Clinical trial NCT03106779
Conditions: Chronic Myelogenous Leukemia
Keywords: Phase 3 Chronic Myelogenous Leukemia CML bosutinib ABL001 tyrosine kinase inhibitor Chronic myelogenous leukemia (CML) chronic myeloid leukemia (CML) chronic myelocytic leukemia (CML) chronic granulocytic leukemia (CGL) cancer of the white blood cells clonal bone marrow stem cell disorder proliferation of mature granulocytes
Sponsor: Novartis Pharmaceuticals
Start date: 2017-10-26; Completion date: 2024-12-04
Enrollment: 233 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this pivotal study was to compare the efficacy of asciminib (ABL001) with that of bosutinib in the treatment of patients with CML-CP having previously been treated with a minimum of two prior ATP-binding site TKIs.

Patients intolerant to the most recent TKI therapy must have had BCR-ABL1 ratio \> 0.1% IS at screening and patients failing their most recent TKI therapy must have met the definition of treatment failure as per the 2013 European LeukemiaNet (ELN) recommendations.

Patients with documented treatment failure as per 2013 ELN recommendations while on bosutinib treatment had the option to switch to asciminib treatment within 96 weeks after the last patient has been randomized on study.

Detailed description:
Patients were randomized in a 2:1 ratio to asciminib 40 mg BID or bosutinib 500 mg QD. Randomization was stratified by major cytogenetic response (MCyR) at screening. Patients with documented treatment failure (specifically meeting lack of efficacy criteria adapted from the 2013 ELN recommendations) while on bosutinib treatment were offered the option to switch to asciminib treatment within 96 weeks after the last patient was randomized to the study.

Arms: arm 1: Patients were randomized to asciminib 40mg BID arm 2: Patients were randomized to bosutinib 500mg QD
Interventions: intervention 1: Asciminib intervention 2: Bosutinib
Intervention descriptions: intervention 1: 40 mg tablets was taken orally twice a day (BID) intervention 2: 500 mg tablets was taken orally once daily (QD)

Protocol documents:
Prot_SAP_001.pdf: 
Asciminib/ABL001 
Oncology Clinical Trial Protocol CABL001A2301 
A phase 3, multi-center, open-label, randomized study of oral 
ABL001 (asciminib) versus bosutinib in patients with Chronic 
Myelogenous Leukemia in chronic phase (CML-CP), 
previously treated with 2 or more tyrosine kinase inhibitors 
Supplement 
 
This supplement contains 
 
1. Protocol CABL001A2301 
a. Protocol – Global Initial version (Version 1.0) 
b. Protocol – Global Final version (Version 3.0) 
c. Protocol – US local version 
d. Protocol – Summary of changes 
 
 
2. Statistical Analysis Plan for Protocol CABL001A2301  
a. Statistical Analysis Plan – Initial version 
b. Statistical Analysis Plan – Final version (Version 3.0) 
c. Statistical Analysis Plan – Addendum 
d. Statistical Analysis Plan – Summary of changes 
 
 
 
 
 
 


 
1. Protocol 
 
 




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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary:.............................................................................................................11
Amendment 1 (10-Apr-2017)............................................................................................17
1
Background........................................................................................................................19
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............19
1.2
Introduction to investigational treatment...............................................................20
1.2.1
Overview of ABL001............................................................................20
1.2.2
Overview of bosutinib...........................................................................26
2
Rationale............................................................................................................................27
2.1
Study rationale and purpose...................................................................................27
2.2
Rationale for the study design ...............................................................................28
2.2.1
Rationale for Biomarker Assessment....................................................29
2.3
Rationale for dose and regimen selection..............................................................29
2.4
Rationale for choice of combination drugs............................................................30
2.5
Rationale for choice of comparators drug bosutinib..............................................30
2.6
Risks and benefits..................................................................................................31
3
Objectives and endpoints...................................................................................................31
4
Study design ......................................................................................................................34
4.1
Description of study design ...................................................................................34
4.2
Timing of interim analyses and design adaptations...............................................35
4.3
Definition of end of study......................................................................................35
4.4
Early study termination..........................................................................................35
5
Population..........................................................................................................................36
5.1
Patient population..................................................................................................36
5.2
Inclusion criteria ....................................................................................................36
5.3
Exclusion criteria...................................................................................................38
6
Treatment...........................................................................................................................40
6.1
Study treatment......................................................................................................40
6.1.1
Dosing regimen .....................................................................................40
6.1.2
Ancillary treatments..............................................................................41
6.1.3
Rescue medication ................................................................................41


