HIV
Human immunodeficiency virus
HNSTD
Highest Non-Severely Toxic Dose
i.v.
intravenous
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IN
Investigator Notification
INN
International Nonproprietary Name
INR
International normalized ratio
IWRS
Interactive Web Response System
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System 
and
Km
Michaelis-Menten constant
K-M
Kaplan-Meyer
LDH
lactate dehydrogenase
LDL
Low density lipoprotein
LFT
Liver function test 
LLN
Lower limit of normal
LLOQ
lower limit of quantification
LSC
Leukemia stem cell
MCyR
Major Cytogenetic Response
mCyR
Minor Cytogenetic Response
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
mL
milliliter(s)
MMR
Major Molecular Response
MRI
Magnetic resonance imaging


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MRSD
Maximum Recommended Starting Dose
MTD
Maximum Tolerated Dose
Nab
Neutralizing antibody
NCCN
National Comprehensive Cancer Network
NCDS
Novartis Clinical Data Standards
NOVDD
Novartis Data Dictionary
NTI
Narrow Therapeutic Index
ObsRO
Observer Reported Outcomes
OS
Overall survival
p.o.
oral(ly)
PBPK
Physiologically based pharmacokinetic
PCR
Polymerase Chain Reaction
PCyR
Partial Cytogenetic Response
PD
Pharmacodynamic(s)
PerfO
Performance Outcomes
P-gp
Permeability glycoprotein
Ph+
Philadelphia chromosome positive
PHI
Protected Health Information
PK
Pharmacokinetic(s)
PLT
Platelets
PPD
Premature Participant Discontinuation
PPS
Per-protocol set
PSD
Premature Subject Discontinuation
PT
prothrombin time
QD
Quaque die/once a day
QMS 
Quality Management System
QT
Q to T interval (ECG)
QTcF
QT interval corrected by Fridericia’s formula
R Value
ALT/ALP x ULN
RAP
The Report and Analysis Plan 
RBC
red blood cell(s)
RDC
Remote Data Capture
RDE
Recommended dose for expansion
REB
Research Ethics Board
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic acid
RoW 
Rest of World
RP2D
Recommended phase two dose


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RQ-PCR
Real time quantitative polymerase chain reaction
s.c.
subcutaneous
SAE
Serious Adverse Event
SAP
The Statistical Analysis Plan (SAP) is a regulatory document which provides evidence 
of preplanned analyses
SBP
Systolic Blood Pressure
SC
Steering committee
sCR
serum creatinine
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBIL
Total bilirubin
TD
Study Treatment Discontinuation
TdP
Torsades de Pointes
TKI
Tyrosine Kinase Inhibitor
TTF
Time to treatment failure
UGT
Uridin diPhospho-glucuronosyltransferase
ULN
Upper limit of normal
ULQ
upper limit of quantification
US
United States
USPI
US prescribing information
UTI
Urinary Tract Infection
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 
Cohort
A specific group of participants fulfilling certain criteria and generally treated at 
the same time
Control drug
A study drug (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)
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 paper source forms 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 
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to sponsors and 
other oversight authorities, as appropriate
Estimand 
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 patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable.
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
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 


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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 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.
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 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 
number
A unique identifier assigned to each randomized participant
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 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
Study treatment 
discontinuation
When the participant permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation 
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 


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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.
Victim drug 
The drug that is affected by the drug-drug interaction
Withdrawal of 
study consent 
(WoC)
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data 


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
Amendment 3 (22-Mar-2022)
At the time of this amendment 25 patient have been enrolled for the study
The primary purpose of this amendment is:
Per FDA guidance, the cohort allocation and asciminib dosage depends on T315I mutational 
status, and to ensure that patients with T315I negative status did not develop a detectable T315I 
mutation post mutation analysis and prior to receiving asciminib. Novartis recognizes that, in 
order to ensure patients have not acquired a new kinase domain mutation, such as T315I, before 
study drug treatment, eligible patients will now require having kinase domain mutation testing 
at Baseline. 
To clarify and address inclusion and exclusion criteria and assessment schedule as listed below
Other administrative edits and typographical corrections are also applied throughout the 
protocol.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Protocol Summary: updated Key Inclusion criteria # 3

Section 5.1: updated Key Inclusion criteria # 3

Section 6.2.4: updated contraceptives language

Table 6-2: updated CTCAE grade from 4.03 to 5

Table 6-2: update Investigations (Hepatic) parameters to match CTCAE Version 5

Table 8-1: Added footnote in Echocardiogram, Pulmonary Function test, 
 

Section 8.1: removed coagulation from Screening

Section 8.1.4: amended week 1 day 1 and week 36 for visit window 

Section 8.3.2.1: added medical monitor 

Section 8.3.2.2: updated title and language


Section 9.1.1: updated treatment failure with ELN criteria

corrected table 9-4 to table 8-7 and table 9-5 to table 8-8

IRBs/IECs

A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.

The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
Amendment 2 (27-Jan-2021) 
Amendment rationale 
At the time of this amendment, there has been no patient enrolled for the study.
The primary purpose of this amendment is:
To prohibit the use of strong CYP3A inhibitors for patients with Ph+ CML-CP harboring the 
T315I mutation receiving asciminib 200 mg BID.
To prohibit the use of  strong CYP3A inducers for all patients in study CABL001AUS04.
To clarify the eligibility criteria regarding the inclusion of patients with mild and moderate 
hepatic impairment in the protocol as follows: Include patients with mild and moderate hepatic 
impairment with total bilirubin ≤ 3.0 x ULN with any AST increase.
Other minor edits and typographical corrections are also applied throughout the protocol.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Section 5.1: Amend inclusion criteria # 9: Inclusion of patients with mild and moderate 
hepatic impairment with total bilirubin ≤ 3.0 x ULN with any AST increase.

Section 5.1: Amended inclusion criteria # 9: Remove the inclusion criteria “Aspartate 
transaminase (AST) ≤ 5.0 x ULN”, “Alanine transaminase ≤ 5.0 x ULN” and “Alkaline 
Phosphatase ≤ 2.5 x ULN

Section 5.1: Remove inclusion criteria # 11

Section 5.2: Added exclusion criteria # 10

Section 6.2.1.1: Updated language for permitted concomitant therapy requiring caution 
and/or action

Section 6.2.2: Updated language for prohibited medication

 

Table 8-4: Removed week 2 day 1 from Physical examination under Assessment 

Section 8.3.2.1: Replaced ERT with central ECG Reader.

Table 16-1: added strong CYP3A inducer and CYP3A inhibitor names in the table

Added Table 16-2 Concomitant medications to be used with caution 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
Amendment 1 (08-Dec-2020) 
Amendment rationale 
At the time of this amendment, there has been no patient enrolled for the study.
The primary purpose of this amendment is:
 
 
  
 
 
 
 
 
 
 
 
Include patients with mild to moderate renal or hepatic impairment in the study. Based on the 
results from the dedicated hepatic (CABL001A2103) and renal (CABL001A2105) impairment 
studies that have already been completed with asciminib, no dose adjustments are needed.
Other minor edits and typographical corrections are also applied throughout the protocol.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Title page: Added AIM4CML name of the study

Section 1.2.2.2: Added a sentence to refer to Asciminib Investigator’s Brochure

Section 2: Clarified the primary endpoint to laboratory evaluation for 24 weeks

Section 2: Clarified the secondary endpoint to laboratory evaluation for 24 weeks

 

Figure 3.1: Updated study design

Section 4.1: Added a sentence to refer to Asciminib Investigator’s Brochure

Section 5.1: Inclusion # 9 Updated renal and hepatic impairment inclusion criteria

Section 5.1: Inclusion # 10 Added use of CYP3A with caution 

Section 5.2: Exclusion # 6 Updated renal and hepatic impairment exclusion criteria

Section 5.2: Exclusion # 10 removed exclusion to use of CYP3A


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
Section 6.2.1.1: Update language for using CYP3A with caution

Section 6.2.2: Removed prohibition of CYP3A inhibitors paragraph

Section 6.7: Updated language from Investigator staff to IRT




Table 8-1: Clarified progression status to be captured on EOT/Early Discontinuation

Section 8.1: Clarified a new patient ID will be assigned to re-screening patients

Section 8.3.3: Formatted the last paragraph

Section 8.4.2: Clarified local hematologic responses

 


 
 
 

 



Section 11.1: Updated data collection 

Section 12.4.2: Clarified supportive analyses to be done for patient (< 65 years; ≥ 65 years)



Section 15: Added new reference

Table 16.1: Updated table as per inclusion # 9 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
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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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
Protocol summary
Protocol 
number
CABL001AUS04
Full Title
An open label, multi-center Phase IIIb study of asciminib (ABL001) monotherapy 
in previously treated patients with chronic myeloid leukemia in chronic phase 
(CML-CP) with and without T315I mutation 
Brief title
A Phase IIIb study of asciminib in CML-CP with and without T315I mutation
Sponsor and 
Clinical Phase
Novartis/ Phase IIIb Study
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
Asciminib (ABL001) is a potent BCR-ABL1 allosteric inhibitor currently being 
developed by Novartis for the treatment of CML (Chronic Myelogenous 
Leukemia). Unlike drugs such as imatinib, nilotinib, dasatinib, bosutinib and 
ponatinib, which bind to the ATP-site of the ABL kinase domain, asciminib binds 
to the myristoyl pocket and consequently, restores the negative regulation of the 
kinase activity1. Given this unique mechanism of action, it has been proven to 
have activity against BCR-ABL1 mutations that are known to confer resistance to 
the ATP site TKIs (tyrosine kinase inhibitors)1. Moreover, the selective binding of 
asciminib is predicted to reduce toxicities, which is an encouraging feature for 
patients where side effects from previous treatments were the reason for drug 
discontinuation.
Based on phase I data, asciminib has been proven safe and effective in patients 
who had more than 2 lines of therapy, with 32% and 44% of those achieving 
MMR in 6 and 12 months, respectively2. The incidence of grade 3/4 treatment 
emergent AEs were mostly less than 10%, which implies a favorable safety 
profile in a heavily pre-treated CML population. 
The ongoing ASCEMBL study is a phase III study, which is investigating the 
efficacy of treatment with asciminib versus bosutinib in CML-CP patients with at 
least 2 prior TKI therapies. Data from this study are expected to be presented at 
an upcoming medical meeting and results will be shared with regulatory 
authorities. 
Despite its phase III design with randomization, questions remain such as safety 
and efficacy on a larger patient population including those harboring the T315I 
mutation and of a daily dosing schedule. A once daily regimen could be more 
convenient as we believe it will greatly improve patient’s adherence as well as 
quality of life. For that dosing schedule, the dose of 80 mg was selected based 
on similar efficacy and safety profile when compared to 40 mg twice daily from 
early phase data. 
The study currently proposed is a phase IIIb open-label study on patients with 
resistant or intolerant CML-CP previously treated with at least 2 prior TKIs in the 
absence of T315I mutation and at least 1 prior TKI in the presence of the T315I 
mutation. Our goal is to gain further efficacy and safety data with asciminib 
monotherapy on a larger population of patients. 
The study will contain the following cohorts:
Cohort A asciminib 40 mg BID
Cohort B asciminib 80 mg QD
Cohort C asciminib 200 mg BID, exclusively for those harboring the T315I 
mutation 


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
As above, patients with CML-CP without the T315I mutation will be randomly 
assigned to either cohort A or B (both primary). Randomization into those 2 
cohorts will be pursued to eliminate selection bias at the time of patient 
allocation. Additionally, there will be a separate cohort enrolling patients 
harboring the T315I mutation to strengthen the body of evidence generated in 
the CABL001X2101 study, which has already treated 58 patients with that 
mutation in the asciminib extension cohort at 200 mg BID showing encouraging 
antileukemic activity and well tolerated safety profile.
Primary 
Objective(s) 

To evaluate safety profile of monotherapy asciminib in CML-CP in 3L 
and beyond, for Cohorts A and B
Secondary 
Objectives

To estimate the rate of patients with molecular response at specific time 
points for Cohort A ,B and C 

To estimate time to molecular response

To evaluate the duration of hematologic and molecular response
Study design
This study will be a multicenter Phase IIIb study of randomized open-label 
asciminib in patients with CML without T315I mutation who have had at least 2 
prior TKIs and CML-CP with T315I mutation with at least 1 prior TKI. The primary 
outcome is to evaluate the safety profile of asciminib with AEs, SAEs and 
laboratory studies’ assessment at 24 weeks of therapy. The secondary endpoints 
will include efficacy and safety measures at 12, 24, 48, 72 weeks of therapy.
For patients without T351I mutation, they will be randomly assigned to the 
following cohorts:
Cohort A (45) where patients will be given asciminib at 40 mg twice daily
Cohort B (45) where patients will receive asciminib at 80 mg daily
Data from CABL001X2101 study showed encouraging efficacy and safety findings 
in 40 mg twice daily and 80 mg daily-treated patients. 
 Cohort C (25), patients harboring the T315I mutation will be treated on the 
dose of 200 mg twice daily. The higher dose required for that patient 
population related to its required concentration to attain optimal blockade 
of the kinase activity2. Patients will continue therapy until disease 
progression, unacceptable toxicity or elective treatment discontinuation. 
Study 
population
One hundred and fifteen (115) patients with CML-CP without T315I mutation who 
have had at least 2 prior TKIs (90 patients) and CML-CP harboring the T315I 
mutation (25 patients) with at least 1 prior TKI will be considered for the current 
study. Patients with a medical history of the T315I mutation at study entry will be 
included in the trial. Previous medical records should be used to confirm the 
patient’s mutational status/history.
Key Inclusion 
criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1.
Written informed consent must be obtained and signed prior to participation 
in the study
2.
Male or female patients with a diagnosis of CML-CP ≥ 18 years of age
3.
Patients must meet all of the following laboratory values at the screening visit:

< 15% blasts in peripheral blood or bone marrow

< 30% blasts plus promyelocytes in peripheral blood or bone marrow

< 20% basophils in the peripheral blood

≥ 50 x 109/L (≥ 50,000/ mm3) platelets

Transient prior therapy related thrombocytopenia (< 50,000/mm3 for ≤ 
30 days prior to screening) is acceptable


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
No evidence of extramedullary leukemic involvement, with the exception 
of hepatosplenomegaly
4.
Mutation Analysis testing performed at screening
5.
Prior treatment with a minimum of:

2 prior ATP-site TKIs (i.e. imatinib, nilotinib, bosutinib, dasatinib or 
ponatinib) in case of absence of T315I mutation

1 prior ATP site TKI (i.e. imatinib, nilotinib, bosutinib, dasatinib or 
ponatinib) in case of presence of T315I mutation
6.
Failure (adapted from the 2020 ELN Recommendations) or intolerance to the 
most recent TKI therapy at the time of screening

Failure for CML-CP patients (CP at the time of initiation of last therapy) 
is defined as meeting at least one of the following criteria.

Three months after the initiation of therapy: >10% BCR-ABL1 on 
International Scale (IS) if confirmed within 1-3 months

Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS 

Twelve months after initiation of therapy: BCR-ABL1 ratio > 1% IS 

At any time after the initiation of therapy, loss of CHR, MR2

At any time after the initiation of therapy, the development of new 
BCR-ABL1 mutations which potentially cause resistance to current 
treatment

At any time 12 months after the initiation of therapy, BCR-ABL1 
ratio ≥ 1% IS or loss of MMR

At any time after the initiation of therapy, new clonal chromosome 
abnormalities in Ph+ cells: CCA/Ph+

Intolerance is defined as:

Non-hematologic intolerance: Patients 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 patient if 
response is already suboptimal)

Hematologic intolerance: Patients with grade 3 or 4 toxicity 
(absolute neutrophil count [ANC] or platelets) while on therapy that 
is recurrent after dose reduction to the lowest doses recommended 
by manufacturer
7.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 
1, or 2
8.
Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of 
screening which are amenable to standardized RQ-PCR quantification.
9.
Adequate end organ function, within 12 days before the first dose of 
asciminib treatment. Patients with mild to moderate renal and hepatic 
impairment are eligible if:

Total bilirubin ≤ 3.0 x ULN   with any AST increase

Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, 
value should be considered not clinically significant and not 
associated with risk factors for acute pancreatitis

Creatinine clearance ≥ 30 mL/min as calculated using Cockcroft-
Gault formula
10. Patients must avoid consumption of grapefruit, Seville oranges or products 
containing the juice of each during the entire study and preferably 7 days 


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before the first dose of study medications, due to potential CYP3A4 
interaction with the study medications. Orange juice is allowed.
11. Patients must have the following electrolyte values (as per central laboratory 
tests) within normal limits or corrected to be within normal limits with 
supplements prior to first dose of study medication:

Potassium (potassium increase of up to 6.0 mmol/L is acceptable at 
study entry if associated with creatinine clearance within normal limits)

Total calcium (corrected for serum albumin); (calcium increase of up to 
12.5 mg/dl or 3.1 mmol/L is acceptable at study entry if associated with 
creatinine clearance within normal limits)

Magnesium, with the exception of magnesium increase > ULN – 3.0 
mg/dL; > ULN - 1.23 mmol/L associated with creatinine clearance 
(calculated using Cockcroft-Gault formula) within normal limits.
Key Exclusion 
criteria
1.
Known second chronic phase of CML after previous progression to AP/BC
2.
Previous treatment with a hematopoietic stem-cell transplantation
3.
Cardiac or cardiac repolarization abnormality, including any 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)

QTcF at screening ≥450 msec (male patients), ≥460 msec (female 
patients)

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 wwwcrediblemeds.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, pulmonary hypertension)
5.
History of acute pancreatitis within 1 year of study entry or past medical 
history of chronic pancreatitis
6.
Known presence of significant congenital or acquired bleeding disorder 
unrelated to cancer
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.
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)
9.
Previous treatment with or known/ suspected hypersensitivity to asciminib or 
any of its excipients.


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10. Treatment with medications that meet one of the following criteria and that 
cannot be discontinued at least one week prior to the start of treatment with 
study treatment; 

For Cohort A (40 mg BID) and for Cohort B (80 mg QD) patients not 
harboring the T315I mutation
o
strong inducers of CYP3A

For Cohort C (200 mg BID for patients harboring the T315I mutation) 
o
strong inducers of CYP3A 
o
strong inhibitors of CYP3A 
11. Participation in a prior investigational study within 30 days prior to 
randomization or within 5 half-lives of the investigational product, whichever 
is longer
12. Pregnant or nursing (lactating) women
13. Women of childbearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 
methods of contraception. 
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy (with or 
without hysterectomy) total hysterectomy or bilateral tubal ligation at 
least 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 sterilization (at least 6 months prior to screening). The 
vasectomized male partner should be the sole partner for that subject.

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 and not of childbearing 
potential if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or 
bilateral tubal ligation at least six weeks before taking study medication. 
In the case of oophorectomy alone, women are considered post-
menopausal and not of childbearing potential only when the 
reproductive status of the woman has been confirmed by follow up 
hormone level assessment.
14. Sexually active males unwilling to use a condom during intercourse while 
taking study treatment and for 3 days after stopping study (only for patients 
treated with asciminib). A condom is required for all sexually active male 
participants on asciminib treatment to prevent them from fathering a child 
AND to prevent delivery of study treatment via seminal fluid to their partner. 


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
In addition, these male participants must not donate sperm for the time 
period specified above.
15. If a patient is presenting with symptoms suggestive of possible COVID-19 
infection, we advise ruling it out by appropriate testing recommended by 
health authorities. 

Nucleic acid amplification tests for viral RNA (polymerase chain 
reaction), in order to measure current infection with SARS-CoV-2

Antigen tests for rapid detection of SARS-CoV-2

Antibody (serology) tests to detect the presence of antibodies to SARS-
CoV-2
Study 
treatment
Asciminib 40 mg BID, 80 mg QD or 200 mg BID (T315I mutation only)
Efficacy 
assessments

Molecular response (RQ-PCR, mutational analysis)

Hematologic Response
Key safety 
assessments

Physical examination

Vital Sign

Height and weight

ECOG performance status

Laboratory chemistry and hematology

Serology

Electrocardiogram (ECG)

Echocardiogram

Pulmonary function tests with DLCO
Data analysis
Primary objective of the study is to assess safety profile of asciminib during 24 
weeks for all patients within each cohort,
Approximately total 115 (45+45+25=115) patients will be enrolled for Cohort A 
(n1=45), Cohort B (n2=45) and for Cohort C (n3=25) for the study. 
For all primary safety analyses, the Safety Set will be used, unless stated 
otherwise. All AEs and SAEs will be summarized. No inferential tests for safety 
analyses will be performed. All primary, secondary 
 variables will 
be summarized descriptively. Categorical data will be presented in frequencies 
and percentages. For continuous data descriptive statistics (mean, standard 
deviation, median 25th and 75th percentiles, min and max) will be provided. As 
appropriate, 95% confidence intervals will also be reported. Kaplan Meier’s 
estimates will be reported for the time to event variables.
As the primary time point is by 24 weeks, the primary analysis will be an interim 
analysis where formal primary DBL will be complete and all analyses will be 
performed. As appropriate, annual interim analyses will be planned for 
publication or any regulatory purpose. No formal interim analysis will be 
performed. 
Key words
Phase IIIb, open-label trial, asciminib, CML-CP, previous treatment with TKIs, 
T315I mutation


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
1
Introduction
1.1
Background
1.1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Chronic myeloid leukemia (CML) is a hematological stem cell disorder characterized by a 
specific chromosomal translocation leading to the Philadelphia (Ph) chromosome which is 
detected in 95% of patients (Nowell and Hungerford 1960; Rowley 1973]). The molecular 
consequence of the translocation is the fusion of the ABL1 proto-oncogene to the BCR gene 
resulting in the production of an activated form of the ABL1 protein tyrosine kinase (TK) 
(Bartram et al 1983; Heisterkamp et al 1983). BCR-ABL1 drives the growth factor 
independence, increased proliferation, genomic instability, suppression of apoptosis and 
alteration of the adhesive properties of CML cells (Hochhaus 2009) and the expression of BCR-
ABL1 in mice results in the development of a CML-like disease (Daley et al 1990; Kelliher et 
al 1990). This evidence that BCR-ABL1 is a genetic driver of CML was subsequently 
confirmed by the clinical efficacy of imatinib in patients (IRIS Study STI571A0106).
Clinically, CML is characterized by overproduction of immature myeloid cells and mature 
granulocytes in the spleen, bone marrow and peripheral blood. Most patients, however, present 
in the CP, characterized by splenomegaly and leukocytosis with generally few symptoms. CML 
progresses through three distinct phases of increasing refractoriness to therapy: chronic phase 
(CP), accelerated phase (AP), and blast crisis (BC). With conventional chemotherapy, such as 
busulfan or hydroxyurea, the median survival time commonly reported for CML was about 4 
years, but progression to AP and BP was only slightly delayed. Interferon-alfa delayed 
progression significantly, with a median survival of approximately 6 years. Allogeneic 
hematopoietic stem cell transplantation provided CML patients the highest chance for cure and 
long term control of the disease. However, during the last decade, TK inhibitor (TKI) therapy 
became the standard treatment for most patients with CML, with complete cytogenetic response 
rates of 70% to 90% and 5-year progression-free survival and overall survival of 80% to 95% 
commonly reported (Vardiman 2009).
The National Comprehensive Cancer Network (NCCN) guideline on CML (NCCN guideline v 
1.2014) and the European Leukemia Net (ELN) (Baccarani et al 2013) recommend continuing 
TKI treatment indefinitely in all responding patients. The first TKI, imatinib mesylate (imatinib, 
STI571, Gleevec™/Glivec™), an adenosine triphosphate (ATP)-competitive TKI with 
selectivity towards BCR-ABL1, revolutionized treatment of CML and significantly improved 
the prognosis of patients since its approval in 2001. It is effective in most patients with CML at 
well-tolerated doses, and is indicated as frontline therapy for Ph+ CML-CP and in patients with 
Ph+ CML in blast crisis (BC), accelerated phase (AP), or in CP after failure of interferon-alpha 
therapy. However, despite the remarkable efficacy of imatinib, some patients are either 
intolerant to the drug or can develop resistance (O’Hare 2006). Imatinib resistance is primarily 
due to nucleotide substitutions in BCR-ABL1, which encode mutant forms of protein’s tyrosine 
kinase domain that impair imatinib binding. Over-expression of the BCR-ABL1 protein may 
also cause resistance. Rates of resistance increase with each stage of progression of CML (CP 
< AP < BC) (Branford 2003).


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Multiple agents, including nilotinib, dasatinib, ponatinib, bosutinib, radotinib (Korea) and 
omacetaxine (USA, Canada) are able to treat various forms of imatinib-resistant CML and are 
currently approved for patients with CML-CP previously treated with prior therapy. With the 
exception of omacetaxine, which is a cytotoxic chemotherapeutic agent, all of these drugs are 
ATP-competitive TKIs. Like imatinib, nilotinib, dasatinib and most recently bosutinib are also 
indicated for the treatment of patients with newly diagnosed CML. The activity of nilotinib or 
dasatinib in patients previously treated with a second generation TKI is not known. In contrast 
to the ATP-competitive TKIs, asciminib inhibits the enzymatic activity of BCR-ABL1 through 
an allosteric mechanism.
1.1.2
Introduction to investigational treatment
Overview of asciminib (ABL001)
Asciminib is a potent orally bioavailable BCR-ABL1 tyrosine kinase inhibitor that specifically 
binds to the allosteric site on the kinase SH1 domain normally occupied by the myristoylated 
Gly2 residue on the N-terminus of ABL1 SH3 domain (Schoepfer et al 2018). The agent inhibits 
the proliferation of CML and ALL cells that are dependent on BCR-ABL1. This mechanism of 
action contrast to that of drugs such as bosutinib (Bosulif®), dasatinib (Sprycel®), imatinib 
(Gleevec®), nilotinib (Tasigna®) and ponatinib (Iclusig®) that bind to the adenosine 
triphosphate(ATP)-site of the kinase SH1 domain.
1.1.2.1
Non-clinical experience
In vitro and in vivo pharmacology data
Asciminib displays potent anti-tumor activity in vivo with a clear pharmacokinetic 
(PK)/pharmacodynamic (PD)/Efficacy relationship [RD-2013-50145]. In a KCL-22 CML blast 
crisis (CML-BC) cell line mouse subcutaneous xenograft model, tumor regression was 
observed at doses of 7.5 mg/kg BID and above when asciminib was administered alone. 
Efficacy in the KCL-22 xenograft model correlated with stable inhibition of the downstream 
PD marker phospho-STAT5, consistent with finding that ABL1 inhibits STAT5 
phosphorylation in KCL22 cells with an IC90 value of approximately 20 nM.
The KCL-22 xenograft model was also used to assess the activity of asciminib and nilotinib as 
single agents and in combination (Figure 1-1). In these experiments, when each agent was 
administered as monotherapy in sequence, initial sensitivity of the tumor was observed to each 
agent, but relapse occurred in each case. The mutations observed were as expected based on 
clinical experience (T315I for nilotinib) or modeling (A337V) for asciminib. In contrast, 
animals treated upfront with the combination of asciminib and nilotinib achieved sustained 
tumor regression with no evidence of disease relapse during the 70 days of treatment or for 80 
days following discontinuation of treatment. Note that in this KCL-22 model, the cells (derived 
from a blast crisis CML patient) were grown as a solid tumor rather than as disseminated disease. 
Also, this model is much more aggressive than chronic phase CML in patients.