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6.1.4
Guidelines for continuation of treatment ..............................................41
6.1.5
Treatment duration................................................................................41
6.2
Dose escalation guidelines.....................................................................................41
6.3
Dose modifications ................................................................................................41
6.3.1
Dose modification and dose delay ........................................................41
6.3.2
Dose adjustments for QTcF prolongation.............................................51
6.3.3
Follow-up for toxicities.........................................................................51
6.3.4
Anticipated risks and safety concerns of the study drug.......................53
6.4
Concomitant medications for patients on ABL001 ...............................................53
6.4.1
Permitted concomitant therapy .............................................................53
6.4.2
Permitted concomitant therapy requiring caution and/or action...........53
6.4.3
Prohibited concomitant therapy ............................................................54
6.4.4
Other concomitant medications.............................................................55
6.5
Concomitant medications for patients on Bosutinib..............................................55
6.5.1
Prohibited concomitant medications.....................................................56
6.6
Patient numbering, treatment assignment or randomization .................................57
6.6.1
Patient numbering .................................................................................57
6.6.2
Treatment assignment or randomization...............................................57
6.6.3
Treatment blinding................................................................................58
6.7
Study drug preparation and dispensation...............................................................58
6.7.1
Study treatment packaging and labeling ...............................................58
6.7.2
Drug supply and storage........................................................................58
6.7.3
Study drug compliance and accountability ...........................................58
6.7.4
Disposal and destruction .......................................................................59
7
Visit schedule and assessments .........................................................................................59
7.1
Study flow and visit schedule................................................................................59
7.1.1
Molecular pre-screening........................................................................69
7.1.2
Screening...............................................................................................69
7.1.3
Run-in period ........................................................................................70
7.1.4
Treatment period ...................................................................................71
7.1.5
Visit windows........................................................................................71
7.1.6
Discontinuation of study treatment .......................................................71
7.2
Assessment types...................................................................................................73
7.2.1
Efficacy assessments.............................................................................73
7.2.2
Safety and tolerability assessments.......................................................75
7.2.3
Pharmacokinetics ..................................................................................80


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7.2.4
Biomarkers ............................................................................................82
7.2.5
Resource utilization...............................................................................85
7.2.6
Patient reported outcomes.....................................................................85
8
Safety monitoring and reporting........................................................................................87
8.1
Adverse events.......................................................................................................87
8.1.1
Definitions and reporting ......................................................................87
8.1.2
Laboratory test abnormalities................................................................88
8.1.3
Adverse events of special interest.........................................................89
8.2
Serious adverse events...........................................................................................89
8.2.1
Definitions.............................................................................................89
8.2.2
Reporting...............................................................................................90
8.3
Emergency unblinding of treatment assignment ...................................................90
8.4
Pregnancies............................................................................................................90
8.5
Warnings and precautions......................................................................................91
8.6
Data Monitoring Committee..................................................................................91
8.7
Steering Committee ...............................................................................................91
9
Data collection and management.......................................................................................92
9.1
Data confidentiality ...............................................................................................92
9.2
Site monitoring ......................................................................................................92
9.3
Data collection.......................................................................................................93
9.4
Database management and quality control............................................................93
10 Statistical methods and data analysis ................................................................................94
10.1
Analysis sets ..........................................................................................................94
10.1.1
Full Analysis Set ...................................................................................94
10.1.2
Safety set ...............................................................................................94
10.1.3
Per-Protocol set .....................................................................................94
10.1.4
Dose-determining analysis set...............................................................95
10.1.5
Pharmacokinetic analysis set.................................................................95
10.1.6
Other analysis sets.................................................................................95
10.2
Patient demographics/other baseline characteristics .............................................95
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................95
10.4
Primary objective...................................................................................................96
10.4.1
Variable.................................................................................................96
10.4.2
Statistical hypothesis, model, and method of analysis..........................96
10.4.3
Handling of missing values/censoring/discontinuations.......................96
10.4.4
Supportive and Sensitivity analyses......................................................97