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Figure 1-1
KCL-22 CML Xenograft
These data are consistent with asciminib being active against nilotinib-resistant mutations and 
nilotinib being active against asciminib-resistant mutations. Consequently, the findings support 
development of asciminib both as single agent as well as in combination with TKIs as initial 
therapy of CML as well as therapy after progression on nilotinib.
In addition, due to asciminib specifically targeting the ABL kinase family (ABL1, ABL2, BCR-
ABL1), asciminib offers the potential for improved safety and tolerability when administered 
as monotherapy when compared to TKIs binding to the ATP site of BCR-ABL1, which are less 
specific towards ABL. Thus, there is the potential for an improved safety profile of asciminib 
in comparison to other TKIs.
Safety pharmacology and toxicology
An extensive toxicology safety evaluation program (subchronic, chronic, reproductive 
toxicology, phototoxicity and genotoxicity studies) was conducted.
Safety pharmacology studies indicate that asciminib is not expected to cause effects on the vital 
functions of the CNS, and the respiratory systems. The IC50 for asciminib in the hERG patch 
clamp is 11.4 μM (4498 ng/mL). No cardiovascular effects were observed in a single dose 
jacketed telemetry study in dogs at doses up to 600 mg/kg or the invasive telemetry 
cardiovascular safety study up to 60 mg/kg. Furthermore, no changes in cardiovascular 
parameters related to QTc prolongation were observed using standard electrocardiography in 
the 4-week dog toxicity study and in cynomolgus monkey toxicity studies (up to 39 weeks of 
treatment).
Asciminib does not show mutagenic, clastogenic, or aneugenic potential in the in vitro assays 
or the MNT assessment in vivo; therefore, no potential risk for human is perceived.
As determined by the results of the phototoxicity assessment (in vitro and in vivo), phototoxic 
potential was identified in the mouse UV-LLNA assay. Given these data, patients should be 
advised to avoid prolonged exposure to sunlight (sunbathing), to avoid sunbed and to use 
sunscreen.
Toxicity studies performed in rats, dogs and cynomolgus monkeys (up to 26, 4 and 39 weeks 
of treatment, respectively) identified the pancreas, liver, hematopoietic system, adrenal and 
gastro-intestinal tract as potential target tissues. 
Fetal malformations and increased visceral and skeletal variants were observed in the rat 
embryo-fetal development study. There was no evidence of effects on reproductive function in 
the fertility study; however there was a slight effect on male sperm motility and/or sperm count 


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in individual animals. Phototoxic potential was identified in the phototoxicity (in vitro and in 
vivo) assessment.
Please refer to the latest [Asciminib Investigator’s Brochure] for more details.
Non-clinical pharmacokinetics and metabolism
The preclinical pharmacokinetic profile of asciminib has been investigated in three species: 
mouse, rat and dog. In these species, asciminib exhibited low to moderate clearance, a moderate 
volume of distribution and a short apparent terminal half-life. Bioavailability was found to be 
low in rodents and moderate to high in dog.
Asciminib displayed high plasma protein binding across all tested species (2-6% free fraction).
The metabolite profile of asciminib has been examined in vitro using rat, dog, monkey and 
human hepatocytes. Interspecies differences were observed in the in vitro metabolism of 
asciminib in hepatocytes, with direct glucuronidation occurred more readily in human, to a 
lesser extent in dog and monkey, and was noticeably absent in rat. However, no unique, major 
metabolites were identified in human hepatocytes. The overall metabolic turnover was low.
The metabolite profile of asciminib has also been examined in vivo in rats. Following 
intravenous and oral administration of [14C-asciminib] to intact rats, asciminib was found to be 
the predominant component of plasma, accounting for ~86 - 91% of radioactivity from 0 - 8 h. 
Asciminib was excreted primarily in the feces, with ~90% of radioactivity detected in the feces 
from 0 - 48 h. Renal elimination represented a minor route, with ~2.4% of radioactivity detected 
in the urine from 0 - 72 h. In the feces, ~58% (intravenous) and ~71% (oral) of the dose was 
associated with unchanged asciminib, with several oxidative metabolites accounting for the 
remaining radioactivity. The metabolites formed in vivo were consistent with those observed in 
vitro. Similar observations were noted in bile-duct cannulated rats.
To assess for potential drug-drug interactions (DDI), studies have been conducted with 
cytochrome P450 (CYP) enzymes and several transporters in vitro.
In human liver microsomes, the major metabolic route of asciminib was found to be 
glucuronidation, followed by oxidative metabolism, consistent with findings from human 
hepatocytes. Several Uridin diPhospho-glucuronosyltransferase (UGT) enzymes were found to 
be capable of asciminib glucuronidation (UGT1A3, UGT1A4, UGT2B7, and UGT2B17). The 
oxidative metabolism of asciminib was also catalyzed by several CYP enzymes. CYP3A4/5 
appears to contribute the most, followed by CYP2C8, CYP4F12, and potentially CYP2D6. 
Though the DDI risk with inhibitors of these enzymes is likely to be minimal, inhibitors of 
CYP3A4/5 still have the potential to increase asciminib concentration. 
In recombinant cellular expression systems, asciminib was identified as a substrate of Breast 
Cancer Resistant Protein (BCRP) (Michaelis-Menten constant (Km) ≈ 4 µM) and permeability 
glycoprotein (P-gp) (Km could not be estimated due to insufficient saturation of efflux activity). 
Late fecal metabolite analysis in the human Absorption, Distribution, Metabolism, and 
Excretion (ADME) study [CABL001A2102] and estimated contributions of different enzyme 
pathways (CYP vs. UGT) by use of in vitro enzyme phenotyping methods, do suggests that at 
least 24% of the parent drug in the feces is due to conversion of a glucuronide (M30.5) 
metabolite back to parent drug (absorption then being maximally 57%). However, this late fecal 


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metabolite analysis could also suggest that the 24% could be active secretion by P-gp (Drug 
Metabolism and Pharmacokinetics [DMPK R1700912]. This is a small percentage (< 25% of 
the clearance by this pathway) with a weak expected impact on asciminib concentrations. 
Overall, inhibitors of BCRP and P-gp may increase asciminib concentration. Therefore, BCRP 
and P-gp inhibitors should be administered with caution.
Based on in vitro phenotyping studies and human ADME study outcome, the physiologically 
based pharmacokinetic (PBPK) model was updated and predicted minimal to no DDI for 
sensitive substrates of CYP3A4, CYP2C8 and CYP2C9 (Drug Metabolism and 
Pharmacokinetics [DMPK-DDI-R1700912]. Indeed, the effect of asciminib 40 mg BID is 
expected to result in increased area under the curve (AUC) of CYP3A4, CYP2C8 and CYP2C9 
probe substrate by 1.21, 1.09 and 1.07. Therefore, the effect of asciminib is expected to be weak 
and hence substrates of CYP2C8, CYP2C9 and CYP3A4 with narrow therapeutic index (NTI) 
would be used with caution. 
Please refer to the latest [Asciminib Investigator’s Brochure] version for more details.
1.1.2.2
Clinical experience
Asciminib is undergoing evaluation in a first-in-human (FIH) phase I clinical study, study 
[CABL001X2101].
This study evaluates patients with 1) CML who have been treated with at least 2 prior TKIs, or 
2) who have the T315I mutation and have been treated with at least 1 prior TKI, or 3) who have 
Acute Lymphoblastic Leukemia (ALL) and have been treated with at least 1 prior TKI. The 
study evaluates administration of asciminib in a BID single agent dosing schedule, as well as 
in a QD single agent schedule, and in combination with nilotinib, imatinib, and dasatinib. In the 
present document, discussion will focus on data from CML patients treated with asciminib BID 
single agent only.
As of March 2020, a total of 305 CML or Ph+ ALL patients have been treated with either single 
agent oral asciminib or in combination cohorts. 150 CML patients have been treated with 
asciminib monotherapy. Based on the preliminary efficacy, safety and tolerability in patients 
with CML-CP or CML-AP treated with asciminib as a single agent on a BID schedule in 
study [CABL001X2101] and the results of a population PK/PD exposure-response model, the 
dose of 40 mg BID has been selected as the recommended dose to be used in future studies in 
patients with CML-CP who do not harbor T315I mutations.
Efficacy:
Preliminary data from the ongoing Phase I FIH study [CABL001X2101] indicate that asciminib 
exhibits single-agent activity in patients with CML who have failed at least two prior TKIs or 
are intolerant to TKIs, as demonstrated by hematologic, cytogenetic and major molecular 
responses (Hughes, 2019). Asciminib has demonstrated anti-tumor activity at doses greater or 
equal to 10 mg BID as well as higher daily doses.
To date, efficacy data in 141 patients with chronic-phase CML treated with single agent 
asciminib therapy (10-200 mg BID and 80-200 mg QD) are available (113 patients without 
T315I mutation and 28 with T315I mutation). Among 113 patients with CP-CML without 
T315I mutation, 92% and 54% of patients achieved complete hematologic response (CHR) and 


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complete cytogenetic response (CCyR), respectively; a major molecular response (MMR) was 
achieved or maintained in 37% and 48% of patients by 6 months and 12 months, respectively. 
Among 28 patients with CP-CML carrying T315I mutation, 88% and 41% of those achieved 
CHR and CCyR, respectively; MMR was achieved in 25% and 28% by 6 months and 12 months, 
respectively.
Please refer to (Hughes, 2019) and the latest [Asciminib Investigator’s Brochure] for more 
details.
Safety:
Asciminib was generally well tolerated in heavily pre-treated CML patients resistant to or 
intolerant of prior TKIs. As of March 2020, 239 patients were evaluable for safety. Seventy six 
study discontinuations have been reported; the most frequent reason for discontinuation was 
progressive disease, reported in 38 patients (15.9%). Adverse events leading to treatment 
discontinuation were reported in 15 patients (6.3%). Death leading to treatment discontinuation 
was reported in 3 patients (1.3%) (one patient in asciminib 20 mg BID due to aspiration 
pneumonia after bypass procedure and two patients with ALL with 80 mg and 160 mg BID due 
to progressive disease).
Among the 150 patients treated with asciminib monotherapy, almost all (94.7%) patients 
reported at least one AE, including 49.3% reported grade 3/4 AEs. The most common AEs (> 
10%) among patients treated with 40 mg BID (n=35), regardless of study drug-relationship, 
were increased lipase, fatigue, diarrhea, thrombocytopenia, neutropenia, arthralgia, rash, 
headache, increased amylase, nausea, vomiting, abdominal pain, pyrexia, upper respiratory tract 
infection, back pain, hypertension, cough, pruritus, pain in extremity, dyspnea, bone pain, 
peripheral oedema, non-cardiac chest pain and insomnia. The most common reported grade 3/4 
event was increased lipase (17.1%).
Forty-seven of 150 patients with CML-CP or CML-AP treated with asciminib single agent 
(31.3%) were reported with serious adverse events (SAE).
Electrocardiogram (ECG) data shows no reported QT prolongation (increase > 60 msec or new 
> 500 msec) in 40 mg BID asciminib monotherapy group. There were no reports of QT 
prolongation (increase > 60 msec) and two reports of new >500 msec (one each in 80 mg QD 
and 120 mg QD) among all asciminib monotherapy group.
Please refer to the latest [Asciminib Investigator’s Brochure] for more details.
Pharmacokinetics:
PK data from 190 patients were available from the [CABL001X2101] study, as of 01-Sep-2017. 
When given as a single agent on a twice daily schedule, patients received escalating doses of 
asciminib ranging from 10 to 200 mg.
Based on the available PK data, asciminib, administered orally is rapidly absorbed with a 
median time to maximum plasma concentration (Tmax) of 2 to 3 hours, independent of dose. 
Systemic exposure of asciminib, following oral administration of single and multiple doses, as 
measured by Cmax and AUC, increased in an approximately dose proportional manner. The 
variability of exposure is low to moderate with inter-patient variability (geometric mean CV %) 


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ranging from approximately 25 to 70% for both Cmax and AUClast. With the twice daily dosing 
regimen, median plasma asciminib accumulation ratios ranged from 1.3 to 2.5. The median 
accumulation half-life was estimated to be 7 to 15 hours.
The data of the hADME study [CABL001A2102] show that the relative contribution of the 
glucuronidation pathway to the total clearance of asciminib via metabolism is estimated to range 
from 30% to 61%, whereas the relative contribution of the oxidative pathway is estimated to 
range from 35% to 63%. CYP3A4 was the main contributor for the clearance of asciminib via 
the oxidative pathway while UGT2B7 and UGT2B17 were responsible for the clearance of 
asciminib via the glucuronidation pathway. There was no metabolite detected with mean 
contribution to plasma radioactivity AUC0-24hours ≥ 10%. Asciminib was the predominant 
drug-related component in plasma at all time points analyzed, ranging from 91.9 to 94.2% of 
the total radioactivity AUC0-24 hours AUC, with an average value of 92.7%.
Please refer to the latest [Asciminib Investigator’s Brochure] for more details.
Exposure-response relationship:
Exposure-efficacy
A preliminary population PKPD model has been developed using data from the 
[CABL001X2101] study (cut-off 02-May-2016). The time course of molecular response 
(change in BCR-ABL1 ratio % IS levels from baseline) was described using a semi-
physiological model accounting for cell maturation, disease progression and existing resistance.
Simulations performed using an asciminib population PK model revealed that a dose of 40 mg 
BID maintains Ctroughs above the clinical (0.07 to 61 ng/mL) threshold in ≥95% of chronic 
phase CML patients without T315I mutation having failed ≥ 2 TKI or intolerant to TKIs. The 
estimates from this clinical study were found to be similar to the threshold trough concentration 
required for 90% inhibition of pSTAT5 derived from a preclinical PK-PD KCL-22 mouse 
xenograft model (free IC90: 30 to 121 ng/mL, after correction for protein binding) and in vitro 
gIC50 assessed in the KCL-22 cell line (1 ng/mL = 2.1 nM after correction for protein binding).
Simulations performed using asciminib population PKPD model revealed that chronic phase 
CML patients having failed ≥ 2 TKI or intolerant to TKIs are likely to exhibit a 1 log10 
reduction of (%) BCR-ABL1 mRNA transcript levels from baseline of ~33% (CI95%: 24-42%) 
at 6 months, and ~42% (CI95%: 32-52%) at 12 months at a dose of 20 mg BID and ~41% 
(CI95%: 31-51%) at 6 months, and ~53% (CI95%: 43-63%) at 12 months at a dose of 40 mg 
BID.
Additional preliminary exposure response analyses (i.e. exploring the relationship between PK 
and both safety and efficacy) support the selected dose.
Please refer to the latest [Asciminib Investigator’s Brochure] for more details
Food effect
The effect of food on asciminib PK was characterized in a Phase I study [CABL001A2101] in 
healthy volunteers. Food was found to influence the pharmacokinetics of asciminib. When 
administered with a low-fat meal, the exposure (AUC) decreased by approximately 30%. The 


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overall exposure decreased by approximately 65% when administered with a high-fat meal. 
Therefore, asciminib will be administered in a fasted state.
1.2
Purpose
Thanks to the advances in CML treatments, many of these patients can now have life expectancy 
similar to the general population. However, there is a significant proportion of patients who 
unfortunately experience treatment failure due to either resistance or intolerance. When 
considering patients treated with frontline imatinib, 31% exhibit treatment failure and progress 
to second-line treatment; of those, half of them progress to third-line treatment (Akard, 2013). 
On patients starting treatment with 2nd generation TKI (2G-TKI), treatment failure rate is at 
13% and when they move on to second-line treatment, around 60% of them exhibit disease 
progression and move on to third-line treatment. 
Given the poor outcomes of patients that progress after successive lines of therapy, there 
remains an unmet need for new compounds that can provide CML patients optimal disease 
management. It is worthwhile mentioning the lack of defined treatments recommendations once 
patients move on to second-line treatment and beyond. NCCN guidelines recommend treating 
patients with any of the 2G-TKIs if imatinib was given as the frontline agent; if 2G-TKI was 
used for first-line treatment, any 2G-TKI can be considered for subsequent treatment, although 
some experts advocate for ponatinib if the reason for treatment discontinuation was related to 
resistance (Hochhaus, 2020). 
In addition, patients harboring T315I mutation have few treatment choices since this mutation 
confers resistance to all TKIs with the exception of Ponatinib. Unfortunately, Ponatinib is 
associated with high risk of cardiovascular complications and many of these patients are then 
not eligible for treatment. Based on data from ongoing study [CABL001X2101], 53.8% of 
CML-CP patients with this mutation who had not been previously treated with Ponatinib were 
able to achieve MMR by 6 months (Hughes, 2020). Therefore, asciminib represents a promising 
agent for this CML-patient population that the current study is attempting to address.
2
Objectives and endpoints
Table 2-1
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s)

To evaluate safety profile of 
monotherapy asciminib in CML-
CP in 3L and beyond, for 
Cohorts A and B

AEs, SAEs and laboratory evaluation for 24 Weeks. 
Secondary Objective(s)
Endpoint(s) for secondary objective(s)

To evaluate safety profile of 
monotherapy asciminib in CML-
CP in all Cohorts A, B and C

AEs, SAEs and laboratory evaluation for cohort A, and 
Cohort C, for 48, 72 weeks

To estimate the rate of patients 
with hematologic and molecular 
response by specific time 
points for Cohort A, B and C

Rate of CHR, MR2, MMR, by 12, 24, 48, 72 weeks of 
therapy

To estimate the rate of patients 
with deep molecular response 

Rate of MR4, MR4.5 by 48, 72 weeks of therapy


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Table 2-1
Objective(s)
Endpoint(s)
by specific time points for 
Cohort A, B and C

To estimate time to 
hematologic and molecular 
response

Time to CHR, MR2, MMR, MR4, MR4.5 

To evaluate the duration of 
hematologic and molecular 
response

Duration of CHR, MR2, MMR, MR4 and MR4.5

To Evaluate the progression 
free survival (PFS) during 72 
weeks

PFS during 24, 48 and 72 weeks

To Evaluate Overall Survival 
(OS) during 72 weeks

OS during 24, 48 and 72 weeks
3
Study design
This study will be a multicenter Phase IIIb open-label, three-cohort study of asciminib in 
patients with CML-CP without T315I mutation who have had at least 2 prior TKIs and CML-
CP harboring the T315I mutation with at least 1 prior TKI. The primary outcome is to evaluate 
the safety profile of asciminib with AEs, SAEs and laboratory studies’ assessment at 24 weeks 
of therapy. The secondary endpoints will consist of:

Additional Safety endpoints including the AES, SAEs and laboratory tests leading to 
treatment discontinuation on weeks 48 and 72

Efficacy measures such as duration, estimated time for achievement and rates of CHR, 
MR2, MMR, MR4, MR4.5 by 12, 24, 48, 72 weeks of therapy

Survival measures such as PFS and OS during 72 weeks of therapy


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Figure 3-1
Study design 
Patient Selection
For patients without T315I mutation, patients will be selected randomly between cohort A, 
where patients will be given asciminib at 40 mg twice daily (BID) and cohort B, where patients 
will receive asciminib at 80 mg daily (QD) to minimize selection bias. Data from 
[CABL001X2101] study showed encouraging efficacy and safety findings in 40 mg twice daily 
and 80 mg daily-treated patients. 
On cohort C, patients harboring the T315I mutation will be treated on the dose of 200 mg twice 
daily (BID). The higher dose required for that patient population is related to its required 
concentration to attain optimal blockade of the kinase activity. Patients will continue therapy 
until disease progression, unacceptable toxicity or elective treatment discontinuation.
4
Rationale
4.1
Rationale for study design
Asciminib (ABL001) is a potent BCR-ABL1 allosteric inhibitor currently being developed by 
Novartis for the treatment of CML. Unlike drugs such as imatinib, nilotinib, dasatinib, bosutinib 
and ponatinib, which bind to the ATP-site of the ABL kinase domain, asciminib binds to the 
myristoyl pocket and consequently, restores the negative regulation of the kinase activity1. Given 
this unique mechanism of action, it has been proven to have activity against BCR-ABL1 
mutations that are known to confer resistance to the ATP-binding site TKIs (tyrosine kinase 
inhibitors). Moreover, the selective binding of asciminib is predicted to reduce toxicities, which 
is an encouraging feature for patients where side effects from previous treatments were the 
reason for drug discontinuation. Based on phase I data, asciminib has been proven safe and 
effective in patients who had more than 2 lines of therapy, with 32% and 44% of those achieving 
MMR in 6 and 12 months, respectively. The incidence of grade 3/4 treatment emergent AEs 
were mostly less than 10%, which implies a favorable safety profile in a heavily pre-treated 
CML population.


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The ongoing ASCEMBL study is a phase III study, which is investigating the efficacy of 
treatment with asciminib versus bosutinib in CML-CP patients with at least 2 prior therapies. 
The release of interpretable results is expected to be in 2020 with subsequent data presentation 
and submission to health authorities. Despite its phase III design with randomization, questions 
remain such as safety and efficacy on a larger patient population including those carrying the 
T315I mutation and of a daily dosing schedule. A once daily regimen could be more 
convenient as we believe it will greatly improve patient’s adherence as well as quality of life. 
For that dosing schedule, the dose of 80 mg was selected based on similar efficacy and safety 
profile when compared to 40 mg twice daily from early phase data3.
The study currently proposed is a phase IIIb open-label study patients with CML-CP without 
T315I mutation who have had at least 2 prior TKIs and CML-CP harboring the T315I mutation 
with at least 1 prior TKI with the aim of gaining further efficacy and safety data with asciminib 
monotherapy on a larger population of patients.
The study will contain the following cohorts:

Cohort A asciminib 40 mg BID

Cohort B asciminib 80 mg QD

Cohort C asciminib 200 mg BID, exclusively for those harboring the T315I mutation
Random Selection of patient
As above, patients with CML-CP without T315I mutation will be randomly selected to either 
cohort A or B (both primary). Patients in those 2 cohorts will be selected randomly to minimize 
selection bias at the time of patient allocation. Additionally, there will be a separate cohort 
(cohort C) enrolling patients harboring the T315I mutation to strengthen the body of evidence 
generated in the [CABL001X2101] study, which has already treated 58 patients with that 
mutation in the asciminib extension cohort at 200 mg bid showing encouraging antileukemic 
activity and well tolerated safety profile.
4.2
Rationale for dose/regimen and duration of treatment
The dose and regimen of asciminib selected for cohort A is 40 mg BID and cohort B is 80 mg 
QD. This dose is supported by pharmacokinetic, efficacy and safety data available from the 
ongoing [CABL001X2101] study. 
During escalating doses of asciminib 10 mg to 200 mg on a continuous BID schedule in study 
[CABL001X2101], the 40 mg BID dose was shown to be active and well tolerated in CML-CP 
patients.
With respect to efficacy, no clear evidence of dose-response relationship was observed across 
dose levels when considering Complete Cytogenetic Response (CCyR) or MMR. However, as 
described below, PK-PD population modeling using change from baseline of BCR-ABL1 
mRNA levels as a PD endpoint suggest a higher probability of achieving ≥1 log reduction at 6 
and 12 months with 40 mg BID versus 20 mg BID.
With respect to safety, asciminib has been regarded as safe with mild toxicities even for patients 
who required higher doses of the drug. Most of the toxicities observed were limited to grade 1 
and 2 [CABL001X2101]. Two patients developed pancreatitis after intra-patient dose escalation 


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to 80 mg BID from 40 mg BID and in one patient at the dose of 150 mg BID. Generally there 
is a trend for higher rates of discontinuation due to AE, DLT (dose limiting toxicity) and grade 
3/4 AE with increasing doses.
With respect to overall exposure, the dose of 40 mg BID and 80 mg QD are expected to result 
in concentrations consistently above IC90 in vitro concentrations. The estimates from study 
[CABL001X2101] were found to be above the threshold trough concentration required for 90% 
inhibition of pSTAT5 derived from a preclinical PK-PD KCL-22 mouse xenograft model (free 
IC90: 30 to 121 ng/mL, after correction for protein binding) and in vitro gIC50 assessed in the 
KCL-22 cell line (1 ng/mL = 2.1 nM after correction for protein binding). Additionally, clinical 
data from the study on patients taking 40 mg BID and 80 mg QD were obtained and as seen on 
Figure 4.1, it showed similar results when it comes to pharmacokinetic parameters.
Figure 4-1
Pharmacokinetic data of 40 mg BID and 80 mg QD  
A preliminary population PK-PD model has been developed using data from the 
[CABL001X2101] study (cut-off 2 May 2016). The time course of molecular response (change 
in BCR-ABL1 ratio % IS levels from baseline) was described using a semi-physiological model 
accounting for cell maturation, disease progression and existing resistance. Simulations 
performed (with 100 patients) using asciminib population PK-PD model revealed that at a dose 
of 40 mg BID, ~41% (CI95%: 31-51%) of chronic phase CML patients having failed ≥ 2 TKI 
or intolerant to TKIs are likely to exhibit a 1 log10 reduction of (%) BCR-ABL1 mRNA 
transcript levels from baseline at 6 months, and 53% (CI95%: 43-63%) at 12 months, and 
predicting higher probability of achieving BCR-ABL1 mRNA ≥ 1 log reduction at 6 and 12 
months with 40 mg BID versus 20 mg BID.
Additional preliminary PK-efficacy and PK-safety analyses to assess the exposure-response 
relationship for asciminib were conducted (Section 1.1.2.2). The efficacy measure used was 
Molecular Response (MR), which is defined as a decline in BCR-ABL1 transcript levels in 
clinical blood samples of patients with Chronic Myeloid Leukemia (CML). MR was evaluated 
as both a continuous variable (BCR-ABL1 transcript levels) and categorical variable (whether 
or not adequate decline in BCR-ABL1 was achieved). The safety measures used were 
occurrence of Common Toxicity Criteria (CTC) grade 2, 3 or 4 laboratory values for lipase and 
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Reviewing the totality of the efficacy, safety, and pharmacokinetic data derived from the 
[CABL001X2101] study, the recommended dose for asciminib in this phase 3 study is 40 mg 
BID. 
Please refer to the latest [Asciminib Investigator’s Brochure] for more details
200 mg BID Dose Rationale for Patients harboring the T315I mutation
Asciminib maintained activity against all BCR-ABL1 constructs, regardless of mutation, at 
concentrations below 50 nM. The most striking example of the difference between asciminib 
and nilotinib, was the activity against the BCR-ABL1 expressing cell line with a T315I mutation. 
Asciminib inhibited the proliferation of cells with T315I mutation in the low nanomolar range, 
in contrast with the exception of ponatinib ATP competitive BCR-ABL inhibitors were, inactive 
at concentrations 600 nM (Figure 4-2) (Schoepfer et al 2018; Report RD-2013-50447).
Figure 4-2
Comparison of the effects of Asciminib with those of ATP-competitive 
BCR-ABL inhibitors approved for the treatment of CML on Luc-Ba/F3 
cells engineered to express drug-resistant BCR-ABL mutants 
Source: (Schoepfer et al 2018)
Based on exposures required for in vitro activity against T315I mutation preclinically, higher 
doses of asciminib (> 160 mg BID) may drive BCR-ABL % IS and major molecular response 
in CML patients with T315I mutation. A 200 mg BID dose was overall deemed safe by BLRM 
and the safety profile was seen to be similar between patients with and without the T315I 
mutation.
4.3
Purpose and timing of interim analyses/design adaptations
See Section 12.8


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4.4
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 adverse events are provided in Section 6.5.4. Patients who have failed 2 prior 
TKIs are at increased risk of progression to more advanced phases of CML such as CML-AP 
and CML-BC. Currently available therapeutic agents in this setting are non-curative and 
patients remain at risk of progressing after short duration of remissions (Khoury 2012).
An important potential risk for patients enrolling on the 80 mg QD arm is the possibility of 
having either higher toxicity or reduced efficacy. However, as mentioned above, the evidence 
to date of such dose on a similar population of patients in the study [CABL001X2101] suggests 
that asciminib is an active and safe agent. Further, the adverse event profile of asciminib is 
similar qualitatively to that observed with other TKIs targeting BCR-ABL1 (Section 1.1.2.2). 
The risk of 80 mg QD of asciminib not being effective has been mitigated in that patients will 
be observed closely for evidence of efficacy, based on assessment of hematologic and molecular 
response data, which will permit rapid decision making as to discontinuation of therapy if 
necessary.
Another relevant risk is the potential for higher rates of toxicity in patients harboring the T315I 
mutation, who will be receiving the dose of 200 mg BID. As previously mentioned, our 
[CABL001X2101] study where more than 50 patients with that mutation were treated with that 
dose showed encouraging safety data and so, it is fairly unlikely that more AEs will be occurring 
in this patient population.
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.
The currently available information suggests that there is equivalence between the two arms 
with respect to benefit / risk to enable inclusion of patients in this study.
There may be unforeseen risks with asciminib which could be serious. Refer to the latest 
[Asciminib Investigator’s Brochure] for additional details.
5
Study Population
One hundred and fifteen (115) patients with CML-CP without T315I mutation who have had at 
least 2 prior TKIs and CML-CP harboring the T315I mutation with at least 1 prior TKI will be 
considered for the current study. Previous medical records should be used to confirm the 
patient’s mutational status/history.
The definition of CML-CP will be according to the European Leukemia Network (ELN) criteria 
(Hochhaus, 2020), 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.