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10.5
Secondary objectives .............................................................................................97
10.5.1
Key secondary objective(s)...................................................................97
10.5.2
Other secondary efficacy objectives .....................................................98
10.5.3
Safety objectives .................................................................................101
10.5.4
Secondary PK objectives.....................................................................102
10.6
Exploratory objectives.........................................................................................103
10.6.1
Exploratory efficacy objectives...........................................................103
10.6.2
Exploratory PK objectives ..................................................................104
10.6.3
Exploratory biomarker objectives.......................................................104
10.6.4
Exploratory Patient Reported Outcomes objectives ...........................105
10.7
Interim analysis....................................................................................................106
10.8
Sample size calculation........................................................................................106
10.9
Power for analysis of key secondary variables....................................................107
11 Ethical considerations and administrative procedures ....................................................107
11.1
Regulatory and ethical compliance......................................................................107
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................107
11.3
Informed consent procedures...............................................................................108
11.4
Discontinuation of the study................................................................................108
11.5
Publication of study protocol and results.............................................................108
11.6
Study documentation, record keeping and retention of documents.....................109
11.7
Confidentiality of study documents and patient records .....................................110
11.8
Audits and inspections.........................................................................................110
11.9
Financial disclosures............................................................................................110
12 Protocol adherence ..........................................................................................................110
12.1
Amendments to the protocol................................................................................110
13 References (available upon request)................................................................................111
14 Appendices ......................................................................................................................113
14.1
Appendix 1 List of CYP3A4 inducers, inhibitors and substrates........................113


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List of figures
Figure 1-1
KCL-22 CML Xenograft.......................................................................21
Figure 4-1
Schematic of Study Design ...................................................................35
List of tables
Table 3-1
Objectives and related endpoints ..........................................................32
Table 6-1
Dose and treatment schedule.................................................................40
Table 6-2
Criteria for dose reduction/interruption and re-initiation of ABL001 
and bosutinib treatment for adverse drug reactions ..............................43
Table 6-3
Dose reduction steps for ABL001 and bosutinib ..................................51
Table 6-4
Packaging and labeling .........................................................................58
Table 7-1
Visit evaluation schedule ......................................................................60
Table 7-2
Blood samples (efficacy primary endpoint)..........................................74
Table 7-3
ECOG Performance status scale ...........................................................77
Table 7-4
Central clinical laboratory parameters collection plan..........................77
Table 7-5
Central ECG collection (all patients) ....................................................79
Table 7-6
Central ECG collection plan for patients in full PK ABL001 group ....79
Table 7-7
Pharmacokinetic blood collection log (Sparse PK-group-ABL001 
arm) .......................................................................................................81
Table 7-8
Pharmacokinetic blood collection log ( Full PK group-ABL001 
arm) .......................................................................................................82
Table 7-9
Biomarker sample collection plan.........................................................84
Table 10-1
Non compartmental pharmacokinetic parameters in full PK group....103
Table 10-2
Detectable effect sizes for key secondary endpoint ............................107
Table 14-1
CYP3A4 inducers................................................................................113
Table 14-2
CYP3A4 inhibitors..............................................................................114
Table 14-3
CYP3A4 substrates: Narrow therapeutic index, sensitive, and 
others...................................................................................................115


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List of abbreviations
ABL
Abelson proto-oncogene
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
BC
Blast crisis
BCRP
Breast Cancer Resistant Protein
BID
bis in diem/twice a day
BUN
Blood urea nitrogen
CBC
Complete Blood Count
CCA
Clonal chromosome abnormalities
CCyR
Complete Cytogenetic Response
CHR
Complete Hematological Response
CI
Confidence Interval
CMH
Cochran–Mantel–Haenszel
CML
Chronic myelogenous leukemia
CP
Chronic phase
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
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DLCO
Carbon monoxide diffusing capacity
DMC
Data Monitoring Committee
DNA
Desoxyribonucleic acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic data capture
ELN
European Leukemia Network
EOT
End of Treatment
eRT
eResearchTechnology, Inc
hADME
Human ADME study (Absorption, Distribution, Metabolism and Excretion) 
HDL
High density lipoprotein
ICF
Informed Consent Form