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5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained and signed prior to participation in the study
2. Male or female patients with a diagnosis of CML-CP ≥ 18 years of age
3. Patients must meet all of the following laboratory values at the screening visit:

< 15% blasts in peripheral blood or bone marrow

< 30% blasts plus promyelocytes in peripheral blood or bone marrow

< 20% basophils in the peripheral blood

≥ 50 x 109/L (≥ 50,000/ mm3) platelets

Transient prior therapy related thrombocytopenia (< 50,000/mm3 for ≤ 30 days prior 
to screening) is acceptable

No evidence of extramedullary leukemic involvement, with the exception of 
hepatosplenomegaly
4. Mutation Analysis testing performed at screening. 
5. Prior treatment with a minimum of:

2 prior ATP-site TKIs (i.e. imatinib, nilotinib, bosutinib, dasatinib or ponatinib) in 
case of absence of T315I mutation

1 prior ATP site TKI (i.e. imatinib, nilotinib, bosutinib, dasatinib or ponatinib) in case 
of presence of T315I mutation
6. Failure (adapted from the 2020 ELN Recommendations) or intolerance to the most recent 
TKI therapy at the time of screening

Failure for CML-CP patients (CP at the time of initiation of last therapy) is defined as 
meeting at least one of the following criteria.

Three months after the initiation of therapy: >10% BCR-ABL1 on International 
Scale (IS) if confirmed within 1-3 months

Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS 

Twelve months after initiation of therapy: BCR-ABL1 ratio > 1% IS 

At any time after the initiation of therapy, loss of CHR, MR2 

At any time after the initiation of therapy, the development of new BCR-ABL1 
mutations which potentially cause resistance to current treatment

At any time 12 months after the initiation of therapy, BCR-ABL1 ratio ≥ 1% IS 
or loss of MMR

At any time after the initiation of therapy, new clonal chromosome abnormalities 
in Ph+ cells: CCA/Ph+

Intolerance is defined as:

Non-hematologic intolerance: Patients 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 
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
Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil 
count [ANC] or platelets) while on therapy that is recurrent after dose reduction 
to the lowest doses recommended by manufacturer
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
8. Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of screening 
which are amenable to standardized RQ-PCR quantification.
9. Adequate end organ function, within 12 days before the first dose of asciminib treatment. 
Patients with mild to moderate renal and hepatic impairment are eligible if:

Total bilirubin ≤ 3.0 x ULN with any AST increase

Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value should 
be considered not clinically significant and not associated with risk factors for 
acute pancreatitis

Creatinine clearance ≥ 30 mL/min as calculated using Cockcroft-Gault formula
10. Patients must avoid consumption of grapefruit, Seville oranges or products containing the 
juice of each during the entire study and preferably 7 days before the first dose of study 
medications, due to potential CYP3A4 interaction with the study medications. Orange 
juice is allowed.
11. Patients must have the following electrolyte values (as per central laboratory tests) within 
normal limits or corrected to be within normal limits with supplements prior to first dose 
of study medication:

Potassium (potassium increase of up to 6.0 mmol/L is acceptable at study entry if 
associated with creatinine clearance within normal limits)

Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 
3.1 mmol/L is acceptable at study entry if associated with creatinine clearance within 
normal limits)

Magnesium, with the exception of magnesium increase > ULN – 3.0 mg/dL; > ULN - 
1.23 mmol/L associated with creatinine clearance (calculated using Cockcroft-Gault 
formula) within normal limits.
5.2
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Known second chronic phase of CML after previous progression to AP/BC
2. Previous treatment with a hematopoietic stem-cell transplantation
3. Cardiac or cardiac repolarization abnormality, including any 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)

QTcF at screening ≥450 msec (male patients), ≥460 msec (female patients)


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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 
wwwcrediblemeds.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, pulmonary 
hypertension)
5. History of acute pancreatitis within 1 year of study entry or past medical history of chronic 
pancreatitis
6. Known presence of significant congenital or acquired bleeding disorder unrelated to 
cancer
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. 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)
9. Previous treatment with or known/ suspected hypersensitivity to asciminib or any of its 
excipients.
10. Treatment with medications that meet one of the following criteria and that cannot be
discontinued at least one week prior to the start of treatment with study treatment; 

For Cohort A (40 mg BID) and for Cohort B (80 mg QD) patients not harboring 
the T315I mutation
o
strong inducers of CYP3A

For Cohort C (200 mg BID for patients harboring the T315I mutation) 
o
strong inducers of CYP3A 
o
strong inhibitors of CYP3A 
11. Participation in a prior investigational study within 30 days prior to randomization or 
within 5 half-lives of the investigational product, whichever is longer
12. Pregnant or nursing (lactating) women
13. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception. 
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
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
Female sterilization (have had surgical bilateral oophorectomy (with or without 
hysterectomy) total hysterectomy or bilateral tubal ligation 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 sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject.

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 and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral 
tubal ligation at least six weeks before taking study 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.
14. Sexually active males unwilling to use a condom during intercourse while taking study 
treatment and for 3 days after stopping study (only for patients treated with asciminib). A 
condom is required for all sexually active male participants on asciminib treatment to 
prevent them from fathering a child AND to prevent delivery of study treatment via 
seminal fluid to their partner. In addition, these male participants must not donate sperm 
for the time period specified above.
15. If a patient is presenting with symptoms suggestive of possible COVID-19 infection, we 
advise ruling it out by appropriate testing recommended by health authorities. 

Nucleic acid amplification tests for viral RNA (polymerase chain reaction), in order to 
measure current infection with SARS-CoV-2

Antigen tests for rapid detection of SARS-CoV-2

Antibody (serology) tests to detect the presence of antibodies to SARS-CoV-2
6
Treatment
6.1
Study treatment
The investigational treatments for this study are asciminib (40 mg BID, 80 mg QD or 200 mg 
BID). Novartis will supply asciminib to the investigational site as 20 mg and 40 mg tablets.
6.1.1
Asciminib Dosing Regimen
Asciminib will be supplied as 20 mg or 40 mg strength tablets will be administered orally in 
accordance with the assigned cohort.


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Cohort A
Cohort B
Cohort C 
40 mg BID
80 mg QD
200 mg BID
Asciminib tablets should be ingested as follows:

Asciminib should be administered in the fasted state: avoid food for at least 2 hours before 
the dose is taken and for at least 1 hour after the dose is taken. Water is permitted during 
this period.

Asciminib should be taken with approximately 8 ounces (240 mL) of water.

Asciminib should be swallowed whole and not chewed or crushed.

If vomiting occurs within the first hour after taking the drug, re-dosing is allowed before 
the next scheduled dose.

If the patient does not take asciminib within 6 hours after the approximate time of the 
usual dosing time, that dose should be skipped and treatment should continue with the 
next daily dose at the prescribed level.
6.1.2
Investigational drugs
Table 6-1
Investigational and control drug
Investigational
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
ABL001 20 mg
Tablet 
Oral use
Open Label; 30 ct 
bottle 
Sponsor (Local)
ABL001 40 mg
Tablet 
Oral use
Open Label; 30 ct 
bottle 
Sponsor (Local)
6.1.3
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.4
Treatment Cohorts 
This is an open label, three-cohort, multi-center phase IIIb study of asciminib (ABL001) 
monotherapy in previously treated patients with chronic myeloid leukemia on chronic phase 
(CML-CP) with and without T315I mutation
Patients without T315I mutation status are selected randomly between Cohort A (without T315I) 
and Cohort B (without T315I). Patients harboring the T315I mutation are allocated to Cohort 
C.
Without T315I mutation
With T315I mutation
Cohort A
Cohort B
Cohort C 
40 mg BID
80 mg QD
200 mg BID
6.1.5
Guidelines for continuation of treatment
Not Applicable see Section 6.5.2


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6.1.6
Treatment duration
The patients are treated in the study up to end of study treatment period defined as up to 72 
weeks after the last patient receives the first dose. Patients may be discontinued from treatment 
with the study drug at any time due to unacceptable toxicity, disease progression and/or at the 
discretion of the investigator or the patient.
6.1.6.1
Treatment beyond disease progression
Not Applicable
6.2
Other treatment(s)
6.2.1
Concomitant therapy
The patient 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 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 non-
drug therapies” section of the eCRF.
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 patient are allowed, provided their use is documented in the patient 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 platelet transfusions for patients with 
anemia and with thrombocytopenia.
Permitted concomitant therapy
Drugs that affect gastric pH
Asciminib does not have a pH-dependent solubility. Drugs that elevate gastric pH will not affect 
asciminib absorption. All acid reducing agents are allowed.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
The in vivo potential of asciminib to interact with sensitive CYP3A4/5, CYP2C8 and CYP2C9 
substrates has been evaluated and would indicate a minimal or negligible risk (Section 1.1.2.1). 
Therefore CYP3A4/5, CYP2C8 and CYP2C9 substrates with narrow therapeutic index (NTI) 
should be used with caution. 
As CYP3A4/5 inhibitors may decrease the metabolism of asciminib and resulting in increased 
plasma concentrations and increased exposure, we recommend using them with caution at 
asciminib 40 mg BID and 80 mg QD. Note: at asciminib 200 mg BID the use of strong 
CYP3A4/5 inhibitors should be avoided (see 6.2.2).


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In recombinant cellular expression systems, asciminib was identified as a substrate of BCRP 
(Km ≈ 4 µM) and P-gP (Km could not be estimated due to insufficient saturation of efflux 
activity). Inhibitors of BCRP and P-gP may increase asciminib concentration. Based on human 
ADME study, P-gp may represent maximally 24% of the total clearance resulting in modest 
increase in AUC. Therefore, both BCRP and P-gp inhibitors should be administered with 
caution. If a medication listed in Section 16 appears on both the list of prohibited and the list of 
medications to be used with caution, the medication is prohibited.
6.2.1.2
Use of bisphosphonates
The use of bisphosphonates regardless of indication is allowed.
6.2.2
Prohibited medication
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 patients. These 
patients may remain in the current study after consultation with Novartis. The administration of 
other tyrosine kinase inhibitors indicated for treatment of CML are not allowed. 
Strong CYP3A inducers 
Any strong CYP3A inducers should be discontinued 7 days before the first dose of study 
medications.
Every effort should be made NOT to concomitantly administer strong CYP3A inducers during 
the study. If administration of a strong CYP3A inducer cannot be avoided during the study and 
cannot be switched to an alternative therapy, investigator should exercise caution while patient 
is on study treatment.
Cohort C only (200 mg BID): Strong CYP3A inhibitors
Any strong CYP3A inhibitors should be discontinued 7 days before the first dose of study 
medications. 
Every effort should be made NOT to concomitantly administer strong CYP3A inhibitors. 
CYP3A inhibitors may decrease the metabolism of asciminib and resulting in increased plasma 
concentrations and increased exposure. If administration of a strong CYP3A inhibitor cannot 
be avoided during the study and cannot be switched to an alternative therapy that does not 
strongly inhibit CYP3A, asciminib must be interrupted.
A list of cytochrome P450 isoenzymes and CYP3A inhibitors may be found at 
medicine.iupui.edu/CLINPHARM/ddis/clinical-table. 
A classification of CYP3A SmPC can be found in Section 16, Table 16-2.
Further information can also be found in the following reference (Venkatakrishnan et al 2001).


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UGT1A/2B inducers
The use of strong inducers of UGT1A/2B is prohibited during the study.
If administration of UGT1A/2B inducer cannot be avoided during the study and cannot be 
switched to an alternative therapy, temporary interruption of study treatment is NOT needed.
QT prolonging agents
As far as possible avoid co-administering drugs with a “Known”, “Possible” or “Conditional” 
risk of Torsades de Pointes (per wwwcrediblemeds.org/) during the course of the study:

If concomitant administration of drugs with a “Known risk of Torsades de Pointes” is 
required and cannot be avoided, study drug must be interrupted. If, based on the investigator 
assessment and clinical need, study treatment is resumed, close ECG monitoring is advised. 

If during the course of the study, concomitant administration of a drug with “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 patient safety.
A list of drugs associated with QT prolongation and/or Torsades de Pointes is available online 
at wwwcrediblemeds.org/. 
Herbal medications
Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko 
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Patients should 
stop using these herbal medications 7 days prior to first dose of study drug.
6.2.3
Rescue medication
Not Applicable
6.2.4
Other Concomitant medications
Anti-emetics
Use of anti-emetics is allowed. Prophylactic anti-emetics should be started only once the patient 
experiences nausea or vomiting, at the discretion of the investigator. It is recommended that 
patients use drugs that do not cause QT prolongation. Please note that some anti-emetics have 
a known risk for Torsade de Pointes and are prohibited (refer to Section 6.2.1.1 and Section 16 
Appendix 1).
Contraceptives
Hormonal contraceptives are allowed as contraception methods. Highly effective contraception 
should be maintained throughout the study and for 7 days after study treatment discontinuation.
Anticoagulation agents
All anticoagulants or anti-aggregation agents may be administered under the discretion of the 
investigator.


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Therapeutic doses of warfarin sodium (Coumadin®) or any other coumadin-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-platelet pro-drugs such as 
clopidogrel, ticlopidine and prasugrel, which require metabolic activation by CYP3A4 and 
CYP2C9. While the weak reversible in vitro inhibition potential of asciminib is unlikely to 
translate into clinical significance as the steady-state plasma concentrations at the maximum 
therapeutic doses are significantly lower than the experimentally determined inhibition 
constants, patients using anti-platelet 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.
6.3
Participant numbering, treatment assignment, randomization 
6.3.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available.
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No.
6.3.2
Treatment assignment
For all CML-CP, with the exception of those harboring the T315I mutation, patients will be 
randomly selected to minimize selection bias at the time of cohort allocation. Those patients 
will be assigned to either Cohort A consisting of asciminib 40 mg BID patients or Cohort B 
consisting of asciminib 80 mg QD. For CML-CP patients harboring the T315I mutation, they 
will be assigned to Cohort C with asciminib 200 mg BID, which is the dose required for that 
patient population. Random selection for cohorts A and B will be for the sole purpose of patient 
selection. The study is not powered to show differences in Primary and Secondary endpoints.
6.4
Treatment blinding
Not Applicable


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6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are not permitted.
6.5.1
Dose escalation guidelines
Dose escalation beyond the dose of 40 mg BID, 80 mg QD or 200 mg BID (for patients 
harboring the T315I mutation) is not permitted
6.5.2
Dose modifications
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow the patient to continue 
the study treatment.
These dose modifications are summarized in Table 6-2. The dose reduction indicated as 
“recommendations” is provided to assist investigators in the event the patient 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 40 mg BID is permitted if a change in the patient’s individual benefit/risk assessment 
at the lower dose level is seen. Re-escalation will be allowed only once for any given patient. 
Permanent treatment discontinuation is mandatory for specific events indicated as such in Table 
6-2. Any dose changes must be recorded on the Dosage Administration Record eCRF.
A patient 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 
cytopenias (Table 6-2). If a patient requires a dose interruption of > 28 days for each non-
hematologic toxicity, then the patient 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 TKI interruption and adequate management (including hematopoietic 
growth factors), then the patient must be discontinued from the study treatment. 
These dose changes must be recorded on the appropriate case report form (CRF).
Table 6-2
Criteria for dose reduction / interruption and re-initiation of asciminib 
treatment for adverse drug reactions. 
Dose modifications for asciminib 
Please note that if a patient requires a dose interruption of > 28 days for each toxicity, then the patient 
must be discontinued from the study treatment
Worst toxicity
CTCAE Grade 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 TKI interruption and adequate management 
(including hematopoietic growth factors), then the patient 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 – 
Recommendation: Maintain dose level


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Dose modifications for asciminib 
Please note that if a patient requires a dose interruption of > 28 days for each toxicity, then the patient 
must be discontinued from the study treatment
Worst toxicity
CTCAE Grade 5
Asciminib
1.0 x 109/L)
Grade 3 (ANC < 1.0 – 
0.5 x 109/L)
Mandatory: Hold 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 (ANC < 0.5 x 
109/L)
Mandatory: Hold 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: Hold dose until resolved, then reduce dose  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


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
Dose modifications for asciminib 
Please note that if a patient requires a dose interruption of > 28 days for each toxicity, then the patient 
must be discontinued from the study treatment
Worst toxicity
CTCAE Grade 5
Asciminib
Grade 3 (PLT < 50 - 25 
x 109/L)
Mandatory: Hold 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: Hold 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: For recurrent Grade 3-4 cytopenias:
If resolved to ≤ Grade 2 in ≤ 14 days, then maintain dose level
If resolved in > 14 days, then reduce asciminib and imatinib dose ↓ 1 dose level 
Non-hematologic adverse reactions except where further specified in individual sections
Grade 1
Recommendation: Maintain dose 
level
Recommendation: Maintain dose level
Grade 2
Recommendation: Hold dose until resolved to ≤ Grade 1, then maintain dose level
Grade 3
Mandatory: Hold dose until resolved to ≤ Grade 1, then reduce dose  1 dose level
Grade 4
Mandatory: Permanently discontinue patient from study drug treatment.
Investigations (Renal)
Serum creatinine
Grade 1 (> ULN - 1.5 x 
ULN)
Recommendation: Maintain dose level
Grade 2 (> 1.5 - 3.0 x 
ULN)
Recommendation: Hold dose until resolved to ≤ Grade 1 or baseline, then maintain 
dose level
Grade 3 (> 3.0 - 6.0 x 
ULN)
Mandatory: Permanently discontinue patient from study drug treatment.
Grade 4 (> 6.0 x ULN)
Mandatory: Permanently discontinue patient from study drug treatment.
Investigations (Hepatic)
Isolated total Bilirubin elevation
> ULN – 1.5 x ULN if 
baseline was normal; > 
1.0 - 1.5 x baseline if 
baseline was abnormal
Recommendation: Maintain dose level
> 1.5 - 3.0 x ULN if 
baseline was normal; > 
1.5 - 3.0 x baseline if 
baseline was abnormal
Recommendation: Hold dose. Monitor LFTsb 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; if 
baseline was normal; > 
3.0 - 10 x baseline if 
baseline was 
abnormal*
Mandatory: Hold dose. Monitor LFTsb 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 patient from study drug treatment. The 
patient should be monitored weekly (including LFTsb), or more frequently if clinically 
indicated, until total bilirubin have resolved to baseline or stabilization over 4 weeks.
> 10.0 x ULN; if 
baseline was normal; > 
10 x baseline if 
baseline was 
abnormal*
Mandatory: Permanently discontinue patient from study drug treatment. The patient 
should be monitored weekly (including LFTsb), or more frequently if clinically 
indicated, until total bilirubin have resolved to baseline or stabilization over 4 weeks.
Isolated AST or ALT elevation


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
Dose modifications for asciminib 
Please note that if a patient requires a dose interruption of > 28 days for each toxicity, then the patient 
must be discontinued from the study treatment
Worst toxicity
CTCAE Grade 5
Asciminib
> ULN - 3.0 x ULN if 
baseline was normal; 
1.5-3.0 x baseline if 
baseline was abnormal
Recommendation: Maintain dose level
> 3.0 - 5.0 x ULN if 
baseline was normal; 
3.0 - 5.0 x baseline if 
baseline was abnormal
Recommendation: Maintain dose level. Repeat LFTsb 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 LFTsb weekly, or more 
frequently if clinically indicated, until resolved to ≤ 3.0 x ULN if baseline was normal 
or 1.5 - 3.0 x baseline if baseline was abnormal


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
Dose modifications for asciminib 
Please note that if a patient requires a dose interruption of > 28 days for each toxicity, then the patient 
must be discontinued from the study treatment
Worst toxicity
CTCAE Grade 5
Asciminib
> 5.0 - 10.0 x ULN if 
baseline was normal; 
5.0 - 10.0 x baseline if 
baseline was abnormal
Mandatory: Hold dose. Repeat LFTsb as soon as possible, preferably within 48-72 
hours from awareness of the abnormal results; monitor LFTsb weekly, or more 
frequently if clinically indicated, until resolved to ≤ 3.0 x ULN if baseline was normal 
or 1.5 - 3.0 x baseline if baseline was abnormal: Then
If resolved in ≤ 14 days, maintain dose level
If resolved in > 14 days, reduce dose  1 dose level
> 10.0 - 20.0 x ULN if 
baseline was normal; > 
10.0 - 20.0 x baseline if 
baseline was abnormal
Mandatory: Hold dose. Repeat LFTsb as soon as possible, preferably within 48-72 
hours from awareness of the abnormal results; monitor LFTsb weekly, or more 
frequently if clinically indicated, until resolved to ≤ 3.0 x  ULN if baseline was normal 
or 1.5 - 3.0 x baseline if baseline was abnormal. Then reduce dose  1 dose level.
> 20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline was 
abnormal
Mandatory: Hold dose. Repeat LFTsb as soon as possible, preferably within 48-72 
hours from awareness of the abnormal results; monitor LFTsb weekly, or more 
frequently if clinically indicated, until resolved to ≤ 3 x ULN (or ≤ 5 x ULN for patients 
with baseline value > 3.0 -5.0 x ULN), then resume treatment at reduce dose  1 
dose level. Only 1 dose reduction is allowed; if reoccurs at > 5 x ULN, discontinue 
patient from study drug treatment.


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
Dose modifications for asciminib 
Please note that if a patient requires a dose interruption of > 28 days for each toxicity, then the patient 
must be discontinued from the study treatment
Worst toxicity
CTCAE Grade 5
Asciminib
Combined c elevations of AST or ALT and total bilirubin
For patients with 
normal baseline ALT 
and AST and total 
bilirubin value:
AST or ALT >3.0 x ULN 
combined with total 
bilirubin >2.0 x ULN 
without evidence of 
cholestasisd
For patients with 
elevated baseline AST 
or ALT or total bilirubin 
value
[AST or ALT>2 x 
baseline AND > 3.0 x 
ULN]
Mandatory: Permanently discontinue patient from study drug treatment.
Repeat as soon as possible, preferably within 48 hours from awareness of the 
abnormal results, then with weekly monitoring of LFTsb), or more frequently if 
clinically indicated, until AST, ALT, or bilirubin have resolved to baseline or 
stabilization over 4 weeks. Refer to Section 6.5.3 for additional follow-up evaluations 
as applicable.
Investigation (metabolic)
Asymptomatic amylase and/or lipase elevation
Grade 1 (> ULN - 1.5 x 
ULN)
Recommendation: Maintain dose level, measure 2x week
Grade 2 (> 1.5 - 5.0 x 
ULN)
Recommendation: Maintain dose level, measure 2x week
Grade 3 (> 5.0 x ULN)
Mandatory: Hold 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., MRI, CT scan or ultrasound).
Grade 4 (> 5.0 x ULN 
and with signs and 
symptoms)
Mandatory: Permanently discontinue patient from study drug treatment. Obtain 
appropriate imaging (i.e., MRI, CT scan or ultrasound).