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ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
K-M
Kaplan-Meyer
LDL
Low density lipoprotein
LFT
Liver function test
LLN
Lower limit of normal
LSC
Leukemia stem cell
MCyR
Major Cytogenetic Response
mCyR
Minor Cytogenetic Response
MMR
Major Molecular Response
MRI
Magnetic resonance imaging
OS
Overall survival
PAS
Pharmacokynetic analysis set
PCR
Polymerase Chain Reaction
PCyR
Partial Cytogenetic Response
PD
Pharmacodynamic
P-gp
Permeability glycoprotein
Ph+
Philadelphia chromosome positive
PHI
Protected Health Information
PK
Pharmacokinetics
PLT
Platelets
PPS
Per-protocol set
QD
Quaque die/once a day
QT
Q to T interval (ECG)
QTcF
QTc Fredericia
REB
Research Ethics Board
RNA
Ribonucleic acid
RQ-PCR
Real time quantitative polymerase chain reaction
RU
Resource Utilization
SAE
Serious Adverse Event
SAP
The Statistical Analysis Plan (SAP) is a regulatory document which provides evidence of 
preplanned analyses
SC
Steering committee
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT 
Serum glutamic pyruvic transaminase
SOP
Standard Operating Procedure
TBIL
Total bilirubin
TKI
Tyrosine Kinase Inhibitor
TTF
Time to treatment failure
UGT
Uridin diPhospho-glucuronosyltransferase
ULN
Upper limit of normal


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USPI
US prescribing information
WBC
White blood cell count


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Glossary of terms
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 subject or study patient
Cycles
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational 
new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are tested 
in a fixed combination. Investigational treatment generally does not include other 
study treatments administered as concomitant background therapy required or 
allowed by the protocol when used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment
Subject Number (Subject 
No.)
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional segments 
such as screening, baseline, titration, washout, etc.
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason
Treatment group
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time points
Withdrawal of consent
Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not 
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Protocol summary:
Title
A phase 3, multi-center, open-label, randomized study of oral ABL001 versus 
bosutinib in patients with Chronic Myelogenous Leukemia in chronic phase (CML-
CP), previously treated with 2 or more tyrosine kinase inhibitors
Brief title
Study of efficacy of CML-CP patients treated with ABL001 versus bosutinib, 
previously treated with 2 or more TKIs
Sponsor and
Clinical Phase
Novartis;
Phase 3
Investigation type
Drug 
Study type
Interventional
Purpose and rationale
Purpose:
The purpose of this pivotal study is to compare the efficacy of ABL001 with that of 
bosutinib in the treatment of patients with CML-CP having previously been treated 
with a minimum of two prior ATP-binding site TKIs with BCR-ABL ratios ≥1% IS at 
screening.
Rationale:
There remains an unmet need for new compounds in patients with CML who have 
failed at least two prior TKIs. Current practice suggests that a second generation 
TKI will have been used for first line therapy for about one half of patients with 
CML, meaning that most patients who have failed at least two prior TKIs will have 
failed at least one if not two second generation TKIs: dasatinib and/or nilotinib. 
Potentially, such patients may also have failed bosutinib and/or ponatinib (Soverini 
2014). Patients having failed at least two TKIs may have limited sensitivity to the 
remaining available agents and, thus, there exists a need for new safe and 
effective therapy. In addition, mutations will have developed in 21 to 33% of 
patients that prevent the use of specific TKIs, increasing the need for a better and 
alternative compound (Soverini 2014). Omacetaxine, a chemotherapeutic agent, is 
available for patients who have failed at least two prior TKIs under these conditions 
but only in the US and Canada. This agent is not available for most patients 
globally, where a bigger unmet medical need is present. Thus, there remains an 
unmet need for patients with CML who have failed at least two prior TKIs despite 
the existence of multiple agents.
Primary Objective
and Key Secondary 
Objective
Primary Objective: To compare the Major Molecular Response (MMR) rate at 24 
weeks of ABL001 versus bosutinib
Key Secondary Objective: To compare MMR rate at 96 weeks of ABL001 versus 
bosutinib


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Secondary Objectives
●
To compare additional efficacy parameters of ABL001 versus bosutinib:
●
cytogenetic response rate (Complete, Partial, Major, Minor, Minimal, no 
response) at and by all scheduled data collection time points, including 24, 48 
and 96 weeks
●
MMR rate at all scheduled data collection time points (except 24 and 96 
weeks which are already covered by primary and key secondary endpoints)
●
MMR rate by all scheduled data collection time points, including 24, 48 
and 96 weeks
●
Time to MMR
●
Duration of MMR
●
Time to CCyR
●
Duration of CCyR
●
Time to treatment failure
●
Progression free survival
●
Overall survival
●
To compare the safety and tolerability profile of ABL001 versus bosutinib by 
type, frequency and severity of adverse events, changes in laboratory values that 
fall outside the pre-determined ranges and clinically notable ECG and other safety 
data (vital signs, physical examination)
●
To characterize the PK of ABL001 in the CML-CP population (Trough plasma 
concentrations, PK parameters in full PK group: Cmax, Tmax, AUC0-12h, CL/F)
Study design
This study is a randomized, phase 3, open-label, active-controlled multi-center 
study. Patients will be randomized to the novel BCR-ABL TKI ABL001 and 
bosutinib in a 2:1 ratio. The randomization is to be stratified to ensure the study 
population is balanced between the arms with respect to the patient’s cytogenetic 
response status at baseline (Major Cytogenetic response (complete or partial) vs 
No major cytogenetic response (minor, minimal or none)).
The study design incorporates a 2:1 randomization, allocating more patients to the 
ABL001 arm in order to learn more about the safety profile of the experimental 
therapy, whereas the safety of bosutinib therapy is well documented. Treatment 
duration for each patient in the present study is for up to 96 weeks after the last 
patient received the first dose, which should be adequate to address both the 
primary objective of the study, i.e. determination of the MMR rate at 24 weeks, as 
well as secondary efficacy and safety objectives.
Population
Two-hundred and twenty-two (222) patients with CML-CP who had prior treatment 
with two or more ATP binding site TKIs will be randomized on a 2:1 basis to 
receive either ABL001 or bosutinib. Patients with known history of T315I and/or
V299L mutations at study entry will be excluded from the trial since bosutinib, the 
comparator, is not approved for these patients.
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Male or female patients with a diagnosis of CML-CP ≥ 18 years of age
2. Patients must meet all of the following laboratory values at the screening visit:
●
< 15% blasts in peripheral blood and bone marrow
●
< 30% blasts plus promyelocytes in peripheral blood and 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
3. BCR-ABL ratio ≥ 1% IS according to central laboratory at the screening 
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4. Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, 
nilotinib, dasatinib, radotinib or ponatinib)
5. Failure or intolerance to the last previous TKI therapy at the time of screening 
(adapted from the 2013 ELN Guidelines Bacarrani 2013)
●
Failure is defined for CML-CP patients (CP at the time of initiation of last 
therapy) as follows. Patients must meet at least 1 of the following criteria.
●
Three months after the initiation of therapy: No CHR or > 95% 
Ph+ metaphases
●
Six months after the initiation of therapy: BCR-ABL ratio > 10% 
IS and/or > 65% Ph+ metaphases
●
Twelve months after initiation of therapy: BCR-ABL ratio > 10% 
IS and/or > 35% Ph+ metaphases
●
At any time after the initiation of therapy, loss of CHR, CCyR or 
PCyR
●
At any time after the initiation of therapy, the development of new 
BCR-ABL mutations
●
At any time after the initiation of therapy, confirmed loss of MMR 
in 2 consecutive tests, of which one must have a BCR-ABL ratio ≥ 1% IS
●
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
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, 
or 2
7. Adequate end organ function as defined by (as per central laboratory tests):
●
Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert’s syndrome who 
may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
●
Aspartate transaminase (AST) ≤ 3.0 x ULN
●
Alanine transaminase (ALT) ≤ 3.0 x ULN
●
Serum amylase ≤ ULN
●
Serum lipase ≤ ULN
●
Alkaline phosphatase ≤ 2.5 x ULN
●
Creatinine clearance ≥ 50ml/min as calculated using Cockcroft-Gault 
formula
8. 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.
9. Written informed consent obtained prior to any screening procedures.
10. 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
●
Magnesium
●
Total calcium (corrected for serum albumin)


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Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Known presence of the T315I or V299L mutation at any time prior to study entry
2. Known second chronic phase of CML after previous progression to AP/BC
3. Previous treatment with a hematopoietic stem-cell transplantation
4. Patient planning to undergo allogeneic hematopoietic stem cell transplantation
5. 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 ms (male patients), ≥460 ms (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 to prolong the QT 
interval and/or known to cause Torsades de Pointes that cannot be 
discontinued or replaced 7 days prior to starting study drug by safe 
alternative medication.
●
Inability to determine the QTcF interval
6. 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)
7. History of acute pancreatitis within 1 year of study entry or past medical history 
of chronic pancreatitis
8. History of elevation in amylase or lipase (> ULN) within 1 year other than that 
which may have occurred with gallstones, trauma, or medical procedures
9. History of acute or chronic liver disease
10. Known presence of significant congenital or acquired bleeding disorder 
unrelated to cancer
11. 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
12. Known history of Human Immunodeficiency Virus (HIV), chronic Hepatitis B 
(HBV), or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface 
antigen (HBs Ag) and Hepatitis B core antibody (HBcAb / anti HBc) will be 
performed at screening
13. 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)
14. 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
●
Moderate or strong inducers of CYP3A
●
Moderate or strong inhibitors of CYP3A and/or P-gp
●
Substrates of CYP3A4/5, CYP2C8, or CYP2C9 with narrow therapeutic 
index
15. Previous treatment with or known/ suspected hypersensitivity to ABL001 or any 
of its excipients.
16. Previous treatment with or known/ suspected hypersensitivity to bosutinib or 
any of its excipients.