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Dose modifications for asciminib 
Please note that if a patient requires a dose interruption of > 28 days for each toxicity, then the patient 
must be discontinued from the study treatment
Worst toxicity
CTCAE Grade 5
Asciminib
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 current antihypertensive drug or change 
treatment plan as per investigator assessment
Systolic BP ≥160 mm 
Hg or Diastolic BP 
≥100 mm Hg 
Mandatory: Hold dose until resolved ≤ Grade 1/baseline, then reduce dose  1 
dose level. Initiate antihypertensive drug/increase the dose of current 
antihypertensive drug or change treatment plan as per investigator 
assessment
CTCAE Grade 4
Mandatory: Permanently discontinue patient from study drug treatment.
Gastro intestinal
Pancreatitis
Grade 2 (radiologic 
findings for pancreatitis 
as per CTCAE v5, for 
increased enzymes 
please see table for 
asymptomatic amylase 
and/or lipase elevation)
Mandatory: If asymptomatic radiologic pancreatitis, hold treatment until recovery of 
the radiologic findings. 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 patient 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: Hold dose until resolved to ≤ grade 1, then maintain dose level.
If diarrhea returns as ≥ grade 2, then hold dose until resolved to ≤ grade 1, then 
reduce dose  1 dose level
Grade 3
Recommendation: Hold dose and discontinue patient from study drug treatment
Grade 4
Mandatory: Permanently discontinue patient from study drug treatment


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Dose modifications for asciminib 
Please note that if a patient requires a dose interruption of > 28 days for each toxicity, then the patient 
must be discontinued from the study treatment
Worst toxicity
CTCAE Grade 5
Asciminib
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: Hold dose until resolved to Grade ≤ 1, then:
If resolved in ≤ 7 days, then reduce dose  1 dose level
If resolved in > 7 days (despite appropriate skin toxicity therapy), then discontinue 
patient from study drug treatment
Grade 4, despite skin 
toxicity therapy
Mandatory: Permanently discontinue patient from study drug treatment.
General disorders and administration site conditions
Fatigue/ Asthenia
Grade 1 or 2
Recommendation: Maintain dose level
Grade 3
Recommendation: Hold 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 Adverse Events (CTCAE Version 5)
b Core LFTs consist of ALT, AST, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x ULN), 
and alkaline phosphatase (fractionated [quantification of isoforms], if alkaline phosphatase > 2.0 x ULN).
c “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin 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 hold dose is 
needed for one parameter and discontinue treatment is required for another parameter). After all elevations 
resolve to the 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 ALP elevation (>2.0 x ULN and R value <2) in patients without bone metastasis, or 
elevation of ALP liver fraction in patients 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 total bilirubin > 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, patients will be discontinued permanently 
from study treatment.
*** Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt 
diarrhea


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Table 6-3
Dose reduction steps for asciminib
Dose reduction*
Starting dose level – 0
Dose level – 1
Asciminib 40 mg 
BID
40 mg tablet BID (total daily dose 80 mg)
20 mg tablet BID (total daily dose 40 mg)
Asciminib 80 mg 
QD
40 mg tablet + 40 mg tablet = 80 mg once 
daily
40 mg tablet once daily
Asciminib 200 
mg BID
40 mg tablet x 5 = 200 mg BID
40 mg tablet x 5 = 200 mg once daily
*Dose reduction should be based on the worst toxicity demonstrated at the last dose.
Asciminib dose reduction below total daily 40 mg is not allowed. 20 mg tablets will be dispensed to patients in 
the instance of dose reduction.
6.5.2.1
Dose adjustments for QTcF prolongation
If QTcF >500 msec or QTcF prolongation >60 msec from baseline is observed at any point 
during study treatment, and confirmed, the below guidance must be followed:
1. Assess the quality of the ECG recording and the QT value and repeat if needed
2. Interrupt study treatment until confirmed resolution of QTcF and as per dose reduction 
guidelines for non-hematological AEs.
3. Determine the serum electrolyte levels (in particular hypokalemia and hypomagnesemia). 
If abnormal, correct abnormalities before resuming study treatment.
4. Review concomitant medication associated with QT prolongation, including drugs with a 
“Known”, “Possible”, or “Conditional risk of Torsades de Pointes” (refer to 
wwwcrediblemeds.org/), and drugs with the potential to increase the risk of study drug 
exposure related QT prolongation.
5. Check the dosing schedule and treatment compliance
After confirming ECG reading at site, if QTcF > 500 msec

Interrupt study treatment

Repeat ECG and confirm ECG diagnosis by a cardiologist or central ECG lab

If QTcF confirmed > 500 msec: 

Correct electrolytes, eliminate culprit concomitant treatments, and identify 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 msec

After resolution to ≤ 480 msec, consider re-introducing treatment at reduced dose, and 
increase ECG monitoring (e.g., pre dose and 2 hours post dose after one week and two 
weeks of treatment re-introduction) 

If QTcF remains ≤ 500 msec after dose reduction, continue planned ECG monitoring 
during subsequent treatment

If QTcF recurs > 500 msec after dose reduction, discontinue subject from trial


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6.5.3
Follow-up for toxicities
Patients whose treatment is permanently discontinued due to a study drug related adverse event 
or clinically significant laboratory value, must 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 patients must be followed up for adverse events and serious adverse 
events for 30 days following the last dose of study treatment. 
6.5.3.1
Follow up on potential drug-induced liver injury (DILI) cases
Participants with transaminase increase combined with total bilirubin increase may be 
indicative of potentially severe 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 total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below:

For participants with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN

For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or 
ALT >3.0 x baseline] OR [ALT or AST > 8.0 x ULN], whichever occurs first, combined 
with [total bilirubin > 2.0 x baseline AND > 2.0 x ULN]
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before 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, total bilirubin, direct and indirect bilirubin, GGT, 
GLDH, prothrombin time (PT)/INR, alkaline phosphatase, albumin, and creatine kinase.
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, ERCP) as appropriate, to rule out an 
extrahepatic cause of cholestasis. Cholestasis (is defined as an 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. For children, 
there are caveats to calculating the R-ratio as normal levels of ALP are higher than in adults 
with standard ranges varying by developmental age. In clinical situations where it is suspected 
that ALP elevations are from an extrahepatic source, the GGT can be used if available. GGT 


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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 (livertox.nih.gov/rucam.html).
Table 6-8 
Provides guidance on specific clinical and diagnostic assessments that 
can be performed to rule out possible alternative causes of observed LFT 
abnormalities.
Disease
Assessment
Hepatitis A, B, C, E
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, 
HCV RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis
ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis
Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic 
steatohepatitis
Ultrasound or MRI
Hypoxic/ischemic 
hepatopathy
Medical history: acute or chronic CHF, hypotension, hypoxia, hepatic 
venous occlusion. Ultrasound or MRI.
Biliary tract disease
Ultrasound or MRI, ERCP as appropriate.
Wilson disease (if <40 yrs 
old)
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; CVD / ischemic hepatitis – ECG, prior 
hypotensive episodes; T1D / glycogenic hepatitis).
.
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 LFT 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.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Total daily dose of study treatment administered with start and end date will be collected on the 
Dosage Administration Record eCRF page. Name, start and end dates of any Concomitant 


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Medications and Surgical and Medical procedures will be collected on the Prior and 
Concomitant medications and Surgical and Medical procedures eCRFs respectively.
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
dispensing patient visit.
6.6.2
Emergency breaking of assigned treatment code
Not Applicable
6.6.3
Special Considerations for COVID-19 infection
All patients that who present with COVID-19 infection or who become COVID-19 positive on 
treatment should be placed immediately on treatment break or delay while a determination is 
made about the next steps
A request to start or continue treatment of COVID-19 positive patients should be considered in 
the context of medical necessity to start or continue treatment with the study drug.
Many patients with previous COVID-19 infection may be appropriate to be considered eligible 
for inclusion in the study if tested negative after initial infection
6.7
Preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
Each study site will be supplied with study drug in packaging as described under investigational 
drugs section.
A unique medication number is printed on the study medication label.
The IRT will select the study treatment to dispense to the subject. The study medication has a 
2-part label (base plus tear-off label), immediately before dispensing the package to the subject, 
site personnel will detach the outer part of the label from the package and affix it to the subject’s 
source document.
6.7.1
Handling of study treatment and additional treatment 
6.7.1.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
the respective Novartis CO Quality Assurance.


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Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.7.1.2
Handling of additional treatment 
Not Applicable
6.7.2
Instruction for prescribing and taking study treatment
See Section 6.1.1
7
Informed consent procedures 
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject.


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Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
Male subjects on asciminib treatment must be informed that if a female partner becomes 
pregnant while the male subject is enrolled in the study, contact with the female partner will be 
attempted to request her consent to collect pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
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. Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants who prematurely discontinue the 
study for any reason should be scheduled for a visit 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 recorded on the CRF.
No eCRF will be used as a source document.
(S) is defined as “Source”
(D) is defined as “Data Based”


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Amended Clinical Trial Protocol Version 03 (Clean)                                                      
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Table 8-1
Assessment schedule 
Category
Protocol 
Section 8
Screening 
Phase
Treatment Phase
Visit name
Screening/ 
Baseline (Day -
21 to -1)
Week 1 Day 1
Week 2 Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
Week 52
Obtain Informed Consent
D
X
(Screening 
window -56 
days)
Eligibility 
checklist/registration
D
X
Cohort Assignment
D
6.3.2
X
Demography
D
8.2
X
Inclusion/exclusion 
criteria
D
5.1
X
Medical History
D
8.2
X
Disease History
D
8.2
X
Mutation status
D
8.2
X
Prior antineoplastic 
therapy
D
8.2
X
Prior TKI therapy
D
8.2
X


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Amended Clinical Trial Protocol Version 03 (Clean)                                                      
              Protocol No. CABL001AUS04
Category
Protocol 
Section 8
Screening 
Phase
Treatment Phase
Visit name
Screening/ 
Baseline (Day -
21 to -1)
Week 1 Day 1
Week 2 Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
Week 52
Prior/concomitant 
medications
D
6.2
X
Continuous
Physical examination
S
8.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Extramedullary 
Involvement
D
8.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance 
status
D
8.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height 
D
8.3
X
Weight
D
8.3
X
X
X
X
X
X
Vital signs
D
8.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory 
assessments
Hematology
D
8.3.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
8.3.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry-
Hemoglobin A1c
D
8.3.1
X
Week 12 and as clinically indicated
Serum Pregnancy 
test (if applicable)
D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis markers
D
X


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Amended Clinical Trial Protocol Version 03 (Clean)                                                      
              Protocol No. CABL001AUS04
Category
Protocol 
Section 8
Screening 
Phase
Treatment Phase
Visit name
Screening/ 
Baseline (Day -
21 to -1)
Week 1 Day 1
Week 2 Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
Week 52
Liver assessments
D
as clinically indicated
Efficacy assessments
Blood collection for 
BCR-ABL1 
quantification by RQ-
PCR
D
8.4.1
X
X
X
X
X
X
Hematologic 
Response 
Assessment
D
8.4.1
X
X
X
X
Cardiac Assessments
ECG
D
8.3.2
X
X
X
X
Xα
X
X
X
X


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Amended Clinical Trial Protocol Version 03 (Clean)                                                      
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Category
Protocol 
Section 8
Screening 
Phase
Treatment Phase
Visit name
Screening/ 
Baseline (Day -
21 to -1)
Week 1 Day 1
Week 2 Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
Week 52
Cardiovascular risk 
factor assessments 
(including Family 
History)
D
8.3.2
X
Echocardiogram
D
8.3.2
X
X*
Pulmonary Function 
Test
D
8.3.2
X*
X*
Adverse events / SAE
D
10.1
X
Continuous


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Amended Clinical Trial Protocol Version 03 (Clean)                                                      
              Protocol No. CABL001AUS04
Category
Protocol 
Section 8
Screening 
Phase
Treatment Phase
Visit name
Screening/ 
Baseline (Day -
21 to -1)
Week 1 Day 1
Week 2 Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
Week 52
Asciminib Drug 
administration
D
6.1
Continuous
Progression Status
D
X
X
X
Category
Protocol 
Section 8
Treatment Phase
EOT /Early 
Discontinuation
30 days Safety 
follow-up
Visit Name
Week 56
Week 60
Week 64
Week 68
Week 72
Prior/concomitant 
medications
D
6.2
Continuous


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Amended Clinical Trial Protocol Version 03 (Clean)                                                      
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Category
Protocol 
Section 8
Treatment Phase
EOT /Early 
Discontinuation
30 days Safety 
follow-up
Visit Name
Week 56
Week 60
Week 64
Week 68
Week 72
Physical examination
S
8.3
X
X
X
X
X
Extramedullary 
Involvement
D
8.3
X
X
X
X
X
ECOG Performance 
D
8.3
X
X
X
X
X
Weight
D
8.3
X
X
Vital signs
D
8.3
X
X
X
X
X
Laboratory assessments
Hematology
D
8.4.1
X
X
X
X
X
Chemistry
D
8.4.1
X
X
X
X
X
Chemistry-
Hemoglobin A1c
D
8.4.1
as clinically indicated
Serum Pregnancy test 
(if applicable)
D
8.3
X
X
X
X
X
Liver assessments
D
as clinically indicated
Efficacy assessments
Blood collection for 
BCR-ABL1 quantification 
by RQ-PCR
D
8.4.1
Xβ
X


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Amended Clinical Trial Protocol Version 03 (Clean)                                                      
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Category
Protocol 
Section 8
Treatment Phase
EOT /Early 
Discontinuation
30 days Safety 
follow-up
Visit Name
Week 56
Week 60
Week 64
Week 68
Week 72
Hematologic Response 
Assessment
D
8.4.2
X
Cardiac Assessments
ECG
D
8.3.2
X
X
Cardiovascular risk 
factor assessments 
(including Family History)
D
8.3.2
X
Echocardiogram
D
8.3.2
X*
Adverse events / SAE
D
10.1.1
Continuous


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Amended Clinical Trial Protocol Version 03 (Clean)                                                      
              Protocol No. CABL001AUS04
Category
Protocol 
Section 8
Treatment Phase
EOT /Early 
Discontinuation
30 days Safety 
follow-up
Visit Name
Week 56
Week 60
Week 64
Week 68
Week 72
Asciminib Drug 
administration 
D
Continuous
Antineoplastic therapies 
since discontinuation of 
study treatment
D
X
Progression status
D
X
X = assessment to be recorded in the clinical database or received electronically from a vendor
S = assessment to be recorded in the source documentation only
α = only applicable to Cohort C
* = If clinically indicated
** = Upon confirmed loss of MMR and/or End of Treatment
β = only applicable if the visit is in-person
Study visits from Week 2 Day 1 will have an allowed “visit window” of +/- 2 day for Week 2 Day 1. Study visits from Week 4 to Week 72 (EOT) will have 
an allowed “visit window” of +/- 7 days.


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
8.1
Screening
Molecular pre-screening
Not Applicable
Screening
Written informed consent must be obtained before any study specific medical procedures are 
performed. All screening/baseline assessments should occur within 21 days before Week 1 Day 
1.
During the screening visit, inclusion and exclusion criteria will be assessed. Screening 
assessments to confirm eligibility must be performed prior to randomization. The results of the 
real time quantitative polymerase chain reaction (RQ-PCR) must be available prior to 
randomization and first dose of study treatment.
For details of assessments required during screening please refer to Table 8-1.
Laboratory baseline assessments (including hematology, chemistry and serum pregnancy test), 
physical examination including extramedullary involvement, performance status, ECG, height, 
weight and vital signs, evaluation of all relevant medical history including cardiovascular risk 
factors, CML disease history, including prior TKI therapy and antineoplastic medication and 
prior and concomitant medication must be performed prior to the first dose of study treatment. 
Patients 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 the first dose of study drug.
A patient who has a laboratory test (peripheral blood test) 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 approximately 2 weeks of the original screening visit 
date. In this case, the subject will not be required to sign another Informed Consent Form (ICF), 
and the original patient 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 patient is considered a screen failure, and must be discontinued from the study.
A new ICF will need to be signed if the investigator chooses to re-screen the patient after a 
patient has screen failed, however, a new patient ID number will be assigned. All required 
screening activities must be performed when the patient is re-screened for participation in the 
study. An individual patient may be re-screened up to three times for the study. Once the number 
of patients screened and enrolled is likely to ensure target enrollment, the Sponsor may close 
the study to further screening. In this case, the patients who screen failed will not be permitted 
to re-screen.
8.1.1
Eligibility screening
Following registration in the IRT for screening, participant eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
Please refer and comply with detailed guidelines in the IRT manual. The investigator site will 
then be allowed to assign treatment to the participant. For treatment assignment, please see 
Section 6.3.2
8.1.2
Information to be collected on screening failures
Participants who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
Case Report Form. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure participants. No other data will be entered into 
the clinical database for participants who are screen failures, unless the participant experienced 
a serious adverse event during the screening phase (see SAE section for reporting details).
Participants who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered an early terminator. The reason for early termination 
should be captured on the appropriate disposition Case Report Form.
8.1.3
Treatment Period
All patients will be given the opportunity to receive study treatment until the end of study 
treatment period as defined in Section 6.1.
During the treatment phase, the patients will receive either asciminib treatment 40 mg BID, 80 
mg QD or 200 mg (if T315I Mutation). 
The dose can be modified, if required from the perspective of tolerance, following the guidance 
in Section 6.5. Treatment will be administered until patient experiences treatment failure, 
unacceptable toxicity, disease progression, death, lost to follow-up and/or treatment is 
discontinued at the discretion of the investigator or withdrawal of consent. 
The patients are advised to adhere to the food restrictions during the treatment (fasting status 
regarding study treatment administration, avoidance of prohibited concomitant medication).
8.1.4
Visit Windows
Study visits from Week 1 Day 1 to Week 2 Day 1 should be completed on the designated date 
[with an allowed “visit window” of +/- 2 day for Week 1 Day 1 and Week 2 Day 1]. All visits 
up until Week 4 day 1 need to be performed live by the treating physician on the site.
Study visits from Week 4 to Week 72 (EOT) should be completed every 4 weeks on the 
designated date [with an allowed “visit window” of +/- 7 days]. After Week 4 day 1, remote 
visits can be performed using tele-medicine approach with the exception of visits on Weeks 12, 
24, 36, 48 and 72. 
A delayed visit will have no impact on the next planned visit. The next visit should be completed 
as scheduled in order to avoid accumulation of additional weeks.
8.2
Participant demographics/other baseline characteristics
Patient demographics and baseline characteristics collected will include the following: date of 
birth, gender (and child bearing potential for female), race and ethnicity, height, weight, all 
relevant medical history including cardiovascular disease history, CML disease history, 


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
including mutation status, and prior and concomitant medication including prior TKI therapy 
and antineoplastic medication.
Physical examination including extramedullary involvement, performance status, vital signs, 
ECGs, and laboratory assessments will be performed at screening.
Significant findings that were present prior to the signing of informed consent must be included 
in the Relevant Medical History/Current Medical Conditions page on the subject’s eCRF. 
Significant new findings that begin or worsen after informed consent must be recorded on the 
AE page of the patient’s eCRF.
The central reading of the screening ECGs as well as the results of the RQ-PCR must be 
available prior to the first dose of study treatment to evaluate eligibility and to stratify the patient.
8.3
Safety and tolerability
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
Significant findings that were present prior to the signing of informed consent must be included 
in the Relevant Medical History/Current Medical Conditions page on the patient’s eCRF. 
Significant new findings that begin or worsen after informed consent must be recorded on the 
AE page of the patient’s eCRF.
For details on AE collection and reporting, refer to AE section.
Table 8-4
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 about the physical examination must be 
present in the source documentation at the study center and will be 
collected on the following visits as specified in Table 8-1 :
Screening
Week 1 Day 1, Week 4
With the exception of Weeks 12, 24, 36, 48 and 72, Physical 
examination can be omitted for the remainder of the protocol. 
Significant findings that were present prior to the signing of informed 
consent must be included in the Medical History page on the patient’s 
eCRF. Significant new findings that begin or worsen after informed 
consent must be recorded on the Adverse Event page of the patient’s 
eCRF. 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. liver and spleen size, any other 
organ involvement).
Vital signs
Vital signs include blood pressure (supine position preferred when ECG 
is collected), pulse measurement, and body temperature and must be 
performed at the following visits as specified in Table 8-1:

Screening


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
Assessment
Specification

Week 1 Day 1

Week 2 Day 1

Week 4
With the exception of Weeks 12, 24, 36, 48 and 72, Vital Signs can be 
omitted if for the remainder of the protocol
Height and weight
Height in centimeters (cm) will be measured at screening only.
Body weight (to the nearest 0.2 pounds [lb] in indoor clothing, but 
without shoes) will be measured at screening and at subsequent time 
points as specified in Table 8-1:

Screening

Week 1 Day 1
With the exception of Weeks 12, 24, 36, 48 and 72, Height and Weight 
can be omitted for the remainder of the protocol
Performance status:
ECOG Performance status scale (Table 8-5) will be used as described in the Table 8-1:

Screening

Week 1 Day 1

Every 4 weeks from Week 4 to Week 72 (End of treatment) or early discontinuation in 
case of premature discontinuation.

More frequent examinations may be performed at the investigator’s discretion, if 
medically indicated.
ECOG Performance status scale will be used as described in Table 8-5.
Table 8-5
Table ECOG Performance Status Scale
Description
Grade
Fully active, able to carry on all pre-disease activities without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature e.g. light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead.
5
8.3.1
Laboratory Evaluations
Central laboratory will be used for analysis of hematology and clinical chemistry as specified 
in the visit schedules in Table 8-1 and Table 8-6 . Details on the collections, shipment of the 
samples and reporting of results by the central laboratory are provided to investigators in the 
[CABL001AUS04 Laboratory Manual]. The time windows granted for laboratory evaluations 
are identical with the corresponding visit time windows for each visit.
Local laboratory analysis are allowed only if there is a clinical suspicion of abnormal laboratory 
values which is supported by a reported adverse event. 


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When abnormal laboratory values or test results constitute an adverse event (i.e. induces clinical 
signs/symptoms or requires therapy) they must be recorded on the Adverse Events eCRF. 
Abnormal laboratory values or test results constitute adverse events only if they induce clinical 
signs or symptoms, are considered clinically significant (e.g. cause study discontinuation or 
constitutes in and of itself a Serious Adverse Event) or require therapy (e.g., any hematologic 
abnormality that requires transfusion or cytokine treatment); and should be recorded on the 
Adverse Events eCRF under the signs, symptoms or diagnosis associated with them. Refer to 
the visit schedule for the collection frequency.
8.3.1.1
Hematology
Hematology labs are to be analyzed at each scheduled visit by a central laboratory as specified 
in Table 8-1 and Table 8-6 . Hematology includes assessment of hemoglobin, platelets count, 
red blood cells, total white blood cell count (WBC) and a full manual differential count 
including basophils, eosinophils, lymphocytes, monocytes, neutrophils, promyelocytes, 
myelocytes, metamyelocytes, blast and other cells (Table 8-6 ).
8.3.1.2
Clinical chemistry
Blood chemistry labs are to be analyzed at each scheduled visits by a central laboratory as 
specified in Table 8-1 and Table 8-6 . Chemistry includes albumin, alkaline phosphatase, ALT 
(SGPT), AST (SGOT), total calcium, total calcium (corrected for albumin), creatinine, 
creatinine clearance, creatine kinase, potassium, magnesium, sodium, phosphate (inorganic 
phosphorus), direct bilirubin, indirect bilirubin, total bilirubin, total cholesterol, LDL 
cholesterol, HDL cholesterol, total protein, triglycerides, blood urea, Blood Urea Nitrogen 
(BUN), uric acid, amylase, lipase and fasting glucose. 
HbA1c is analyzed at screening/baseline, week 12 and as clinically indicated.
The hepatitis markers HbsAg, HbcAb/anti-Hbc are analyzed at screening/baseline (Table 8-6 ).
Table 8-6 
Clinical laboratory parameters collection plan
Test Category
Test Name
Frequency
Hematology
Hemoglobin, platelets, red blood cells, 
white blood cells, WBC morphology with 
differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils, 
promyelocytes, myelocytes, 
metamyelocytes, blast and other)
Screening/baseline, Week 1 Day 1, 
Week 2 Day 1, every 4 weeks from 
week 4 up to Week 72 (EOT) and as 
clinically indicated
Chemistry
Hemoglobin A1c
Screening/baseline, Week 12 and as 
clinically indicated 
Chemistry
Creatinine clearance
Screening/baseline 


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
Test Category
Test Name
Frequency
Chemistry
Albumin, alkaline phosphatase, ALT 
(SGPT), AST (SGOT), total calcium, 
total calcium (corrected for albumin), 
creatinine, creatine kinase, potassium, 
magnesium, sodium, phosphate 
(inorganic phosphorus), direct bilirubin, 
indirect bilirubin, total bilirubin, total 
cholesterol, LDL cholesterol, HDL 
cholesterol, total protein, triglycerides, 
blood urea or Blood Urea Nitrogen 
(BUN), uric acid, amylase, lipase, 
glucose (fasting) 
Screening/baseline, Week 1 Day 1, 
Week 2 Day 1, every 4 weeks from 
week 4 up to week 72, (EOT), and as 
clinically indicated 
Hepatitis 
markers
HbsAg, HbcAb /anti-Hbc
Screening/baseline
Serum 
Pregnancy test 
(if applicable)
Serum ß-HCG testing
Screening/baseline, every 4 weeks 
up to week 72 (EOT), unscheduled
8.3.2
Cardiac Assessments
8.3.2.1
Electrocardiogram (ECG)
After the subject has rested approximately 10 minutes in a semi-supine position, standard 12-
lead ECGs must be obtained in triplicate with a recommended minimal interval of 5 minutes 
between each ECG at the time points specified in Table 8-1, and Table 8-5. In this case 
recording of ECGs should be planned according to the true time of blood sample 
 
 rather than to the scheduled time point.
A standard 12 lead ECG will be performed:

For Cohort A, B and C at screening and/or baseline, Week 1 day 1, Week 2 Day1, Week 4 
Day 1, Week 12 Day 1, Week 24 Day 1, Week 36 Day 1, Week 48 Day 1, Week 60 Day 
1, Week 72 Day 1 (end of study).

Cohort C will require additional Week 8 Day 1 ECG in addition to the schedules 
mentioned above. 
Table 8-2
ECG collection plan 
Week (or Cycle)
Time
ECG Type
Number of ECGs (per 
Visit)
Screening/Baseline 
Day -21 to -1 / (all 
patients)
3 serial ECGs at the 
screening visit
12 Lead
3
Week 1 Day 1
3 serial ECGs at 2 h 
post dose
12 Lead
3
Week 2 Day 1
3 serial ECGs pre-
dose and at 2, 3, 4 h 
post dose
12 Lead
12


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
Week (or Cycle)
Time
ECG Type
Number of ECGs (per 
Visit)
Week 4 Day 1
3 serial ECGs pre-
dose
12 Lead
3
Week 8 Day 1*
3 serial ECGs pre-
dose
12 Lead
3
Week 12 Day 1
3 serial ECGs pre-
dose
12 Lead
3
Week 24 Day 1
3 serial ECGs pre-
dose
12 Lead
3
Week 36 Day 1
3 serial ECGs pre-
dose
12 Lead
3
Week 48 Day 1
3 serial ECGs pre-
dose
12 Lead
3
Week 60 Day 1+
3 serial ECGs pre-
dose
12 Lead
3
Week 72 Day (end of 
study) 1
3 serial ECGs 30 min 
post-dose
12 Lead
3
Unscheduled or 
Unplanned sample
3 serial ECGs
12 Lead
3
30 min +/- 5min allowed
* Week 8 day 1 assessment is only applicable to Cohort C and in-person 
visit
+ only applicable to in-person visit
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 
[CABL001AUS04 ECG Manual].
Three serial ECGs (triplicate) should be performed ½ hour prior to dosing for pre-dose 
assessment. The serial ECGs should be taken approximately 5 minutes apart. All 3 ECGs for 
each time point should be sent to central ECG reader. Readings for QTc prolongation will be 
based on the average seen in the scans for each time point. The enrollment of patients 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 msec (male) or ≥ 460 msec (female) by automated reading, an immediate 
manual central reading must be requested by either contacting the medical monitor or by calling 
central ECG reader. The patient may not be dosed if the average of the manually read ECGs 
confirms a QTcF ≥ 450 msec (male) or ≥ 460 msec (female).
Dose adjustments in case of QT prolongation should be performed per Section 6.5.2.1
Additional unscheduled ECGs may be repeated at the discretion of the investigator at any time 
during the study as clinically indicated. 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.
All ECGs, including unscheduled triplicate safety ECGs with clinically relevant findings, 
collected during the study should be transmitted to the central core ECG laboratory for review.


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The results of the centrally assessed ECGs are automatically transferred into the clinical 
database.
Clinically significant ECG abnormalities present at screening should be reported on the Medical 
History eCRF page. New or worsened clinically significant findings occurring after informed 
consent must be recorded on the Adverse Events eCRF page.
8.3.2.2
Echocardiogram
Echocardiograms will be performed to monitor cardiac safety. Assessments are scheduled at 
screening/baseline, and if clinically indicated at Week 20 and end of treatment visits. 
Echocardiogram is the only acceptable assessment for cardiac safety. The echocardiogram will 
be performed at the discretion of the treating physician locally if he/she recommends assessing 
the left ventricular ejection fraction due to potential concerns for cardiac safety. Any clinically 
significant findings will be collected and reported in the database (i.e. reported as adverse 
events).
8.3.2.3
Cardiovascular risk factor assessment
Cardiovascular events (CVE) including ischemic heart disease, peripheral arterial occlusive 
disease and ischemic cerebrovascular events have been reported in CML patients receiving TKI 
therapies as specified in Table 8-1. Since the study treatment in the trial is TKIs (asciminib), 
the cardiovascular risk factors (hypertension, tobacco use, raised blood glucose (diabetes), 
physical inactivity, unhealthy diet, cholesterol/lipids, overweight and obesity) of each patient 
will be collected prior to randomization and end of treatment. This will also include the patients 
Family History.
8.3.2.4
Pulmonary function test
Pulmonary function test will only be performed if clinically indicated by treating physician. 
The pulmonary function test with the plethysmograph includes the assessment of the lung 
volumes FEV1, FVC, FEV1/FVC, TLC and VC. In addition the DLCO to evaluate the gas 
exchange will be assessed at the same time of testing if indicated. Any clinically significant 
findings will be collected and reported in the database (i.e. reported as adverse events). 
8.3.3
Pregnancy and assessments of fertility
All women of childbearing potential have to complete a serum pregnancy test at the screening 
visit, at every monthly visit until end of treatment visit. Pregnancy testing is not required for 
patients 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. Refer to Table 
8-1 and Table 8-6  of the Visit evaluation schedules. Serum pregnancy test will be performed 
by a central laboratory.
Pregnancies diagnosed in female patients participating in the study (including female partners 
of male patients) should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the Oncology Novartis Chief Medical Office and Patient Safety (CMO&PS) 
Department.


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During the whole study, women of childbearing potential should employ the use of highly 
effective contraception. Highly effective contraception methods are defined in Section 5.2.
Sexually active males on asciminib treatment must use a condom during intercourse while 
taking the drug and for at least 3 days after stopping treatment and should not father a child 
within this period. A condom is required to be used also by vasectomized men in order to 
prevent delivery of the drug via seminal fluid. In addition, male participants must not donate 
sperm for the time period specified above.
8.3.4
Other safety evaluations
Not Applicable
8.3.5
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/participant population.
8.4
Efficacy
8.4.1
Molecular Response
Molecular response (MR) BCR-ABL1 will be assessed in all patients assigned Cohort A, B and 
C. The molecular response for all patients are to be assessed centrally. 
Levels of BCR-ABL1 transcripts will be determined by real-time quantitative PCR (RQ-PCR) 
testing of peripheral blood and analyzed at a central testing laboratory. Log reduction in BCR-
ABL1 transcripts levels from the standardized baseline value, or the percent ratio of BCR-ABL1 
transcripts versus control gene (ABL) transcripts converted to a reference standard, 
international scale (Hughes and Branford 2006), will be calculated for each sample.
MR2 and related variables are defined as the following:

Rate of MR2 where MR2 is defined as a ≥ 2 log reduction in BCR-ABL1 transcripts 
compared to the standardized baseline equivalent to ≤ 1% BCR-ABL1/ABL % by 
international scale as measured by RQ-PCR, confirmed by duplicate analysis of the same 
sample

Time to MR2 defined as the time from the date of start of study treatment to the date of 
the first documented MR2

Duration of MR2 defined as the time from the date of first documented MR2 to the 
earliest date of loss of MMR, progression to AP or BC, or CML-related death
Major molecular response (MMR) and related variables are defined as the following:

Rate of Major Molecular Response (MMR) where MMR is defined as a ≥ 3.0 log 
reduction in BCR-ABL1 transcripts compared to the standardized baseline equivalent to ≤ 
0.1 % BCR-ABL1/ABL % by international scale as measured by RQ-PCR, confirmed by 
duplicate analysis of the same sample

Time to MMR defined as the time from the date of start of study treatment to the date of 
the first documented MMR,

Duration of MMR defined as the time from the date of first documented MMR to the 
earliest date of loss of MMR, progression to AP or BC, or CML-related death.


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MR4 and related variables are defined as the following:

Rate of MR4 where MR4 is defined as a ≥ 4 log reduction in BCR-ABL1 transcripts 
compared to the standardized baseline equivalent to ≤ 0.01% BCR-ABL1/ABL % by 
international scale as measured by RQ-PCR, confirmed by duplicate analysis of the same 
sample

Time to MR4 defined as the time from the date of start of study treatment to the date of 
the first documented MR4,

Duration of MR4 defined as the time from the date of first documented MMR to the 
earliest date of loss of MR4, progression to AP or BC, or CML-related death.
MR4.5 and related variables are defined as the following:

Rate of MR4.5 where MR4.5 is defined as a ≥ 4.5 log reduction in BCR-ABL1 transcripts 
compared to the standardized baseline equivalent to ≤ 0.0032% BCR-ABL1/ABL % by 
international scale as measured by RQ-PCR, confirmed by duplicate analysis of the same 
sample

Time to MR4.5 defined as the time from the date of start of study treatment to the date of 
the first documented MR4.5

Duration of MR4.5 defined as the time from the date of first documented MMR to the 
earliest date of loss of MR4.5, progression to AP or BC, or CML-related death
Loss of Responses 
Loss of MR2 is defined as increase of BCR-ABL1/ABL to > 1% by international scale (IS). 
BCR-ABL less than 1% according to the IS can be regarded as an equivalent to CCyR. Loss of 
MR2 must be confirmed by subsequent sample analysis within 4 to 6 weeks.
Loss of MMR is defined as increase of BCR-ABL1/ABL to > 0.1% by international scale (IS) 
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. Loss of MMR 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 to AP/BC or CML-related death. 
Mutational Analysis (T315I mutation)
Mutational analysis will be performed at a Novartis designated laboratory by Sanger sequencing 
for T315I mutation at Screening if T315I mutational analysis is not confirmed and upon 
confirmed loss of MMR and/or at end of treatment. Please see Section 8.5.3.
The blood samples will be taken as described in Table 8-1, and Table 8-6 .


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Table 8-3
Blood samples (efficacy secondary endpoint)
Sample Type
Volume
Visit
Time point
20 mL
Screening/Baseline
Pre-dose
20 mL
Week 4
Pre-dose
20 mL
Week 12
Pre-dose
20 mL
Week 24
Pre-dose
20 mL
Week 36
Pre-dose
20 mL
Week 48
Pre-dose
20 mL
Week 60β
Pre-dose
Blood for BCR-ABL1 
quantification by RQ-PCR
20 mL
(Week 72) End of Treatment
Anytime
5 mL
Screening
Pre-dose
Blood for BCR-ABL1 Mutation 
analysis by Sanger 
Sequencing
No sample collected 
- testing is 
performed on the 
“Blood for BCR-
ABL1 quantification 
by RQ-PCR” sample
Upon confirmed loss of MMR and/or End of 
Treatment
Anytime
β = only applicable if the visit is in-person
During the study, peripheral blood samples will be collected into PAXgene™ Blood RNA tubes 
for all RQ-PCR assessments. Detailed instructions for the collection, handling, and shipment of 
RQ-PCR and mutation samples are outlined in the [CABL001AUS04 Laboratory Manual].
8.4.2
Hematologic Response
Hematologic response assessments are to be done locally at the site. The hematology parameters 
required to be evaluated are listed in Table 8-6.
A complete hematologic response (CHR) is defined as all of the following present for ≥ 4 weeks:

WBC count <10 x 109/L

Platelet count <450 x 109/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
Loss of CHR
Loss of CHR is defined if patients exhibit:

WBC count >10 x 109/L

Platelet count >450 x 109/L

Basophils >5%

Any blasts and promyelocytes in peripheral blood

Myelocytes + metamyelocytes > 5% in peripheral blood


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8.5
Additional assessments 


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e 
 
 
8.5.3
Biomarkers
At the screening the selection of patient in each cohort will based on the mutational status of 
T315I during screening as mentioned in the visit schedule Table 8-1. Patient’s BCR-ABL1 
mutation status needs to be available and results have to be done within 6 months of screening.
In addition, mutational analysis will be performed at screening to confirm the historical T315I 
mutational record if available.


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8.5.4
Imaging
Not Applicable


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9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the subject or the investigator.
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Patients who discontinue the study treatment for an adverse event suspected to be related to 
study drug or an abnormal laboratory value suspected to be related to study drug must be 
followed as described in Section 8
Patients may also be discontinued from the study treatment if any of the following occurs:

discovery of patient ineligibility

errors in treatment compliance [study treatment, other prescribed or non-prescribed 
medications]

missed/unscheduled/off schedule/incomplete/incorrect assessments

major protocol deviation

use of prohibited treatment refer to Section 15-Appendices

any other protocol deviation that results in a significant risk to the patient’s safety
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 new T315I mutations during the study, the patient must be 
discontinued from the study treatment. The Novartis Managed Access Program (MAP) 
ABL001A02401M Cohort will be available for those patients without a reasonable 
alternative options if treating physician and patient still choose to pursue treatment with 
Asciminib. 

In the event of a pregnancy during study, if a patient wants to pursue the pregnancy then 
patient must be discontinued from the study treatment. However, in the event of a 
spontaneous miscarriage or in the event of elective abortion, the patient is permitted to 
continue study treatment.

In the event of treatment failure the patient must be discontinued from the study treatment. 
The following events will constitute ‘treatment failure’, defining failure of a third line 
treatment:

No CHR at three months after initiation of therapy or thereafter

BCR-ABL1 ratio > 10% IS at 24 weeks after initiation of therapy or thereafter

BCR-ABL1 ratio > 1% IS at 48 weeks after initiation of therapy or thereafter

Loss of CHR, MR2 at any time after initiation of therapy 


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
Detection of new BCR-ABL1 mutations which potentially cause resistance to study 
treatment (asciminib) at any time after initiation of therapy 

Confirmed loss of MMR in 2 consecutive tests (Section 8.5) (BCR-ABL1 > 0.1%) 

In the event of disease progression the patient 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 the 
peripheral blood or 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
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent section,). Where possible, they should return 
for the assessments indicated in the assessment schedule. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made 
to contact the subject/pre-designated contact as specified in the lost to follow-up section. This 
contact should preferably be done according to the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
9.1.2
Withdrawal of informed consent
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:

Does not want to participate in the study anymore, and

Does not want any further visits or assessments, and

Does not want any further study related contacts
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information.


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Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of 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.
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.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.3
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination: 

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 participant welfare and safety. 
Should early termination be necessary, participants must be seen by treating physician as soon 
as possible and treated as a prematurely withdrawn participant. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the participant’s interests. The investigator or sponsor depending 
on local regulation will be responsible for informing IRBs/IECs of the early termination of the 
trial.
9.2
Study completion and post-study treatment 
The patients are treated in the study up to end of study treatment period defined as up to 72 
weeks after the last patient receives the first dose unless patients have discontinued treatment 
earlier. The end of the study will occur when the last patient enrolled (40 mg BID, 80 mg QD 
or 200 mg BID cohort) into the study completes 72 weeks of treatment or experience treatment 
failure. 


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The primary analysis (cut-off date) is defined as the date when all patients (in Cohort A, B and 
C) have been on study treatment for 24 weeks (Section 12) or discontinued earlier. 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. Patients who are ongoing at the time 
of the primary analysis will continue to receive the study treatments (asciminib) during the 
study treatment period as defined above. 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 patients in the study is analyzed and summarized in a final CSR.
After the end of the study treatment period the assigned study treatment will be made available 
to patients 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, an expanded 
access/compassionate use /managed access program or access to commercial supplies in 
applicable countries.
10
Safety monitoring and reporting 
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained.
Adverse events 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.
Adverse events 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].
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s eCRF. Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.


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Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) 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. Information about any deaths (related to an Adverse Event or not) will also be collected 
through a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:
1. The severity grade (CTCAE Grade 1-5)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 10.1.2 
and which seriousness criteria have been met
7. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
If the event worsens the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined a new entry for this event should be reported in the eCRF noting 
the start date when the event improved from having been Grade 3 or Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Natural progression or deterioration of the malignancy under treatment (including loss of 
response, progression to accelerated phase or blast crisis and death due to disease progression), 
will be recorded as part of the efficacy evaluation and should NOT be reported as an AE/SAE.
Signs and symptoms clearly associated with the disease under study should NOT be reported 
as AEs unless they are newly emergent (i.e. not previously observed in the patient), judged by 
the Investigator to be unusually severe or accelerated, or if the Investigator considers 
deterioration of disease-related signs and symptoms to be caused directly by the study drug. If 


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there is any uncertainty about an AE being due solely to the disease under study, it should be 
reported as an AE or SAE as appropriate.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
o
routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition 
o
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
o
social reasons and respite care in the absence of any deterioration in the 
subject’s general condition
o
treatment on an emergency outpatient basis for an event not fulfilling any 
of the definitions of a SAE given above and not resulting in hospital 
admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.


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10.1.3
SAE reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Each re-occurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
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 Novartis study treatment, an oncology Novartis 
Chief Medical Office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug 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 Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
10.1.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 


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form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.
Pregnancy outcome should be collected for the female partners of any male who 
receivedasciminib treatment in this study. Consent to report information regarding pregnancy 
outcome should be obtained from the mother.
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.
10.1.5
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing CRF 
(Yes/No)
Document in AE eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with an 
AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional Safety Monitoring
Not Applicable
10.2.1
Data Monitoring Committee 
Not Applicable


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10.2.2
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.
10.2.3
Adjudication committee
Not Applicable
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.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
Data collected by third parties (biochemistry, PCR assessments, 
) will be sent 
electronically to Novartis.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
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adverse events 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.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. 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 (or 
delegated CRO) representative will review the protocol and data capture requirements (i.e. 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of 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 (or delegated CRO). 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 each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
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12
Data analysis and statistical methods
Data from all participating centers will be combined. Data from all centers participating in this 
study will be aggregated for analyses. A contract Research organization will conduct all 
analyses and will report data from all centers.
The primary analysis of the primary endpoint will be performed after all patients have 
completed 24 week follow-up from the first dose of study medication or discontinued earlier. 
Selected efficacy and safety analysis will be updated annually. A final Clinical Study Report 
(CSR) will be produced once all patients complete the study.
All AEs, SAEs and other safety parameters will be summarized by cohort. No inferential tests 
for safety analyses will be performed. All primary, secondary 
 variables will be 
summarized descriptively by Cohort. Categorical data will be presented in frequencies and 
percentages. For continuous data descriptive statistics (mean, standard deviation, median 25th 
and 75th percentiles, min and max) will be provided. As appropriate, 95% confidence intervals 
will also be reported. Kaplan Meier’s estimates will be reported for the time to event variables.
Detail analysis methods will be available in the Statistical Analysis Plan (SAP).
12.1
Analysis sets
The analysis sets to be used are defined as below. The FAS will be used as the primary efficacy 
analysis set. The Safety Set will be used for all the safety analysis. 
The screened patients comprises all patients who have signed informed consent/assent and 
screened in the study. The enrolled comprises all patients who are enrolled in the study. 
Enrollment is defined as the point at which the patient meets all inclusion/exclusion criteria, 
and the patients’
12.1.1
Full Analysis Set (FAS)
The FAS comprises all patients to whom study treatment has been assigned Patients will be 
analyzed according to the treatment regimen.
12.1.2
Safety Set (SS)
The Safety Set includes all patients who received at least one dose of study medication. Patients 
will be analyzed according to the study treatment (regimen) they received.
12.1.3
Per-Protocol Set (PPS)
The PPS consists of a subset of the patients in the FAS without any major deviation, and who 
are compliant with requirements of the clinical study protocol (CSP).
The detailed exclusion criteria of PPS will be determined prior to the primary/final analysis 
based on the identified major protocol deviations.
 
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12.1.5
Other analysis sets
Not Applicable
12.1.6
Efficacy/evaluable set
Not Applicable
12.2
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for the FAS. Relevant medical histories and current medical conditions at baseline 
will be summarized by system organ class and preferred term.
12.3
Treatments 
The duration of exposure will be summarized for study treatment and for each study cohort A, 
B and C. The dose intensity (computed as the ratio of actual cumulative dose received and actual 
duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity 
and planned dose intensity) will be summarized for each study drug component by descriptive 
statistics.
The number of participants will be summarized by study treatment and by study cohort.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system.
12.4
Primary objective / analysis of the primary endpoint(s)
Primary Objective(s)
To evaluate safety profile of monotherapy asciminib in CML-CP in 3L and beyond for Cohorts 
A, and B
Primary objective is to assess the safety profile of ABL001 (40 mg and 80 mg). For all primary 
safety analyses, the Safety Set will be used, unless stated otherwise. 
The variables for the primary analysis are incidence and severity of AEs and SAEs, changes in 
laboratory values and vital signs, incidence of notable ECG abnormalities
12.4.1
Statistical hypothesis, model, and method of analysis
No formal hypothesis testing is planned for this study. Analyses of the safety data are described 
in Section 12.7.
12.4.2
Handling of missing values/censoring/discontinuations
Missing data for measures of safety and efficacy will not be imputed.
12.4.3
Supportive analyses
Subgroup analyses will be performed on the based on the patient’s baseline status:


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
Age:  (< 65 years; ≥ 65 years)

Patients with resistance 

Previous treatment with Ponatinib

By number of prior TKI therapies
Data will be only summarized within each subgroup.
Additionally, as the study is ongoing during COVID 19 pandemic, in order to address the impact 
of COVID-19 (if any) on discontinuation, protocol deviations, disease status, dose interruptions, 
AEs and labs assessments and on missing data will be explored.
As appropriate, a sensitivity analysis will be performed on the primary efficacy evaluating the 
impact of COVID-19 on the study. 
12.5
Secondary objectives / analysis of secondary endpoints
12.5.1
Secondary objective(s)
Secondary Objective(s)

To estimate the rate of hematologic and molecular responses at specific time points for 
Cohort A, B and C

Rate of CHR, MR2, MMR, MR4, MR4.5 in 12, 24, 48, 72 weeks of therapy

To estimate time to hematologic and molecular response

Time to CHR, MR2, MR4, MR4.5 in 12, 24, 48, 72 weeks of therapy

To evaluate the duration of hematologic and molecular response

Duration of MR1, MR2, MMR, MR4 and MR4.5

To evaluate Progression Free Survival (PFS)

To evaluate Overall Survival (OS)
12.5.2
Secondary objectives
For all secondary efficacy analyses, the Full Analysis Set (FAS) will be used, unless stated 
otherwise. 
12.5.2.1 Rate of CHR, MR2, MMR, MR4, MR4.5 by 12, 24, 48, 72 weeks of 
therapy
For secondary efficacy analysis, proportion of patients achieving the response levels will be 
presented together with an exact 95% Clopper-Pearson confidence interval. 

The rate of Complete Hematologic Response (CHR ) by 12, 24, 48 and 72 weeks. CHR is 
defined as all of the following present for ≥ 4 weeks:

WBC count <10 x 109/L

Platelet count <450 x 109/L

Basophils <5%

No blasts and promyelocytes in peripheral blood

Myelocytes + metamyelocytes < 5% in peripheral blood


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
No evidence of extramedullary disease, including spleen and liver

The rate of molecular response (MR2) by 12, 24, 48 and 72 weeks after the start of first 
study medication. MR2 is defined as ≥ 2 log reduction of BCR-ABL transcript from 
standardized baseline or ≤ 1% BCR-ABL/ABL % by international scale, measured by 
real-time quantitative PCR (RQ-PCR).

The rate of major molecular response (MMR) by 12, 24, 48 and 72 weeks after the start of 
first study medication. MMR is defined as ≥ 3 log reduction of BCR-ABL transcript from 
standardized baseline or ≤ 0.1% BCR-ABL/ABL % by international scale, measured by 
real-time quantitative PCR (RQ-PCR).

The rate of molecular response (MR4) after the star by 12, 24, 48 and 72 weeks after the 
start of first study medication. MR4 is defined as ≥ 4 log reduction of BCR-ABL 
transcript from standardized baseline or ≤ 0.01% BCR-ABL/ABL % by international 
scale, measured by real-time quantitative PCR (RQ-PCR).

The rate of the molecular response (MR4.5) by 12, 24, 48 and 72 weeks after the start of 
first study medication. MR4.5 is defined as ≥ 4.5 log reduction of BCR-ABL transcript 
from standardized baseline or ≤ 0.0032% BCR-ABL/ABL % by international scale, 
measured by real-time quantitative PCR (RQ-PCR).
12.5.2.2 Time to CHR, MR2, MR4, MR4.5 in 12, 24, 48, 72 weeks of therapy
Time to achieving a response level is defined as the time from the date of the first dose of study 
medication to the first documented achievement of a response level.
Time to achieve a specific response level will be analyzed using the Kaplan-Meier Product-
Limit method. Patients who are known to be without achieving that response level will be 
censored at the last adequate assessment. Estimates of the 25th, median and 75th percentile of 
the time to achieve a response level and their 95% confidence intervals will be provided, if 
applicable.
12.5.2.3 Duration of MR2, MMR, MR4 and MR4.5
Duration of Response (DOR) is the time from the date of the first documented a molecular 
response level to the date of first documented loss of the response level or death due to any 
cause, whichever occurs first. 
The start date is the date of first documented response level and the end date is defined as the 
date of the first documented loss of that response level or death due to any cause. Participants 
continuing without that event will be censored at the date of their last adequate response 
assessment. 
DOR for each response level will be analyzed using the Kaplan-Meier Product-Limit method. 
Estimates of the 25th, median and 75th percentile of the DOR and their 95% confidence 
intervals will be provided, if applicable.


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12.5.2.4 Progression Free Survival
Progression Free Survival (PFS) is defined as time from the first dose of study medication to 
disease progression to AP/BC or death due to any cause, whichever occurs first, by 24, 48 and 
72 weeks.
For patients without progression, the time is censored at the latest date the patient was known 
to be alive and without progression (on or before the cut-off date).
PFS will be analyzed using the Kaplan-Meier Product-Limit method. Patients who do not
progress will be censored at the last adequate assessment. Estimates of the 25th, median and
75th percentile of the PFS and their 95% confidence intervals will be provided, if applicable.
12.5.2.5 Overall Survival
Overall Survival (OS) is defined as the time from the first dose of study medication to death 
due to any cause during 24, 48 weeks and 72 weeks during study.
If a patient is not known to have died, then OS will be censored at the latest date the patient was 
known to be alive (on or before the cut-off date). All deaths will be taken into account whatever 
the death occurred, i.e. even after interruptions, or discontinuation of study treatment due to any 
reason. 
OS will be analyzed using the Kaplan-Meier Product-Limit method. Patients who do not
progress will be censored at the last adequate assessment. Estimates of the 25th, median and
75th percentile of the OSS and their 95% confidence intervals will be provided, if applicable.


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12.7
Safety objectives
12.7.1
Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment received.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to x days after last dose of 
study medication
12.7.2
Adverse events (AEs)
All information obtained on adverse events will be displayed by treatment and participant.
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period. The number (and percentage) of participants with treatment emergent 
AEs will be summarized by primary system organ class, preferred term and maximum severity 
(based on CTCAE grades). Separate summaries will be provided for study medication related 
adverse events, deaths, serious adverse events, adverse events leading to treatment 
discontinuation, and adverse events leading to dose adjustment. The number (and percentage) 
of participants with adverse events will be summarized by primary system organ class, preferred 
term and maximum severity.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, adverse events leading to treatment discontinuation, and adverse events leading 
to dose adjustment.
The incidence of adverse events will be summarized by system organ class and or preferred 
term, severity (based on CTCAE grades), type of adverse event, relation to study treatment.
Serious adverse events and non-serious adverse events will be tabulated.
Selected summaries of adverse events will be produced for the overall safety period. All deaths 
(on-treatment and post-treatment) will be summarized.
All AEs, deaths, and serious adverse events (including those from the pre- and post-treatment 
periods) will be listed and those collected during the pre-treatment, post-treatment and overall 
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12.7.3
Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI CTCAE version 
5.0. The calculation of CTCAE grades will be based on the observed laboratory values only, 
clinical assessments will not be taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
For laboratory tests where grades are not defined by CTCAE v5, results will be categorized as 
low/normal/high (or other project-specific ranges, if more suitable) based on laboratory normal 
ranges.
The following summaries will be generated separately for hematology and biochemistry tests: 
For laboratory tests where grades are defined by CTCAE v5

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will 
be counted only once for the worst grade observed post-baseline.

Shift tables to compare baseline CTCAE grades to the worst on-treatment grade For 
laboratory tests where grades are not defined by CTCAE v5

Shift tables using the low/normal/high/(low and high) (or project specific) classification 
to compare baseline to the worst on-treatment value.
Listing of all laboratory data with values flagged to show the corresponding CTCAE v5 grades 
if applicable and the classifications relative to the laboratory normal ranges will be presented.
12.7.4
Other safety data 
ECG
A 12-lead ECG including PR, QRS, QT, QTcF, QTcB and RR intervals will be obtained for 
each patient during the study. ECG data will be read and interpreted centrally.
Absolute values/change from baseline will be summarized over time. As appropriate, the 
number and percent of patients will be tabulated by category. In addition, a listing of patients 
with at least one notable ECG value will be produced.
Vital signs
Data on vital signs will be tabulated and summarized descriptively as follows:

Number and frequency of patients who shift from non-notable at baseline to notable 
post- baseline (details about the definition of notable abnormal results will be given in 
the SAP)

All information collected will be listed and notable values will be flagged.
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12.8
Interim analysis
As the primary time point is by 24 weeks, the primary analysis will be an interim analysis. The 
primary analysis will be performed when the last patient completes 24 weeks of treatment or 
discontinues early. 
As appropriate, annual interim analyses will be planned for publication or any regulatory 
purpose. No formal interim analysis will be performed. Only summary statistics will provided. 
Final Analysis will be performed when the last patient completes 72 weeks or discontinues early. 
A final CSR will be written.
12.9
Sample size calculation
This is an open label, three-cohort study to assess safety and efficacy of study of asciminib 
(ABL001) monotherapy in patients with chronic myeloid leukemia in chronic phase (CML-CP) 
previously treated with at least 2 prior TKIs (tyrosine kinase inhibitors) and CML-CP patients 
harboring the T315I mutation previously treated with at least 1 prior TKIs
For all CML-CP with the exception of those harboring the T315I mutation, there will be 
randomization to eliminate selection bias at the time of cohort allocation. Those patients will 
be assigned to either Cohort A consisting of asciminib 40 mg BID patients or Cohort B 
consisting of asciminib 80 mg QD. For CML-CP patients harboring the T315I mutation, they 
will be assigned to Cohort C with asciminib 200 mg BID, which is the dose required for that 
patient population. It is worthwhile mentioning that randomization for cohorts A and B will be 


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pursued for patient selection only. The study is not powered to show differences in Primary and 
Secondary endpoints between study cohorts.
Primary objective of the study is to assess safety profile of this combination drug during 24 
weeks for all cohort patients.
A sample size of 40 evaluable patients for Cohort A is estimated based on a two- sided 95% 
confidence interval for an incidence rate of an AE using the large sample normal approximation 
that will extend 0.12 from the observed incidence rate of an AE (precision or margin of error of 
12%) for an expected incidence rate of 18%. Considering drop-out rate of 10%, approximately 
45 patients will be enrolled for safety assessment for the Cohort A of this study.
Retaining the same assumptions, approximately 45 patients will also be enrolled for Cohort B.
Additionally for Cohort C, approximately 25 patients will be enrolled.
Thus, approximately total 115 (45+45+25=115) patients will be enrolled for Cohort A (n1=45) 
and Cohort B (n2=45) and for Cohort C (n3=25) of the study.
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, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).


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For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of 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.
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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15
References
References are available upon request
[ASCO (2020)]ASCO Special Report: A guide to Cancer Care Delivery during the COVID-
19 Pandemic. American Society of Clinical Oncology
[Baccarani M, Deininger MW, Rosti G, et al (2013)] European LeukemiaNet 
recommendations for the management of chronic myeloid leukemia: 2013. Blood; 
122(6):872-84.
[Bartram CR, de Klein A, Hagemeijer A, et al (1983)] Translocation of c-ab1 oncogene 
correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. 
Nature; 306(5940):277-80. [Basnayake C, Ratnam D (2015)] Blood tests for acute 
pancreatitis. Aust Prescr 38:128-30.
[Bosulif® SmPC]
[Bosulif® USPI]
[Branford S, Rudzki Z, Walsh S, et al (2003)] Detection of BCR-ABL mutations in patients 
with CML treated with imatinib is virtually always accompanied by clinical resistance, and 
mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. 
Blood; 102(1):276-83.
[Daley GQ, Van Etten RA, Baltimore D (1990)] Induction of chronic myelogenous leukemia 
in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science; 247(4944):824-30. 
[Guidance for Industry Reproductive and Developmental Toxicities - Integrating Study 
Results to Assess Concerns] Food and Drug Administration Center for Drug Evaluation and 
Research. September 2011.
[Gambacorti-Passerini C, Brümmendorf TH, Kim DW, et al (2014)] Bosutinib efficacy and 
safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: 
Minimum 24-month follow-up. Am J Hematol; 89(7):732-42.
[García-Gutiérrez V, Martinez-Trillos A, Lopez Lorenzo JL, et al (2015)] Bosutinib shows 
low cross intolerance, in chronic myeloid leukemia patients treated in fourth line. Results of 
the Spanish compassionate use program. Am J Hematol; 90(5):429-33. [Heisterkamp N, 
Stephenson JR, Groffen J, Hansen PF, et al (1983)] Localization of the c-ab1 oncogene 
adjacent to a translocation break point in chronic myelocytic leukaemia. Nature; 
306(5940):239-42.
[Hanson, K, Caliendo AM., Arias CA, et al (2020)] Infectious Diseases Society of America 
G8uidelines on the Diagnosis of COVID-19. Infectious Diseases Society of America. Version 
1.01
 
 


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[Hochhaus, A. & Baccarani, M. & Silver, Richard & Schiffer, C. & Apperley, J. & Cervantes, 
F. & Clark, R. & Cortes, J. & Deininger, M. & Guilhot, F. & Hjorth-Hansen, H. & Hughes, T. 
& Janssen, J. & Kantarjian, H. & Kim, D. & Larson, Richard & Lipton, Jeffrey & Mahon, 
François-Xavier & Mayer, J. & Hehlmann, R.. (2020)]. European LeukemiaNet 2020 
recommendations for treating chronic myeloid leukemia. Leukemia. 34. 10.1038/s41375-020-
0776-2.
[Hughes TP, Hochhaus A, Branford S, et al (2010)] Long-term prognostic significance of 
early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an 
analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood; 
116(19):3758-3765.
[Hughes, Timothy & Mauro, Michael & Cortes, Jorge & Minami, Hironobu & Rea, Delphine 
& DeAngelo, Daniel & Breccia, Massimo & Goh, Yeow-Tee & Talpaz, Moshe & Hochhaus, 
Andreas & le Coutre, Philipp & Ottmann, Oliver & Heinrich, Michael & Steegmann, Juan & 
Deininger, Michael & Janssen, Jeroen & Mahon, François-Xavier & Minami, Yosuke & 
Yeung, David & Kim, Dong-Wook]. (2019). Asciminib in Chronic Myeloid Leukemia after 
ABL Kinase Inhibitor Failure. The New England journal of medicine. 381. 2315-2326. 
10.1056/NEJMoa1902328.
[Hochhaus A, Saussele S, Rosti G, et al (2017)] Chronic myeloid leukaemia: ESMO Clinical 
Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol (2017) 28 (suppl 4): 
iv41–iv51.
[Hochhaus A, O'Brien SG, Guilhot F, et al (2009)] Six-year follow-up of patients receiving 
imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia; 23(6):1054-61.
[Jabbour, Elias & Bixby, Dale & Akard, Luke]. (2012). Clinical roundtable monograph: 
Unmet needs in the management of chronic myelogenous leukemia. Clinical advances in 
hematology & oncology : H&O. 10. 1-16.
[Kelliher MA, McLaughlin J, Witte ON, et al (1990)] Introduction of a chronic myelogenous 
leukemia-like syndrome in mice with v-Abl and BCR/ABL. Proc Natl Acad Sci USA 87; 
6649-53.
[Khoury HJ, Kim D, Zaritskey A, et al (2010)] Safety and efficacy of thirdline bosutinib in 
imatinib (IM) and dasatinib (DAS) resistant or intolerant chronic phase (CP) chronic myeloid 
leukemia (CML) [abstract]. J Clin Oncol; 28 (Suppl; abstr 6514):15s. 
[Klemmt L, Scialli AR. (2005)] The transport of chemicals in semen. Birth Defects Res (Pt 
B); 74:119–131. 
[Khoury HJ, Cortes JE, Kantarjian HM, et al (2012)] Bosutinib is active in chronic phase 
chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood; 
119(15):3403-12. 
[National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in 
Oncology-Chronic Myeloid Leukemia] v4.2018 – January 24, 2018. [Nowell Hungerford DA 
(1960)] A minute chromosome in chronic granulocytic leukemia. Science; 132: 1497-1501.
[O’Brien S, Radich JP, Abboud CA, et al (2013)] Chronic Myelogenous Leukemia, Version 
1.2014: Featured Updates to the NCCN Guidelines. J Natl Compr Canc Netw; 11(11):1327- 
40.


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[O’Hare T, Corbin A S, Druker B J (2006)] Targeted CML therapy: controlling drug 
resistance, seeking cure. Current opinion in Genetics & development, 16:92-99.
[Rowley JD (1973)] A new consistent abnormality in chronic myelogenous leukemia 
identified by quinacrine, fluorescence and Giemsa staining. Nature; 243:290-93.
[Schoepfer J, Jahnke W, Berellini G, et al. (2018)] Discovery of Asciminib (ABL001), an 
Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1. J Med Chem. 
2018;61(18):8120-8135. doi:10.1021/acs.jmedchem.8b01040
 
 
 
 
 
[Vardiman J.W. (2009)] Chronic Myelogenous Leukemia, BCR-ABL+. Am J Clin Pathol; 
132:250-260.
[Venkatakrishnan K, Von Moltke LL, Greenblatt DJ (2001)] Human drug metabolism and the 
cytochromes P450: application and relevance of in vitro models. The Journal of Clinical 
Pharmacology; 41: 1149-1179.


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Amended Clinical Trial Protocol Version 03 (Clean)                                  Protocol No. CABL001AUS04
16
Appendices
16.1
Appendix 1 List of concomitant medications for patients on 
asciminib
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited in Section 6.2 for patients.
The following lists are based on the internal [Pharmacokinetic Sciences memorandum on Drug- 
Drug Interaction] (release date: January 2018), 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 questions. If a medication appears on 
both the list of prohibited and the list of medications to be used with caution, the 
medication is prohibited.
Table 16-1
Prohibited concomitant medications for asciminib 
Category
Drug Names
Strong inducers of 
CYP3A 
carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, rifabutin, 
rifampicin, St. John’s wort (Hypericum perforatum)3
UGT1A1/2B7 
inducers
UGT1A1: carbamazepine, cigarette smoke, rifampicin, testosterone propiate, UGT2B7: 
Barbiturates
Cohort C only :
Strong inhibitors of 
CYP3A
atazanavir/ritonavir1, danoprevir/ritonavir1, darunavir/ritonavir1, elvitegravir/ritonavir1, 
indinavir/ritonavir1, lopinavir/ritonavir1, saquinavir/ritonavir1, tipranavir/ritonavir1, 
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak)1, boceprevir, clarithromycin, 
cobicistat, conivaptan, grapefruit juice2, idelalisib, indinavir, itraconazole, ketoconazole, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, telaprevir, telithromycin, 
troleandomycin, voriconazole
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: 
Possible
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-ER, 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


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Category
Drug Names
TdP/QT risk: 
Conditional
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
1 Combination ritonavir-boosted regimens are listed here in the DDI memo as strong CYP3A inhibitors (to avoid 
potential confusion), even though some are considered moderate CYP3A inhibitors in the UW DDI Database. 
2 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparationdependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a 
certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when 
another preparation was used (e.g., low dose, single strength).
3 Herbal product
Table 16-2
Concomitant medications to be used with caution 
Category
Drug Names
Cohorts A and B 
only:
Strong inhibitors of 
CYP3A
atazanavir/ritonavir1, danoprevir/ritonavir1, darunavir/ritonavir1, elvitegravir/ritonavir1, 
indinavir/ritonavir1, lopinavir/ritonavir1, saquinavir/ritonavir1, tipranavir/ritonavir1, 
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak)1, boceprevir, clarithromycin, 
cobicistat, conivaptan, grapefruit juice2, idelalisib, indinavir, itraconazole, ketoconazole, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, telaprevir, telithromycin, 
troleandomycin, voriconazole
Narrow therapeutic 
index substrates of 
CYP2C8
paclitaxel
Narrow therapeutic 
index substrates of 
CYP2C9
phenytoin, warfarin
Narrow therapeutic 
index substrates of 
CYP3A
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus, terfanadine 
BCRP
Inhibitors
abacavir, amprenavir, atorvastatin, ,curcumin3, cyclosporine3,  daclatasvir, declatasvir3, 
delavirdine, efavirenz, elbasvir, eltrombopag3, elvitegravir3, erlotinib, fluvastatin, 
fostamatinib, fumitremorgin, gefitinib, grazoprevir, lapatinib3, ledipasvir3, lopinavir, 
paritepravir3, pitavastatin, rosuvastatin, simvastatin, sulfasalazine, tipranavir3, velpatasvir, 
venetoclax
P-gp inhibitors
alogliptin, amiodarone4, azithromycin4, canaglifozin, captopril4, carvedilol4, clopidrogel, 
cremophor RH40, curcumin, diltiazem4, dronedarone4, elacridar4, eliglustat, felodipine4, 
fluvoxamine4, fostamatinib, ginko4,5, isavuconazole, ivacaftor, lopinavir, milk thistle 
(silymarin, silibinin)4,5, nifedipine4, nitredipine4,ombitasvir, paritaprevir, propafenone, 
quercetin,4, ritonavir4, sequinavir4, schisandra chinesis extract4,5, simepravir, St. John’s 
wort extract (Hypericum perforatum)4,5, suvorexant, talinolol4, telaprevir4, telmisartan4, 
ticagrelor4, tipranavir4, tolvaptan4, valspodar, vandetanib, verapamil4, voclosporin, 
vorapaxar
1 Combination ritonavir-boosted regimens are listed here in the DDI memo as strong CYP3A inhibitors (to avoid 
potential confusion), even though some are considered moderate CYP3A inhibitors in the UW DDI Database. 
3 Evidence of in vivo DDI
4 Dual P-gp and CYP3A4 inhibitor
5 Herbal product

SAP_001.pdf: 
Clinical Development 
ABL001/ASCIMINIB 
CABL001AUS04 / NCT04666259
An open label, multi-center Phase IIIb study of asciminib (ABL001) 
monotherapy in previously treated patients with chronic myeloid   
leukemia in chronic phase (CML-CP) with and without T315I        
mutation (AIM4CML) 
Statistical Analysis Plan (SAP)
 Template version 4.0, Effective from 23-Apr-2021 
Document type: 
SAP Documentation 
Document status: 
Amendment 2.0 
Release date: 
16-Feb-2024
Number of pages: 
42 


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Document History – Changes compared to previous final version of SAP 
 
 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
06- Apr- 2021 
 
Prior to DB 
First Patient 
First Visit 
Creation of final 
version 
N/A - First version 
NA 


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SAP Amendment 1.0 
 
   CABL001AUS04 
13- Jan- 2023 
Prior to DB lock 
of primary 
analysis 
Creation of 
Amendment 1.0 
 
Replaced ‘sequentially’ 
allocated with ‘randomly’ 
allocated in all instances  
Removed the note on cut-ff 
date for primary analysis 
Removed week 60 
assessment and updated 
time interval for week 72 in 
table for molecular 
assessment 
Added statement for 
mapping EOT assessment 
Added week 72 for 
hematologic response 
assessment 
  
 
 
 
 
Updated the criteria for 
generating TFLs for 
subgroup analysis 
Replaced duration of 
exposure with non-zero 
dose with Time on 
treatment 
Deleted cardiovascular risk 
factors not mentioned in 
Ecrf 
Deleted section on liver 
function risk assessment as 
the data is not collected 
Updated the secondary 
objectives to align with 
protocol 
Updated the criteria to 
handle missing MMR rates 
 
All sections 
 
 
           Section 2.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 2.2.1 
Section 2.4.1 
Section 2.6.5.3 
Section 2.8 
Section 2.8.3 


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   CABL001AUS04 
 
 
 
Updated the change to 
protocol specified analysis 
 
 
Section 4 
15- Feb- 2024 Prior to DB lock 
of Interim 
analysis 
Creation of 
Amendment 2.0 
 
 
 
 
 
 
Updated time windows for 
week 48 and 72 for 
molecular response 
 
 
 
 
 
 
 
 
Section 2.1.1 
 
 
 
 
 


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   CABL001AUS04 
Table of contents 
Table of contents ..................................................................................................................................... 5 
1 Introduction ................................................................................................................................................ 11 
1.1 
Study design ............................................................................................................................. 11 
1.2 
Study objectives and endpoints ................................................................................................ 13 
2 Statistical methods ...................................................................................................................................... 14 
2.1 Data analysis general information ................................................................................................... 14 
2.1.1 General definitions .......................................................................................................... 15 
2.2 
Analysis sets ............................................................................................................................. 19 
2.2.1 
Subgroup analyses ................................................................................................. 19 
2.3 
Patient disposition, demographics, and other baseline characteristics ..................................... 20 
2.3.1 Demographics and baseline characteristics ..................................................................... 20 
2.3.2 Diagnosis and extent of cancer - CML............................................................................ 20 
2.3.3 Medical history ............................................................................................................... 20 
2.3.4 Patient disposition ........................................................................................................... 21 
2.3.5 Protocol deviations .......................................................................................................... 21 
2.4 
Treatments (study medication, rescue medication, concomitant therapies, compliance)......... 22 
2.4.1 
Duration of exposure to study medication ............................................................ 22 
2.4.2 
Prior, concomitant and post therapies/medication................................................. 23 
2.5 
Analysis of the primary objective ............................................................................................ 24 
2.5.1 
Primary endpoint ................................................................................................... 25 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................................... 25 
2.5.3 
Handling of missing values ................................................................................... 25 
2.6 
Safety analyses ......................................................................................................................... 25 
2.6.1 
Adverse events (AEs) ............................................................................................ 25 
2.6.2 
Adverse events of special interest / grouping of AEs ............................................ 26 
2.6.3 
Deaths .................................................................................................................... 26 
2.6.4 
Laboratory data ..................................................................................................... 26 
2.6.5 
Other safety data .................................................................................................... 27 
2.7 Analysis of the key secondary objective ......................................................................................... 28 
2.8 Analysis of the secondary objective(s) ............................................................................................ 28 
2.8.1 Secondary safety endpoints ............................................................................................. 29 
2.8.2  Secondary efficacy endpoints .......................................................................................... 29 
2.8.3 Handling of missing values/censoring/discontinuations ................................................. 32 
2.8.4 Statistical hypothesis, model, and method of analysis .................................................... 32 
 32 
 33 
 34 
 34 


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 35 
2.10 Interim analysis ............................................................................................................................. 35 
3 
Sample size calculation ......................................................................................................................... 35 
4 
Change to protocol specified analyses ................................................................................................... 36 
5 
Appendix ............................................................................................................................................... 36 
5.1 
Imputation rules ....................................................................................................................... 36 
5.1.1 
Study drug ............................................................................................................. 36 
5.1.2 
AE, ConMeds and safety assessment date imputation .......................................... 36 
5.2 
AEs coding/grading.................................................................................................................. 38 
5.3 
Laboratory parameters derivations ........................................................................................... 38 
5.3.1 Derivation of PCR results and loss of response(s) .......................................................... 39 
5.4 
Listing of AESIs ...................................................................................................................... 41 
6 
Reference ............................................................................................................................................... 42 


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List of abbreviations 
 
ABL 
Abelson proto-oncogene 
ADME 
Absorption, Distribution, Metabolism, and Excretion 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATP 
Adenosine triphosphate 
AUC 
Area under the curve 
AV 
block Atrioventricular block 
b.i.d. 
bis in die/twice a day 
BC 
Blast crisis 
BCR 
Breakpoint Cluster Region gene 
BCR-ABL 
BCR-ABL fusion gene (also called the Philadelphia chromosome) 
BID 
bis in diem/twice a day 
BMI 
Body Mass Index 
CBC 
Complete Blood Count 
CDP 
Clinical Development Plan 
CDS 
Core Data Sheet 
CHR 
Complete Hematological Response 
CI 
Confidence Interval 
CK 
Creatinine Kinase 
 
 
CML 
Chronic Myelogenous Leukemia 
CML-AP 
Chronic Myelogenous Leukemia-Accelerated Phase 
CMO&PS 
Chief Medical Office and Patient Safety 
CO 
Country Organization 
CO2 
carbon dioxide 
 
 
CP 
Chronic phase 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 


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CYP3A4 
Cytochrome P450 3A4 
DBP 
Diastolic Blood Pressure 
DDI 
Drug-drug interaction 
DLCO 
Carbon monoxide diffusing capacity 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
DQF 
Data Query Form 
DS&E 
Drug Safety and Epidemiology 
DSMB 
Data Safety Monitoring Board 
DSUR 
Development safety update report 
ECG 
Electrocardiogram 
eCOA 
Electronic Clinical Outcome Assessment 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELN 
European Leukemia Network 
EOT 
End of Treatment 
eSAE 
Electronic Serious Adverse Event 
eSource 
Electronic Source 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIH 
First In Human 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GDPR 
General Data Protection Regulation 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-glutamyl transferase 
H 
Hour 
hADME 
Human ADME study (Absorption, Distribution, Metabolism and Excretion) 
HBsAg 
Hepatitis B surface antigen 
HDL 
High density lipoprotein 
i.v. 
Intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IWRS 
Interactive Web Response System 
IRB 
Institutional Review Board 


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IRT 
Interactive Response Technology that includes Interactive Voice Response 
System and  
Km 
Michaelis-Menten constant 
K-M 
Kaplan-Meyer 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LFT 
Liver function test 
LLN 
Lower limit of normal 
LLOQ 
lower limit of quantification 
LSC 
Leukemia stem cell 
MCyR 
Major Cytogenetic Response 
mCyR 
Minor Cytogenetic Response 
 
 
 
MedDRA 
Medical dictionary for regulatory activities 
Mg 
milligram(s) 
mL 
milliliter(s) 
MMR 
Major Molecular Response 
MRI 
Magnetic resonance imaging 
NCDS 
Novartis Clinical Data Standards 
 
 
NOVDD 
Novartis Data Dictionary 
 
 
OS 
Overall survival 
p.o. 
oral(ly) 
 
 
PCR 
Polymerase Chain Reaction 
PCyR 
Partial Cytogenetic Response 
PD 
Pharmacodynamic(s) 
Ph+ 
Philadelphia chromosome positive 
PHI 
Protected Health Information 
 
 
PLT 
Platelets 
PPD 
Premature Participant Discontinuation 
PPS 
Per-protocol set 
 
 
PSD 
Premature Subject Discontinuation 
PSUR 
Periodic safety update report 
PT 
prothrombin time 
QD 
Quaque die/once a day 
QMS 
Quality Management System 
QT 
Q to T interval (ECG) 
QTcF 
QT interval corrected by Fridericia’s formula 
R Value 
ALT/ALP x ULN 
RAP 
The Report and Analysis Plan 
RBC 
red blood cell(s) 


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RDC 
Remote Data Capture 
RDE 
Recommended dose for expansion 
REB 
Research Ethics Board 
RNA 
Ribonucleic acid 
RoW 
Rest of World 
RP2D 
Recommended phase two dose 
RQ-PCR 
Real time quantitative polymerase chain reaction 
s.c. 
Subcutaneous 
SAE 
Serious Adverse Event 
SAP 
The Statistical Analysis Plan (SAP) is a regulatory document which provides 
evidence of preplanned analyses 
SBP 
Systolic Blood Pressure 
SC 
Steering committee 
sCR 
serum creatinine 
SD 
Standard deviation 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBIL 
Total bilirubin 
TD 
Study medication Discontinuation 
TdP 
Torsades de Pointes 
TKI 
Tyrosine Kinase Inhibitor 
TTF 
Time to treatment failure 
UGT 
Uridin diPhospho-glucuronosyltransferase 
ULN 
Upper limit of normal 
ULQ 
upper limit of quantification 
US 
United States 
USPI 
US prescribing information 
UTI 
Urinary Tract Infection 
WBC 
White blood cell(s) 
WHO 
World Health Organization 
WoC 
Withdrawal of Consent 
 
 
 
 
 
 
 
 
 
 
 


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   CABL001AUS04 
1 Introduction 
This statistical analysis plan (SAP) describes all planned analyses of primary objective, secondary 
objectives 
 for the clinical study reports (CSR) of study 
CABL001AUS04, a phase 3b, multi-center, open-label, study of oral asciminib monotherapy in 
patients with Chronic Myelogenous Leukemia in chronic phase (CML-CP), previously treated with 
at least 2 ATP-site tyrosine kinase inhibitors (TKI) (i.e. imatinib, nilotinib, bosutinib, dasatinib or 
ponatinib) in case of absence of T315I mutation or previously treated with at least 1 ATP-site tyrosine 
kinase inhibitors (i.e. imatinib, nilotinib, bosutinib, dasatinib or ponatinib) in case of presence of 
T315I mutation. 
The main purpose of this document is to describe the statistical methodology that will be used for this 
clinical study.  
The analysis described here will be conducted by Novartis using statistical software SAS® Version 
9.4 or higher, according to the Statistical methods and data analysis Section 12of the study protocol. 
Unless otherwise specified, the statistical methodologies including the analysis sets, analysis models, 
algorithms and conventions are following the Oncology study protocol CABL001AUS04 version 03. 
 
1.1 Study design 
This study will be a multicenter Phase IIIb open-label, three-cohort study of asciminib in patients 
with CML-CP without T315I mutation who have had at least 2 prior TKIs and CML- CP harboring 
the T315I mutation with at least 1 prior TKI (Figure 1-1). Approximately 115 patients will be enrolled 
in the study. 90 patients without T315I mutation will be randomly selected in Cohort A & B (45 
patients per Cohort). Remaining 25 patients with T315I mutation will be enrolled in Cohort C. 
The study will contain following Cohorts: 
• Cohort A (45): where patients will receive asciminib at 40 mg twice daily 
• Cohort B (45): where patients will receive asciminib at 80 mg once daily 
• 
Cohort C (25): patients harboring the T315I mutation will be treated on the dose of 200 mg 
twice daily. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1-1 
Schematic of study design 
 
For patients without T315I mutation, patients will be selected randomly between Cohort A, where 
patients will be given asciminib at 40 mg twice daily (BID) and Cohort B, where patients will receive 
asciminib at 80 mg daily (QD) to minimize selection bias. In Cohort C, patients harboring the T315I 
mutation will be enrolled and treated on the dose of 200 mg twice daily (BID). The higher dose 
required for that patient population is related to its required concentration to attain optimal blockade 
of the kinase activity. Patients will continue therapy until disease progression, unacceptable toxicity, 
or elective treatment discontinuation. 
AEs, SAEs, and laboratory evaluation for 24 weeks is the primary endpoint in this study. AEs, SAEs 
and laboratory evaluation for Cohort A, B and Cohort C, during 48, 72 weeks is the secondary safety 
endpoint. 
The primary analysis will be performed after all patients have been followed for at least 24 weeks or 
have discontinued study earlier. The end of study medication analysis will be performed after all 
patients have been followed for at least 72 weeks or have discontinued study earlier. The PFS/OS 
update analysis will be performed during 24, 48 and 72 weeks of the last patient received the first 
study dose. 
No formal interim efficacy analysis is planned in this study. As the primary time point is by 24 weeks, 
the primary analysis will be an interim analysis performed when the last patient completes 24 weeks 
of treatment or discontinues early. As appropriate, annual interim analyses may be planned for 
publication or any regulatory purpose. Only summary statistics will be provided. 
Final Analysis will be performed when the last patient completes 72 weeks of treatment or 
discontinues early. 
 
 


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1.2 
Study objectives and endpoints 
Table 1-1 
Objective(s) Endpoint(s) 
Primary Objective(s) 
Endpoint(s) for primary objective(s) 
• To evaluate safety profile of monotherapy 
asciminib in CML- CP in 3L and beyond, for 
Cohorts A and B 
• AEs, SAEs and laboratory evaluation for 
24 Weeks. 
Secondary Objective(s) 
Endpoint(s) for secondary objective(s) 
• To evaluate safety profile of monotherapy 
asciminib in CML- CP in 3L and beyond, 
for Cohort C 
• AEs, SAEs and laboratory evaluation for 
24 Weeks. 
• To evaluate safety profile of monotherapy 
asciminib in CML- CP in all Cohorts A, B 
and C 
• AEs, SAEs and laboratory evaluation for 
Cohort A, Cohort B and Cohort C, during 
48, 72 weeks 
• To estimate the rate of patients with 
hematologic and molecular response by 
specific time points for Cohort A, B and C 
• Rate of CHR, MR2, MMR, by 12, 24, 48, 
72 weeks of therapy 
• To estimate the rate of patients with deep 
molecular response by specific time points 
for Cohort A, B and C 
• Rate of MR4, MR4.5 by 48, 72 weeks of 
therapy 
• To estimate time to hematologic and 
molecular response 
• Time to CHR, MR2, MMR, MR4, MR4.5 
• To evaluate the duration of hematologic 
and molecular response 
• Duration of CHR, MR2, MMR, MR4 and 
MR4.5 
• To Evaluate the progression free survival 
(PFS)  
• PFS during 24, 48 and 72 weeks 
• To Evaluate Overall Survival (OS)  
• OS during 24, 48 and 72 weeks 
 
 
 
 
 


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2 Statistical methods 
2.1 Data analysis general information 
All analysis will be performed by Novartis. 
It is planned that the data from all centers that participate in this protocol will be used for analysis. 
Analysis datasets and statistical outputs will be produced using the most recent SAS® Version 9.4 
(SAS Institute Inc., Cary, NC, USA) or higher, and stored in Novartis global programming & 
statistical environment (GPS).  
There is no formal planned interim analysis.  
Data included in the analyses 
The analysis data cut-off dates for the planned analyses are: 
• 
Primary analysis: After random allocation of all patients in their respective Cohort, have been 
on study medication for 24 weeks or discontinued earlier, i.e., LPFT + 24 weeks.  
• 
Final safety, efficacy 
 analyses: 30 days after all patients have been on treatment 
for at least 72 weeks or discontinued earlier, i.e., LPFT + 72 weeks + 30 days. (Note: After the 
study medication period, the assigned study medication will be made available, may be outside 
of this study, to patients who in the opinion of the investigators are still deriving clinical benefit.) 
  
All statistical analyses will be performed using all data collected in the database up to the respective 
data cut-off date. All data with an assessment date or event start date (e.g., vital sign assessment date 
or start date of an adverse event) prior to or on the cut-off date will be included in the analysis. Any 
data collected beyond the cut-off date will not be included in the analysis and will not be used for any 
derivations.                  
All events with start date before or on the respective cut-off date and end date after the respective 
cut-off date will be reported as ongoing. The same rule will be applied to events starting before or on 
the respective cut-off date and not having documented end date. This approach applies, in particular, 
to adverse event and concomitant medication reports. For these events, the end date will not be 
imputed and therefore will not appear in the listings. 
General analysis conventions 
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for the 
analysis. Due to expected small number of patients enrolled at centers, no center effect will be 
assessed. 
Categorical data (e.g., gender, race, etc.) will be summarized by frequency and percentages by 
Cohort along with 95% Confidence interval (as appropriate); a missing category will be included as 
applicable. Percentages will be calculated using the number of patients in the relevant Cohort as the 
denominator. 95% Confidence Interval for the percentages will be evaluated using Clopper-pearson 
method.  
Continuous data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e., mean, standard deviation, median, minimum, Q1, Q3, and maximum) by Cohort
 
 
 
 For time to event and duration, , median, 25th percentile & 75th percentile, 


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estimated rate by specific timepoints will be reported along with their respective 95% Confidence 
interval(s). 
2.1.1 General definitions 
Investigational drug and study medication 
Investigational drug will refer to the ABL001 only. Whereas study medication will refer to ABL001 
[asciminib (40 mg BID, 80 mg QD or 200 mg BID)]. Novartis is supplying asciminib to the 
investigational site as 20 mg and 40 mg tablets. 
 
Treatment Cohorts 
Patients without T315I mutation status are selected randomly between Cohort A (without T315I) and 
Cohort B (without T315I). Patients harboring the T315I mutation are allocated to Cohort C. 
 
Without T315I mutation 
With T315I mutation 
Cohort A 
Cohort B 
Cohort C 
40 mg BID 
80 mg QD 
200 mg BID 
 
Date of first administration of study medication 
The date of first administration of study medication is derived as the first date when a non-zero dose 
of study medication was administered as per the Dosage Administration Record (DAR) electronic 
case report form (eCRF). The date of first administration of study medication will also be referred as 
start of study medication. 
The date of first administration of study medication is the same as the date of first administration of 
investigational drug. 
Date of last administration of study medication 
The date of last administration of study medication is defined as the last date when a non-zero dose 
of study medication was administered as per the DAR eCRF. 
The date of last administration of study medication is the same as the date of last administration of 
investigational drug. 
Study day 
The study day describes the day of the event or assessment date, relative to the reference start date. 
• The date of the event (visit date, onset date of an event, assessment date, etc.) − reference 
start date + 1 if event is on or after the reference start date; 
• The date of the event (visit date, onset date of an event, assessment date, etc.) − reference 
start date if event precedes the reference start date. 
 
The reference start date for safety assessments (e.g., adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption, 
 etc.) is the start of study medication.  
 
The reference start date for all other, non-safety assessments (e.g., molecular response, survival time, 
disease progression, ECOG performance status, 
 etc.) is the date of 
random allocation of patient to their respective Cohort. 
The study day will be displayed in the data listings. If an event starts before the reference start date, 
the study day displayed on the listing will be negative. 
For “time since event” data (e.g., medical history), the duration (in days) will be calculated as 
treatment start date-diagnosis date. 


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Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 (=365.25/12) days. If duration is 
reported in months, duration in days will be divided by 30.4375. If duration is reported in years, 
duration in days will be divided by 365.25. 
A week length is defined as 7 days. If duration is reported in weeks, duration in days will be evaluated 
by dividing duration in weeks by 7. All the time related study endpoints will be reported in Weeks, 
until stated or specified.  
Baseline 
For safety & efficacy evaluations, the last available assessment on or before the date of start of study 
medication of asciminib (40 mg BID, 80 mg QD & 200 mg BID) is taken as ‘‘baseline” assessment. 
For pre-dose electrocardiogram (ECG), the last available assessment before the treatment start 
date/time is used for baseline. 
For ECGs, where study requires multiple replicates per time point, the average of these measurements 
would be calculated for baseline (if not already available in the database). 
In rare cases where multiple laboratory measurements meet the baseline definition, with no further 
flag or label that can identify the chronological order, then the following rule should be applied: If 
values are from central and local laboratories, the value from central assessment should be considered 
as baseline.  
If patients have no value as defined above, the baseline result will be missing. 
On-treatment assessment/event and observation periods 
For adverse event, reporting the overall observation period will be divided into two mutually 
exclusive segments: 
• Pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study medication 
• On-treatment period: from date of first administration of study medication to 30 days after 
date of last actual administration of any study medication (including start and stop date).  
 
Note: Patients will be treated for up to LPFT + 72 weeks. This will be the last actual administration 
of study medication for each patient if the patient has not discontinued study medication earlier. 
After this period, the assigned study medication will be made available, may be outside of this 
study, to patients who in the opinion of the investigators are still deriving clinical benefit.  
 
Visit window 
Windows for multiple assessments 
In order, to summarize molecular response, Hematologic Response, 
 collected over time 
(including unscheduled visits), the assessments will be time slotted. The following general rule will 
be applied in creating the assessment windows: If more than one assessment is done within the same 
time window, the assessment performed closest to the target date will be used. If two assessments 
within a time window are equidistant from the target date, then the average of the two assessments 
will be used. If multiple assessments on the same date, then the average will be used. Data from all 
assessments (scheduled and unscheduled), including multiple assessments, will be listed. 
 
 


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Table 2-1 
Time windows for molecular response (BCR-ABL1 quantification by RQ- 
PCR) 
 
Assessment 
Target day of assessment 
Time Interval 
Baseline 
≤ 1 
≤ Day 1# 
Week 4 
29 
Day 2 to day 57 
Week 12 
85 
Day 58 to day 127 
Week 24 
169 
Day 128 to day 211 
Week 36 
253 
Day 212 to day 295 
Week 48 
337 
Day 296 to day 421 
Week 72 
505 
Day 422 to day 589 
# Day 1 = Date of random allocation of patients 
EOT assessments are mapped to the time points as needed. 
 
Table 2-2 
Time windows for Hematologic response assessment 
 
Assessment 
Target day of 
assessment 
Time Interval 
Week 12 
85 
Day 2 to day 127 
Week 24 
169 
Day 128 to day 211 
Week 36 
253 
Day 212 to day 295 
Week 48 
337 
Day 296 to day 421 
Week 72 
505 
Day 422 to day 589 
# Day 1 = Date of random allocation of patients 
EOT assessments are mapped to the time points as needed. 
 
 
 
 
 
 
 
 
 
 
 


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Last contact date 
The last contact date will be derived for patients not known to have died at the respective analysis 
data cut-off date using the last complete date among the following: 
Table 2-5   Last contact date data sources  
 
 
 
Source data 
Conditions 
 
Date of random allocation 
No condition 
 
Last contact date/last date patient was known to 
be alive from Survival Follow-up page 
Patient status is reported to be alive, lost to follow-up 
or unknown 
 
Start/End dates from further antineoplastic 
therapy 
Non-missing medication/procedure term 
 
Start/End dates from drug administration record 
Non-missing dose. Doses of 0 are allowed 
 
End of treatment date from end of treatment page 
No condition 
 
Any specific efficacy (molecular or cytogenetic) 
assessment date if available 
Evaluation is marked as ‘done’ 
 
Laboratory/
collection dates 
Sample collection marked as ‘done’ 
 
Vital signs date 
At least one non-missing parameter value 
 
Performance status date 
Non-missing performance status 
 
Start/End dates of AE 
Non-missing verbatim term 
 
 
The last contact date is defined as the latest complete date from the above list on or before the 
respective data cut-off date. The cut-off date will not be used for last contact date unless the patient 
was seen or contacted on that date. No date post cut-off date will be used. Completely imputed 
dates (e.g., the analysis data cut-off date programmatically imputed to replace the missing end 
date of a dose administration record) will not be used to derive the last contact date. 
The last contact date will be used for censoring of patients in the analysis of overall survival. 


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2.2 
Analysis sets 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) comprises all patients to whom study medication has been assigned. 
According to the intent to treat principle, patients will be analyzed according to the study medication 
and Cohort they have been assigned.  
All the secondary efficacy endpoints will be analyzed using FAS. 
Safety Set (SS) 
The Safety Set (SS) includes all patients who received at least one dose of study medication. Patients 
will be analyzed according to the study medication (regimen) they actually received. 
The primary and all safety endpoints analysis will be performed on Safety Set. 
 
 
  
 
 
. 
Patient Classification 
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific patient classification. 
During the study, major and minor protocol deviations will be identified and collected on an ongoing 
basis as they occur. Refer to special data handling in data management documents. The decision 
whether patients will be included or excluded in the appropriate analysis sets will be determined 
based on the severity levels of the PDs. 
 
2.2.1 
Subgroup analyses 
Subgroup analyses will be performed based on the patient’s baseline status: 
• Age: (< 65 years; ≥ 65 years) 
• Patients with resistance: (BCR-ABL ratio at baseline >10%) 
• Previous treatment with Ponatinib (Yes or No) 
• By number of prior TKI therapies: 2, 3, ≥4 
 
Summary tables and figures will be generated only for subgroups with at least 5% of the total sample 
size of full analyses set (for efficacy endpoint) or safety set (for safety endpoint).  
 
All primary and secondary endpoints will be analyzed and summarized within each subgroup. 
Additionally, as the study is ongoing during COVID-19 pandemic, to address the impact of COVID-
19 (if any) AEs, SAEs, Abnormal lab findings and notable vital signs will be summarized and 
reported if COVID-19 infected patient count exceeds 5% of the total sample size of safety set. 
As appropriate, given the significance of the impact of COVID-19 on the enrolled patients, a 
sensitivity analysis may be performed on the safety and efficacy data evaluating the impact of 
COVID-19 on the study, if COVID-19 infected patient count exceeds 5% of the total sample size. 


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2.3 Patient disposition, demographics, and other baseline characteristics 
2.3.1 Demographics and baseline characteristics 
FAS will be used for all baseline and demographic summaries and listings unless otherwise specified. 
Patient demographics and baseline characteristics collected will include the following: date of birth, 
gender (and childbearing potential for female), race and ethnicity, height, weight, all relevant medical 
history including cardiovascular disease history, CML disease history, including mutation status, and 
prior and concomitant medication including prior TKI therapy and antineoplastic medication. 
Physical examination including, extramedullary involvement, performance status, vital signs, ECGs, 
and laboratory assessments performed at screening will be summarized by Cohort. 
Summaries will be reported for all patients. No inferential statistics will be provided. 
All demographic and baseline disease characteristics data will be summarized by Cohort. Categorical 
data (e.g., age groups: < 65, and ≥ 65 years, sex, race, ethnicity, ECOG performance status) will be 
summarized by frequency counts and percentages; the number and percentage of patients with 
missing data will be provided. Continuous data (e.g., age, weight, height, body mass index) will be 
summarized by descriptive statistics (N, mean, median, standard deviation, minimum and maximum), 
where BMI (kg/m2) will be calculated as weight[kg] / (height[m]2) using weight at screening. 
The number (%) of patients in each Cohort A, B & C (“With T315I Mutation” or “Without T315I 
Mutation”) based on data obtained from the IRT system will be summarized based on their respective 
assigned cohort for all the patients in their respective analysis sets.  
 
2.3.2 Diagnosis and extent of cancer - CML 
All diagnosis and extent of CML data will be summarized by Cohort. One summary table will 
include time (years) since initial diagnosis (descriptive statistics with N, mean, median, 
standard deviation, minimum and maximum) and historical mutation (frequency counts and 
percentages). Another table will include extramedullary involvement (frequency counts and 
percentages). 
 
2.3.3 Medical history 
Significant findings that were present prior to the signing of informed consent will be included 
in the Relevant Medical History/Current Medical Conditions page on the patient’s eCRF. 
Significant new findings that begin or worsen after informed consent will be recorded on the 
AE page of the patient’s eCRF and will be summarized & listed overall and by Cohort. 
Medical history and ongoing conditions, including toxicity grade entered on eCRF will be 
summarized and listed by Cohort. The summary will be presented by primary system organ 
class (SOC), preferred term (PT) and Cohort. Medical history and current medical conditions 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. 
The MedDRA version used for reporting will be specified in the CSR and as a footnote in the 
applicable tables/listings. 
 
In addition, separate summary tables & listings will be produced for medical history possibly 
contributing to pulmonary diseases, and cardiovascular events. 
 


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2.3.4 Patient disposition 
All randomly allocated patients by center will be summarized for all enrolled patients by Cohort 
using the FAS The number (%) of enrolled patients included in the FAS will be presented overall 
and by Cohort. The number (%) of screened, enrolled and not - enrolled patients and the reasons 
for screening failure will also be displayed. The number (%) of patients in the FAS who are still 
on treatment, who discontinued the study phases and the reason for discontinuation will be 
presented overall and by Cohort. 
The following summaries will be provided (with % based on the total number of FAS patients): 
• 
Number (%) of patients who were enrolled (based on data from IRT system) 
• 
Number (%) of patients who were enrolled but not treated (based on DAR eCRF page 
not completed for any study medication component) 
• 
Primary reason for not being treated (based on “End of Screening Phase” and 
“Withdrawal of Informed Consent(s)” eCRF pages) 
• 
Number (%) of patients who were treated (based on DAR eCRF pages of each study 
medication completed with non-zero dose administered) 
• 
Number (%) of patients who completed the study medication (based on the 
“Completion of Treatment disposition phase” Disposition eCRF page) 
• 
Number (%) of patients who discontinued the study medication (based on the “End 
of Treatment Disposition” page) 
• 
Primary reason for study medication phase discontinuation (based on the “End 
of Treatment Disposition” page) 
• 
Number (%) of patients who have entered the safety follow-up (based on the 
“Completed/Discontinuation of Post-Treatment follow-up” Disposition eCRF page) 
• 
Number (%) of patients who completed the safety follow-up (based on the 
“Completion of Post-Treatment follow-up” Disposition eCRF page) 
• 
Number (%) of patients who discontinued the safety follow-up (based on the 
“Discontinuation of post-Treatment follow-up” Disposition eCRF page) 
• 
Primary reason for safety follow-up discontinuation (based on the “Discontinuation of 
post-Treatment follow-up” Disposition eCRF page) 
 
Safety follow-up will not be reported in the disposition summary for primary analyses 
timepoint (24 weeks).  
2.3.5 Protocol deviations 
The number (%) of patients in all the analysis sets with CSR reportable protocol deviations will 
be tabulated by deviation category (as specified in the Study Specification Document) overall and 
by Cohort. All CSR reportable protocol deviations will be listed. 
 
 


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2.4 
Treatments (study medication, rescue medication, 
concomitant therapies, compliance) 
2.4.1 
Duration of exposure to study medication 
The safety set (SS) will be used for all summaries of study medication. 
The duration of exposure will be summarized for each study cohort A, B and C. The dose 
intensity (computed as the ratio of actual cumulative dose received and actual duration of 
exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned 
dose intensity) will be summarized for each study cohort by descriptive statistics.  
• The number of participants will be summarized for SS by study cohort. 
• The number (%) of patients who have dose reductions or interruptions, and the reasons, will 
be summarized by cohort. 
• Patient level listings of all doses administered on medication along with dose change 
reasons will be produced. 
• Duration of exposure to study medication is considered by taking into account the duration 
of exposure of non-zero doses to the investigational drug or control. 
•  Time on treatment(weeks) =  [(date  of   last administration of study medication) – (date of 
first administration of study medication) – (days with zero dose) + 1] / 7. 
• Duration of exposure to study treatment (weeks) =  [(date  of   last administration of study 
medication) – (date of first administration of study medication) + 1] / 7. 
• The date of last administration of study medication is defined in Section 2.1.1. 
• Summary of duration of exposure of study medication will include categorical summaries 
based on intervals (<24 weeks, ≥24 weeks and < 48 weeks, ≥48 weeks and < 72 
weeks, >=72 weeks) and continuous summaries (i.e., mean, standard deviation etc.). 
 
Cumulative dose 
Cumulative dose of a study medication is defined as the total dose given during the study 
medication exposure. 
The planned cumulative dose for a study medication refers to the total planned dose as per the 
protocol up to the last date of study medication administration. The calculations for the three 
separate doses of study medication are: 
• Cohort A (ABL001): 40 mg/administration × 2 (administration/day) × duration of 
exposure (days)  
• Cohort B (ABL001): 80 mg/administration × 1 (administration/day) × duration of 
exposure (days)  
• Cohort C (ABL001): 200 mg/administration × 2 (administration/day) × duration of 
exposure (days) 
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the patient is on the study medication as documented in the DAR eCRF. It is the sum of 
the non-zero total daily doses recorded over the dosing period. For patients who did not take 
any drug the actual cumulative dose is by definition equal to zero. The actual cumulative dose 
will be summarized for each of the Cohort. 
 
 


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Dose intensity and relative dose intensity 
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows: DI 
(mg/day) = Actual cumulative dose (mg) / Duration of exposure to study treatment(days). 
For patients who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity (PDI) is defined as: 
PDI (mg/day) = Planned cumulative dose (mg) / Duration of exposure to study treatment(days). 
Relative dose intensity (RDI (%)) is defined as follows: 
RDI (%) = [DI (mg/day) / PDI (mg/day)]*100. 
DI and RDI (%) will be summarized separately for all the three study Cohorts. 
 
Dose changes, interruptions or permanent discontinuations 
The number of patients, who have dose reductions, dose interruptions or permanent 
discontinuations, and the reasons, will be summarized separately for all the three study cohorts. 
‘Dose Reduced’, ‘Dose Interrupted’ and ‘Dose Permanently Discontinued’ fields from the 
DAR eCRF pages will be used to determine the dose reductions, dose interruptions, and 
permanent discontinuations, respectively. 
The corresponding fields, ‘Reason for Dose Reduction’, ‘Reason for Dose Interruption and 
‘Reason for Permanent Discontinuation’ will be used to summarize the reasons. 
A dose change occurs when total daily dose is different from the most recently planned dose. 
For patients in Cohort A, there is only one planned dose, i.e., 40 mg b.i.d. For patients in Cohort 
B, there is only one planned dose, i.e., 80 mg/day QD. For patients in Cohort C, the initial 
planned dose is 200 mg b.i.d i.e., 400 mg/day. 
For summarizing interruptions and reasons, multiple entries for interruption that are entered on 
consecutive days with different reasons will be counted as separate interruptions. However, if 
the reason is the same in the mentioned multiple entries on consecutive days, then it will be 
counted as one interruption. 
Reduction: A dose reduction is where the actual total daily dose is lower than the most recently 
planned dose. Therefore, any dose reduction to correct a dosing error will not be considered a 
dose reduction. Only dose reduction is collected in the eCRF and will be summarized for the 
patient’s data available. 
2.4.2 
Prior, concomitant and post therapies/medication  
Prior antineoplastic therapy/medications 
The number and percentage of patients who received any prior anti-neoplastic therapy 
/medications will be summarized by cohort and also for the lowest anatomical therapeutic 
classification (ATC) class and preferred term. Summaries will include total number of 
regimens. 
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD). 
Details regarding WHO-DD version will be included in the footnote in the tables/listings. 
The above analyses will be performed using the SS. 
 
 


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Post treatment anti-neoplastic therapy/medication 
The number and percentage of patients who received any anti-neoplastic medication and/or 
therapy since discontinuation of study medication will be summarized by cohort for setting 
(e.g., adjuvant, metastatic, etc.) and for the lowest anatomical therapeutic classification (ATC) 
class and preferred term. Summaries will include total number of regimens, reason for initiation 
of new therapy, indication, route of administration and reason for discontinuation of therapy. 
Anti-neoplastic medications will be coded using the WHO-DD. Details regarding WHO-DD 
version will be included in the footnote in the tables/listings. 
The above analyses will be performed using the SS. 
 
Prior and Concomitant therapies/Medications 
Prior and Concomitant therapies/medications are defined as all interventions (therapeutic 
treatments and procedures) other than the study medication administered to a patient coinciding 
with the study medication period. Prior therapies include medications (other than study drugs) 
and medical procedures started and ended prior to the start date of study medication. 
Concomitant therapies include medications (other than study drugs) and medical procedures 
starting on or after the start date of study medication but no later than 30 days after last dose of 
study medication or starting prior to the start date of study medication and continuing after the 
start date of study medication. 
Prior and Concomitant therapies/medications will be coded using the World Health 
Organization (WHO) Drug Reference Listing (DRL) dictionary that employs the WHO ATC 
classification system and summarized by the lowest ATC class and PT using frequency counts 
and percentages. Surgical and medical procedures will be coded using MedDRA and 
summarized by SOC and PT. These summaries will include: 
• 
Prior therapies/medications started and ended prior to the start date of study 
medication. 
• 
Concomitant therapies/medications: 
1. 
Therapies/medications starting on or after the start of study medication but no later 
than 30 days after last dose of study medication and 
2. 
Therapies/medications starting prior to start of study medication and continuing 
after the start of study medication. 
All prior & concomitant therapies/medications will be listed. Any concomitant 
therapies/medications starting and ending prior to the start of study medication or starting more 
than 30 days after the last date of study medication will be flagged in the listing. The safety set 
will be used for all concomitant therapies/medications’ tables and listings. 
 
2.5 
Analysis of the primary objective 
The primary objective is to evaluate safety profile of monotherapy asciminib in CML-CP in 3L 
and beyond for Cohorts A, and B. For all primary safety analyses, the Safety Set (SS) will be 
used, unless stated otherwise. 
The variables for the primary analysis are incidence and severity of AEs and SAEs, changes in 
laboratory values and vital signs, incidence of notable ECG abnormalities.  
 
 


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2.5.1  Primary endpoint 
The primary endpoint is to evaluate the safety profile of monotherapy asciminib (ABL001) with 
AEs, SAEs and laboratory studies’ assessment during 24 weeks of therapy in CML-CP patients, 
for Cohorts A and B i.e., without T315I mutation status. All safety analyses will be based on 
the safety set (SS).  
AE summaries will include all AEs occurring during on-treatment period. All AEs collected in 
the AE eCRF page will be listed along with the information collected on those AEs e.g., AE 
relationship to study drug, AE outcome, etc. AEs with start date outside of on-treatment period 
will be flagged in the listings. 
AEs will be summarized by number and percentage of patients having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A patient with multiple occurrences of an AE will be counted only 
once in the respective AE category. A patient with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables. Abnormal lab findings, vital signs and notable ECG abnormalities will also be 
summarized by cohort as explained in Safety analysis section 2.6. 
2.5.2 Statistical hypothesis, model, and method of analysis 
No formal hypothesis testing is planned for this study. 
For all safety analyses, the safety set will be used.  
2.5.3 Handling of missing values 
Missing data for measures of safety will not be imputed. 
 
2.6 
Safety analyses 
All safety analyses will be based on the safety set (SS). All listings and tables will be presented 
by Cohort.  
2.6.1 Adverse events (AEs) 
All the adverse events reported after administration of study drug to 30 days after the last date 
of drug to the patient are known as treatment emergent adverse events (TEAEs). 
The summary tables for adverse events (AEs) will summarize only on-treatment events, with a 
start date during the on-treatment period (treatment-emergent AEs). In addition, a separate 
summary for death including on-treatment deaths will be provided. All AE will be listed and 
those collected during the on-treatment period (TEAE) will be flagged. 
TEAEs will be summarized by number and percentage of patients having at least one AE in 
each primary system organ class (SOC) and for each preferred term (PT) using MedDRA 
coding. A patient with multiple occurrences of an AE will be counted only once in the 
respective AE category. A patient with multiple CTCAE grades for the same preferred term 
will be summarized under the maximum CTCAE grade recorded for the event. TEAE with 
missing CTCAE grade will be included in the ‘All grades’ column of the summary tables. 
In TEAE summaries, the primary system organ class will be presented alphabetically, and the 
preferred terms will be sorted within primary SOC in descending frequency. The sorting order 
for the preferred term will be based on their frequency in the ABL001 arm Cohort A. 
The following treatment emergent adverse event summaries will be produced by Cohort:  
• Overview of TEAEs and deaths  


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• TEAEs by SOC and PT  
• Summary by relationship  
• Seriousness  
• Leading to treatment discontinuation  
• Leading to dose interruption/adjustment  
• Requiring additional therapy and leading to fatal outcome  
For posting to ClinTrial.gov and EudraCT, a summary table of on-treatment deaths and 
serious AEs and another summary table of non-serious AEs by treatment, both including 
occurrences (an occurrence is defined as >1 day between start and prior end date of 
record of same preferred term) and sorted by SOC and PT, will be presented as well. 
All the adverse events will be graphically displayed by Cohorts using bar chart. 
 
2.6.2 Adverse events of special interest / grouping of AEs 
 
Data analysis of AESIs 
An adverse event of special interest (AESI) are defined as adverse events (serious or non-serious) 
which are of scientific and medical concern specific to compound ABL001 as mentioned in Table 5-
5. 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. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety data. 
The latest approved version of CRS prior to the respective database lock will be used. 
For each specified AESI, number and percentage of patients with at least one event of the AESI 
occurring during the on-treatment period will be summarized. 
Summaries of these AESIs will be provided by cohort. If sufficient number of events occurred, 
analysis of time to first occurrence will be applied. 
A listing of all grouping levels down to the MedDRA PTs used to define each AESI will be generated. 
 
2.6.3 Deaths 
Separate summaries for on-treatment / TEAE and all deaths will be produced by system organ class 
and preferred term, by cohort. 
All deaths will be listed, where on treatment deaths will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened patients. 
 
2.6.4 Laboratory data 
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of 
CTCAE grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or 
higher. Grade 5 will not be used. Details of CTCAE grading and imputation rules are presented in 
Appendix 5.3. 
For laboratory tests where grades are not defined by CTCAE v5.0, results will be categorized as 
low/normal/high based on laboratory normal ranges. 


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On analyzing laboratory, data from all sources (central and local laboratories) will be combined. The 
summaries will include all assessments available for the laboratory parameter collected no later than 
30 days after the last study medication administration date. 
The following summaries will be produced separately for hematology and biochemistry laboratory 
data (by laboratory parameter and cohort): 
• 
Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only for the worst grade observed post-baseline in the on-treatment period. 
• 
Shift tables to compare baseline CTCAE grades to the worst on-treatment grade for 
laboratory tests where grades are not defined by CTCAE v5.0 
• 
Shift tables using the low/normal/high/ (low and high) (or project specific) classification 
to compare baseline to the worst on-treatment value. 
• 
Newly or worsening laboratory abnormalities will be summarized, separately. 
 
The following listings will be produced separately for hematology and biochemistry for the 
laboratory data: 
• 
Listings of all laboratory data, with corresponding CTCAE grades and classification 
relative to the laboratory normal range. Lab data collected during the post-treatment 
period with corresponding CTCAE v5 grades will be flagged. 
• 
Listing of all CTCAE grade 3 or 4 laboratory toxicities 
• 
Box plot(s) for all laboratory parameters over time will be plotted and displayed by 
Cohort. 
 
2.6.5 Other safety data 
 
2.6.5.1 ECG and cardiac imaging data 
12-lead ECGs including PR, QRS, QT, QTcF and RR intervals will be obtained centrally for each 
patient during the study. ECG data will be read and interpreted centrally. 
Absolute values/change from baseline will be summarized over time. As appropriate, the number 
and percent of patients will be tabulated by category. In addition, a listing of patients with at least 
one notable ECG value will be produced. 
 
Data handling 
The average of the triplicate ECG parameters at each time point will be used in the analyses. 
Data analysis 
The number and percentage of patients with notable ECG values will be presented by Cohort. 
Notable values are defined below: 
• QT, QTcF 
• New value of > 480 and ≤ 500 ms 
• New value of > 500 ms 
• HR 
• Increase from baseline >25% and to a value > 100 bpm 
• Decrease from baseline >25% and to a value < 50 bpm 
 
 


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• PR 
• Increase from baseline >25% and to a value > 200 ms 
• New value of > 200 ms 
• QRS 
• Increase from baseline >25% and to a value > 120 ms 
• New values of QRS > 120 ms 
A listing of only the patients with notable ECG values will be produced. In the listing the 
assessments collected during the on-treatment period will be flagged. 
2.6.5.2 Vital signs 
Data on vital signs will be tabulated and summarized descriptively as follows: 
• Number and percentage of patients who shift from non-notable at baseline to 
notable post- baseline. Also, bar chart with 95% CI will be presented for the 
notable changes.   
The number and percentage of patients with notable vital sign values (high/low) in systolic 
blood pressure, diastolic blood pressure, pulse rate, weight and temperature will be presented 
by Cohort. 
A listing of notable vital sign values will be produced. In the listing, the assessments collected 
outside of on-treatment period will be flagged. 
2.6.5.3 Cardiovascular and Pulmonary risk factor assessment 
Prior to random allocation of patients to cohort and at the end of treatment, cardiovascular risk factors 
collected will be listed by cohort.    
Prior to random allocation of patients to cohort and at Week 20, pulmonary function tests including 
assessment of the lung volumes FEV1, FVC, FEV1/FVC, TLC, VC and DLCO will be performed, if 
clinically indicated. A listing will be presented by cohort. 
 
 
 
 
 
 
2.7 Analysis of the key secondary objective 
Not applicable 
2.8 Analysis of the secondary objective(s) 
 
The secondary objective(s) of the study are: 
• To estimate the rate of hematologic and molecular responses at specific time points for 
• Cohort A, B and C 
• Rate of CHR, MR2, MMR, MR4, MR4.5 in 12, 24, 48, 72 weeks of therapy 
• To estimate time to hematologic and molecular response 
• Time to CHR, MR2, MR4, MR4.5 in 12, 24, 48, 72 weeks of therapy 


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• To evaluate the duration of hematologic and molecular response 
• Duration of MR1, MR2, MMR, MR4 and MR4.5 
• To evaluate Progression Free Survival (PFS) 
• To evaluate Overall Survival (OS) 
 
2.8.1 Secondary safety endpoints 
The secondary safety endpoints are:  
• AEs, SAEs and laboratory evaluation for Cohort A, Cohort B and Cohort C, by 48, 72 weeks 
 All secondary safety analysis will be performed similar to the above primary safety analysis using 
Safety set (SS) by 48, 72 weeks. Additionally, a separate safety summary up to 24 weeks will be 
provided for Cohort C.  
 
2.8.2  Secondary efficacy endpoints 
The secondary efficacy endpoints are: 
• Rate of CHR, MR2, MMR, by 12, 24, 48, 72 weeks of therapy 
• Rate of MR4, MR4.5 by 24, 48, 72 weeks of therapy 
• Time to CHR, MR2, MMR, MR4, MR4.5 
• Duration of CHR, MR2, MMR, MR4 and MR4.5 
• PFS during 24, 48 and 72 weeks 
• OS during 24, 48 and 72 weeks 
For all secondary efficacy analyses, the Full Analysis Set (FAS) will be used, unless stated 
otherwise. 
For secondary efficacy analysis, proportion of patients achieving the response levels will be 
presented together with an exact 95% Clopper-Pearson confidence interval. For time to event 
and duration, PFS & OS, median, 25th percentile & 75th percentile will be reported along with 
their respective 95% Confidence Interval.  
 
Rate of CHR, MR2, MMR, by 12, 24, 48, 72 weeks of therapy and Rate of MR4 & 
MR4.5 by 24, 48, 72 weeks of therapy  
• 
The rate of Complete Hematologic Response (CHR) by 12, 24, 48 and 72 weeks. CHR 
is defined as all of the following present for ≥ 4 weeks: 
 WBC count < 10 x 109/L 
 Platelet count < 450 x 109/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 
• 
The rate of molecular response (MR2) by 12, 24, 48 and 72 weeks after the start of first 
study medication. MR2 is defined as ≥ 2 log reduction of BCR-ABL transcript from standardized 
baseline or ≤ 1% BCR-ABL/ABL % by international scale, measured by real-time quantitative 
PCR (RQ-PCR). 
 
 


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• 
The rate of major molecular response (MMR) by 12, 24, 48 and 72 weeks after the start of 
first study medication. MMR is defined as ≥ 3 log reduction of BCR-ABL transcript from 
standardized baseline or ≤ 0.1% BCR-ABL/ABL % by international scale, measured by real-time 
quantitative PCR (RQ-PCR). 
• 
The rate of molecular response (MR4) by 24, 48 and 72 weeks after the start of first study 
medication. MR4 is defined as ≥ 4 log reduction of BCR-ABL transcript from standardized baseline 
or ≤ 0.01% BCR-ABL/ABL % by international scale, measured by real-time quantitative PCR (RQ-
PCR). 
• 
The rate of the molecular response (MR4.5) by 24, 48 and 72 weeks after the start of first 
study medication. MR4.5 is defined as ≥ 4.5 log reduction of BCR-ABL transcript from standardized 
baseline or ≤ 0.0032% BCR-ABL/ABL % by international scale, measured by real-time quantitative 
PCR (RQ-PCR). 
For rate of MR2, MMR, MR4, MR4.5 by any pre-specified time point patients will be consider as 
responder if he/she achieve the particular response at least once by the specific timepoint. If patient 
discontinuing the treatment prior to a specific time point due to any reason and not achieved the 
particular response before the discontinuation will be considered as non-responder. 
For each time point, the proportion of patients achieving the specific response levels will be presented 
together with an exact 95% Clopper-Pearson confidence interval by cohort. The rates over time will 
be displayed graphically using the Bar Charts with 95% C.I. as whiskers.  
Note: Patient(s) who have reported for molecular response(s) at baseline will not be included in time 
to event analyses.  
 
Time to CHR, MR2, MR4, MR4.5 in 72 weeks of therapy 
Time to achieving a response level is defined as the time from the date of the first dose of study 
medication to the first documented achievement of a response level. 
Time to achieve a specific response level will be analyzed using the Kaplan-Meier Product- Limit 
method. Patients who are known to be without achieving that response level will be censored at the 
last molecular & hematologic assessment.  
The estimated cumulative incidence rates and 95% confidence intervals at 12, 24, 48 and 72 
weeks will be presented. The cumulative incidence curve will be plotted., if applicable. The 
analyses will be performed using FAS by cohort. 
 
For patients in the FAS who have not experienced any molecular and/or hematologic response, the 
time will be censored as follows in the Kaplan-Meier analysis: 
 
• If a patient does not achieve the specified response before the cut-off date for the analysis, 
censoring time will be the last molecular assessment (PCR) date on treatment prior to the 
cut-off date or the EoT visit, whichever comes first. 
• If a patient discontinues study treatment prior to achieving a response for a reason other 
than disease progression or death, then the patient will be censored at the last molecular 
assessment (PCR) date on treatment prior to the cut-off date or the EoT visit, whichever 
comes first. 
 
 


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• If a patient discontinues study treatment prior to achieving a response due to progression 
or death, then the censoring time will be set to the longest follow-up time in the treatment 
group, that is, consider the response is impossible to reach. 
In case no on-treatment response assessment was performed, the patient will be censored 
at day 1. 
Duration of CHR, MR2, MMR, MR4 and MR4.5 
Duration of Response (DOR) is the time from the date of the first documented molecular (MR2, 
MMR, MR4, MR4.5) or Hematologic (CHR) response to the date of first documented loss of that 
response or death due to any cause or progression to AP/BC, whichever occurs first. 
The start date is the date of first documented response and the end date is defined as the date of the 
first documented loss of that response or death due to any cause or progression to AP/BC. Participants 
continuing without that event will be censored at the date of their last adequate molecular of 
hematologic response assessment. 
DOR for each response level will be analyzed using the Kaplan-Meier Product-Limit method. 
Estimates of DOR at specific timepoint and the 25th, median and 75th percentile of the DOR and 
their 95% confidence intervals will be provided, if applicable. 
 
2.8.1.1 
Other secondary efficacy endpoints 
Progression-Free-Survival (PFS) is defined as time from the first dose of study medication to 
disease progression to AP/BC or death due to any cause, whichever occurs first during 24,48 and 72 
weeks.  
For patients without progression, the patient will be censored at the last molecular assessment date 
the patient was known to be alive and without progression (on or before the cut-off date). 
PFS will be analyzed using the Kaplan-Meier Product-Limit method. Patients who do not progress 
will be censored at the last adequate assessment. Estimates of the 25th, median and 75th percentile 
of the PFS and their 95% confidence intervals will be provided, if applicable. 
 
Overall survival (OS) is defined as the time from the first dose of study medication to death due to 
any cause during 24, 48 weeks and 72 weeks during study. 
If a patient is not known to have died, then OS will be censored at the latest date the patient was known 
to be alive (on or before the cut-off date). All deaths will be taken into account whatever the death 
occurred, i.e., even after interruptions, or discontinuation of study medication due to any reason. 
OS will be analyzed using the Kaplan-Meier Product-Limit method. Patients who do not progress 
will be censored at the last adequate assessment. Estimates of the 25th, median and 75th percentile 
of the OS and their 95% confidence intervals will be provided, if applicable. 
 
 


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2.8.3 Handling of missing values/censoring/discontinuations 
MMR rates by specific time points:  
Patients without any documented response for which an evaluable response assessment was never 
provided will be considered as non-responders for the period of time up to that time point. 
Molecular response category by specific time points: The category “Missing” will be assigned to 
patients for whom an evaluable response assessment was never provided. 
Time to MMR: For patients in the FAS who have not experienced any MMR, the time will be 
censored as follows in the Kaplan-Meier analysis: 
If a patient does not achieve the specified response before the cut-off date for the analysis, censoring 
time will be the last molecular assessment (PCR) date on treatment prior to the cut-off date or the 
EoT visit, whichever comes first. 
If a patient discontinues study treatment prior to achieving a response for a reason other than disease 
progression or death, then the patient will be censored at the last molecular assessment (PCR) date 
on treatment prior to the cut-off date or the EoT visit, whichever comes first. 
If a patient discontinues study treatment prior to achieving a response due to progression or death, 
then the censoring time will be set to the longest follow-up time in the treatment group, that is, 
consider the response is impossible to reach.  
In case no on-treatment response assessment was performed, the patient will be censored at day 1. 
Duration of MMR: For patients who have not experienced any event (loss of MMR, progression to 
AP/BC, or CML-related death), the duration will be censored at the last molecular assessment (PCR) 
date on treatment. 
PFS: For patients who have not experienced protocol defined event (disease progression to AP/BC 
or death from any cause), the patients will be censored at the date of last study assessment (PCR, 
cytogenetic, hematologic or extramedullary) before the cut-off date.  
OS: Patients who are alive at the time of the analysis data cutoff date will be censored at the date of 
last contact (see Section 2.1.1) before the cut-off date. 
 
2.8.4 Statistical hypothesis, model, and method of analysis 
There is no formal hypothesis to test in this study.  
 
 
 


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2.10 Interim analysis 
As the primary time point is by 24 weeks, the primary analysis will be an interim analysis. The primary 
analysis will be performed when the last patient completes 24 weeks of treatment or discontinues 
early. 
As appropriate, annual interim analyses will be planned for publication or any regulatory purpose. 
No formal interim analysis will be performed. Only summary statistics will be provided. 
Final Analysis will be performed when the last patient completes 72 weeks or discontinues early. A 
final CSR will be written. 
 
3 
Sample size calculation 
This is an open label, three-cohort study to assess safety and efficacy of study of asciminib (ABL001) 
monotherapy in patients with chronic myeloid leukemia in chronic phase (CML-CP) previously 
treated with at least 2 prior TKIs (tyrosine kinase inhibitors) and CML-CP patients harboring the 
T315I mutation previously treated with at least 1 prior TKIs. 
For all CML-CP with the exception of those harboring the T315I mutation, there will be random 
allocation of patients to eliminate selection bias at the time of cohort allocation. Those patients will 
be assigned to either Cohort A consisting of asciminib 40 mg BID patients or Cohort B consisting of 
asciminib 80 mg QD. For CML-CP patients harboring the T315I mutation, they will be assigned to 
Cohort C with asciminib 200 mg BID, which is the dose required for that patient population. It is 
worthwhile mentioning that random allocation of patients in cohorts A and B will be pursued for 
patient selection only. The study is not powered to show differences in Primary and Secondary 
endpoints between study cohorts. 
Primary objective of the study is to assess safety profile of this combination drug during 24 weeks 
for all cohort patients. 
A sample size of 40 evaluable patients for Cohort A is estimated based on a two- sided 95% 
confidence interval for an incidence rate of an AE using the large sample normal approximation that 
will extend 0.12 from the observed incidence rate of an AE (precision or margin of error of 12%) for 
an expected incidence rate of 18%. Considering drop-out rate of 10%, approximately 45 patients will 
be enrolled for safety assessment for the Cohort A of this study. 
Retaining the same assumptions, approximately 45 patients will also be enrolled for Cohort B. 
Additionally for Cohort C, approximately 25 patients will be enrolled. 
Thus, approximately total 115 (45+45+25=115) patients will be enrolled for Cohort A (n1=45) and 
Cohort B (n2=45) and for Cohort C (n3=25) of the study. 
 


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4 
Change to protocol specified analyses 
No change to the protocol specified analysis has been made. 
 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
The following rules should be used for the imputation of the dose end date for a given study 
medication component. 
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going: 
The patient should be treated as on-going and the cut-off date should be used as the dose end 
date. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available: 
• Case 1: The dose end date is completely missing, and the EOT completion date is complete, 
then this latter date should be used. 
• Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date: 
Use Dec31yyyy 
• Case 3: Only Year(yyyy) of the dose end date is available and yyyy = the year of EOT date: 
Use EOT date 
• Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy 
= the year of EOT date and mm < the month of EOT date: 
Use last day of the Month (mm) 
• All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study. 
• After imputation, compare the imputed date with start date of treatment, if the imputed date is < 
start date of treatment: 
• Use the treatment start date 
Patients with missing start dates are to be considered missing for all study medication 
component related calculations and no imputation will be made. If start date is missing then 
end-date should not be imputed. 
 
5.1.2 
AE, ConMeds and safety assessment date imputation 
The imputations specified in this section are only used for analyses of time to and duration of 
AEs and concomitant medications. 


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Table 5-1  Imputation of start dates (AE, CM) and assessments (LB, EG, VS)  
 
Missing 
Element 
Rule 
day, month, 
and year 
• No imputation will be done for completely missing dates 
day, month 
• If available year = year of study medication study medication start date 
then 
o If stop date contains a full date and stop date is earlier than study 
medication study medication start date then set start date = 
01JanYYYY 
o Else set start date = study medication study medication start date. 
• If available year > year of study medication study medication start date 
then 01JanYYYY 
• If available year < year of study medication study medication start date 
then 01JulYYYY 
Day 
• If available month and year = month and year of study medication 
study medication start date then 
o If stop date contains a full date and stop date is earlier than study 
medication study medication start date then set start date= 
01MONYYYY. 
o Else set start date = study medication study medication start date. 
• If available month and year > month and year of study medication 
study medication start date then 01MONYYYY 
• If available month and year < month year of study medication study 
medication start date then 15MONYYYY 
 
Table 5-2  Imputation of end dates (AE, CM) 
 
 
Missing 
Element 
Rule 
(*=last treatment date plus 30 days not > (death date, cut-off date, 
withdrawal of consent date)) 
day, month, 
and year 
• 
Completely missing end dates (incl. ongoing events) will be imputed by 
the end date of the on-treatment period* 
day, month 
• 
If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
Day 
• 
If partial end date contains month and year, set end date = earliest of last 
day of the month or end date of the on-treatment period* 
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data 
listings. 
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 


 
 
 
 
 
5.1.2.1 Other imputations 
 
Incomplete date of initial diagnosis of cancer 
Completely missing dates will not be imputed. Partial dates of diagnosis will be compared 
to the treatment start date. 
 
• If DIAG year < study treatment start date year and DIAG month is missing, the imputed 
DIAG date is set to the mid-year point (01JULYYYY). 
• Else if DIAG month is not missing, the imputed DIAG date is set to the mid-month 
point(15MONYYYY). 
• If DIAG year = study treatment start date year and (DIAG month is missing OR DIAG 
month is equal to study treatment start month), the imputed DIAG date is set to one day 
before study treatment start date. 
 
5.2 
AEs coding/grading 
Adverse events are coded using the latest available version of Medical dictionary for 
regulatory activities (MedDRA) terminology. 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. 
The CTCAE represents a comprehensive grading system for reporting the acute and late 
effects of cancer treatments. CTCAE grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 is not necessarily twice as bad as a grade 1). 
 
5.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation 
of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. The criteria to assign CTCAE grades are given 
in Novartis internal criteria for CTCAE grading of laboratory parameters (embedded 
below). The latest available version of the document based on the underlying CTCAE 
version v5.0 at the time of analysis will be used. For laboratory tests where grades are not 
defined by CTCAE v5.0, results will be graded by the low/normal/high (or other project-
specific ranges, if more suitable) classifications based on laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or 
higher. Grade 5 will not be used. For laboratory tests that are graded for both low and 


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high values, summaries will be done separately and labelled by direction, e.g., sodium 
will be summarized as hyponatremia and hypernatremia. 
EASE LAB - CTC 
grades in Novartis On 
Imputation Rules 
CTCAE grading for blood differentials is based on absolute values. However, this data 
may not be reported as absolute counts but rather as percentage of white blood cells 
(WBC). 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 
xxx count = (WBC count) * (xxx %value / 100) 
The following rules will be applied to derive the WBC differential percentages when only 
differential counts are available for a xxx differential 
xxx %value = (xxx count × 100) / WBC count 
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and 
albumin at the same assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1 and calcium values in mmol/L will be converted to mg/dL by dividing 
by 0.2495. For calculation of laboratory CTCAE grades 0 and 1, the normal range for 
derived corrected calcium is set to the same limits (in mg/dL) as for calcium. 
CTCAE grades for the derived absolute WBC differential counts (neutrophils, 
lymphocytes) and corrected calcium will be assigned as described above for grading. 
 
5.3.1 Derivation of PCR results and loss of response(s) 
Scaling towards an international standard will be performed for all molecular results using 
laboratory specific conversion factors. In this process, the raw ratio between BCR-ABL and 
the control gene ABL is calculated and multiplied by the lab -specific conversion factor 
([Branford and Hughes 2006]). Therefore, using the international unit, the BCR-ABL ratio 
will be presented in %. The MRDx assay using PAXgene TM Blood RNA tubes from MMD 
laboratory will be used in this study. The lab conversion factor for this assay is 1.1. 


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The BCR-ABL ratio in IS % is calculated by multiplying the raw BCR-ABL ratio with the 
lab-specific conversion factor and then by 100: 
BCR-ABL ratio (in %) = (BCR-ABL / ABL) * conversion factor * 100 
For consistency with elsewhere reported molecular response rates, the result may be 
expressed also as log-reduction. This is defined as the following: 
BCR-ABL Log-Reduction = -log10 (BCR-ABL ratio in %)  
For example, -log10 (0.001) = 3 log reduction for a ratio of 0.1%. 
The following binary variables will be used when molecular response is reported. 
 
Table 5-3  Response categories for molecular response 
 
 
MR (Molecular Response) 
BCR-ABL ratio 
(%) 
Log-reduction category 
MMR 
Yes 
≤ 0.1% 
≥ 3-log reduction 
No 
> 0.1% 
< 3-log reduction 
MR2 
Yes 
≤ 1% 
≥ 2 log reduction 
No 
> 1% 
< 2 log reduction 
MR4 
Yes 
≤ 0.01% 
≥ 4 log reduction 
No 
> 0.01% 
< 4 log reduction 
MR4.5 
Yes 
≤ 0.0032% 
≥ 4.5-log reduction 
No 
> 0.0032% 
< 4.5-log reduction 
 
Loss of Responses 
 
Loss of MR2 is defined as increase of BCR-ABL/ABL to > 1% by international scale (IS). 
BCR-ABL less than 1% according to the IS can be regarded as an equivalent to CCyR. Loss of 
MR2 must be confirmed by subsequent sample analysis within 4 to 6 weeks. 
 
Loss of MMR is defined as increase of BCR-ABL/ABL to > 0.1% by international scale (IS) 
in association with a ≥ 5-fold rise in BCR-ABL from the lowest value achieved on study 
treatment and replicated by a second analysis of the same sample. Loss of MMR must be 
confirmed by subsequent sample analysis within 4 to 6 weeks showing loss of MMR associated 
with a ≥ 5-fold rise in BCR-ABL from the lowest value achieved on study treatment, unless it 
is associated with confirmed loss of CHR to AP/BC or CML-related death. 
 
 


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5.4 Listing of AESIs 
 
All the adverse event of special interest (AESI) that are of scientific and medical concern 
specific to compound ABL001, collected from previous trials are mentioned below with 
Preferred Term (PT) and system Organ Class (SOC) in Table 5-5. 
 
Table 5-4      List of AESIs reported for ABL001(Asciminib) 
Preferred Tem 
System Organ Class 
Pancreatic toxicity 
Gastrointestinal disorders 
Hemorrhage 
Vascular disorders 
Edema and fluid retention 
General disorders and administration 
site conditions 
Hepatotoxicity (including laboratory terms) 
Hepatobiliary disorders 
Myelosuppression (Leucopenia) 
Blood and lymphatic system disorders 
Hypersensitivity 
Immune system disorders 
Hepatotoxicity (clinical events) 
Hepatobiliary disorders 
GI toxicity 
Gastrointestinal disorders 
Pancreatic toxicity (clinical events) 
Gastrointestinal disorders 
Myelosuppression (Thrombocytopenia) 
Blood and lymphatic system disorders 
Hepatotoxicity (including laboratory terms) 
Hepatobiliary disorders 
QTc prolongation 
Cardiac disorders 
Ischemic heart and CNS conditions 
Vascular disorders 
Hepatotoxicity (including laboratory terms) 
Hepatobiliary disorders 
Hepatotoxicity (including laboratory terms) 
Hepatobiliary disorders 
Cardiac failure (clinical events) 
Cardiac disorders 
Phototoxicity 
Skin and subcutaneous tissue disorders 
Myelosuppression (cytopenias affecting more 
than one lineage) 
Blood and lymphatic system disorders 
Myelosuppression (Erythropenia) 
Blood and lymphatic system disorders 
Ischemic heart and CNS conditions 
Vascular disorders 
Reproductive toxicity 
Reproductive system and breast 
disorders 
Hepatitis B virus reactivation 
Infections and infestations 
Hepatotoxicity (clinical events) 
Hepatobiliary disorders 
 
 
 
 
 


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6 
Reference 
1. Armitage P, McPherson CK and Rowe BC (1969). Repeated significance 
tests on accumulating data. J .R. Statist. Soc. A, 132, 232-244. 
2. Baccarani M, Deininger DW, Rosti G, et al (2013). European LeukemiaNet 
recommendations for the management of chronic myeloid leukemia: 2013. 
Blood; 122(6):872-84. 
3. Branford S, Hughes T (2006) Diagnosis and monitoring of chronic myeloid 
leukemia by qualitative and quantitative RT-PCR. Methods Mol Med; 125:69-92. 
4. Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median 
Survival Time. Biometrics, 38, 29 - 41. 
5. Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits 
illustrated in the case of the binomial. Biometrical, 26, 404-413. 
6. Collet D (1994). Modelling survival data in medical research. London, Chapman & 
Hall. 
7. Gambacorti-Passerini C, Brümmendorf TH, Kim DW, et al (2014). Bosutinib 
efficacy and safety in chronic phase chronic myeloid leukemia after imatinib 
resistance or intolerance: Minimum 24-month follow-up. Am J Hematol; 89(7):732-
42. 
8. García-Gutiérrez V, Martinez-Trillos A, Lopez Lorenzo JL, et al (2015). Bosutinib 
shows low cross intolerance, in chronic myeloid leukemia patients treated in fourth 
line. Results of the Spanish compassionate use program. Am J Hematol; 90(5):429-
33. 
9. Khoury HJ, Cortes JE, Kantarjian HM, et al (2012). Bosutinib is active in chronic 
phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib 
therapy failure. Blood; 119(15):3403-12. 
10. Mantel, N. and Joseph L Fleisś (1980). Minimum expected cell size requirements 
for the Mantel-Haenszel one degree-of-freedom Chi-Square Test and a related 
rapid procedure. American Journal of Epidemiology, 112, 129-134. 
11. European LeukemiaNet recommendations for the management of chronic myeloid 
leukemia: 2013; Prepublished online 2013 Jun 26. doi: 10.1182/blood-2013-05-
501569; PMCID: PMC4915804; PMID: 23803709