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17. Participation in a prior investigational study within 30 days prior to 
randomization or within 5 half-lives of the investigational product, whichever is 
longer
18. Pregnant or nursing (lactating) women
19. Women of child-bearing potential, defined as all women physiologically capable 
of becoming pregnant, unless they are using highly effective methods of 
contraception during dosing and for 3 days after last dose of ABL001. 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 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.
20. 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 tubal ligation at least six weeks ago. In the case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of child bearing potential.
21. Sexually active males unless they use a condom during intercourse while 
taking the drug during treatment and for 3 days after stopping treatment and should 
not father a child in this period. A condom is required to be used also by 
vasectomized men as well as during intercourse with a male partner in order to 
prevent delivery of the drug via semen.
Investigational and 
reference therapy
ABL001 40 mg BID
Bosutinib 500 mg QD
Efficacy assessments
Molecular response (RQ-PCR, mutational analysis)
Cytogenetic response ( Bone Marrow Aspirate)
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


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Other assessments
●
PK sampling (full/sparse)
●
Bone Marrow Biopsy
●
Patient Report Outcomes (MDASI-CML, PGIC, WPAI, EQ--5D-5L, resource 
utilization)
Data analysis
The primary efficacy variable of the study is the Major Molecular Response (MMR) 
rate at 24 weeks. A patient will be counted as having achieved MMR at 24 weeks if 
he meets the MMR criteria (BCR-ABL ratio ≤0.1%) at 24 weeks.
The MMR rate at 24 weeks will be calculated based on the FAS and according to 
the Intent To Treat (ITT) principle. MMR rate and its 95% confidence interval based 
on the Pearson-Clopper method will be presented by treatment group. Confidence 
interval for the difference in MMR rate between treatment groups will be provided 
using the Wald method.
The Mantel-Haenszel estimate of the common risk difference and the 
corresponding 95% confidence interval will also be provided.
The key secondary endpoint is MMR rate at 96 weeks.
Formal statistical testing of the key secondary endpoint will be performed only if the 
primary endpoint is significant by means of a gatekeeping procedure to control the 
overall alpha level. 
Key words
Phase III, open-label, randomized trial, ABL001 bosutinib, CML-CP, prior treatment 
with 2 or more TKIs






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1
Background
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. 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-ABL, 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 combat 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 and dasatinib 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, ABL001 inhibits the enzymatic activity of BCR-ABL1 through an 
allosteric mechanism.
There remains an unmet need for new compounds in patients with CML who have failed at 
least two prior TKIs. Current practice suggests that a second generation TKI will have been 
used for first line therapy for about one half of patients with CML, meaning that most patients 
who have failed at least two prior TKIs will have failed at least one if not two second 
generation TKIs: dasatinib and/or nilotinib. Potentially, such patients may also have failed 
bosutinib and/or ponatinib (Soverini 2014). Patients having failed at least two TKIs may have 
limited sensitivity to the remaining available agents and, thus, there exists a need for new safe 
and effective therapy. In addition, mutations will have developed in 21 to 33% of patients that 
prevent the use of specific TKIs, increasing the need for a better and alternative compound 
(Soverini 2014). Omacetaxine, a chemotherapeutic agent, is available for patients who have 
failed at least two prior TKIs under these conditions but only in the US and Canada. This 
agent is not available for most patients globally, where a bigger unmet medical need is present. 
Thus, there remains an unmet need for active and safe drugs in patients with CML who have 
failed at least two prior tyrosine kinase inhibitors (TKI), even in the presence of approved 
drugs, as described below.
1.2
Introduction to investigational treatment
1.2.1
Overview of ABL001
ABL001 is an orally bioavailable specific BCR-ABL inhibitor with a novel mechanism of 
action. In contrast to inhibitors such as imatinib, nilotinib and dasatinib that bind within the 
ATP-binding site of the ABL kinase domain, ABL001 inhibits ABL tyrosine kinase activity 
by binding to a particular allosteric site on the kinase domain, which has only been identified 
on ABL1, ABL2 and BCR-ABL1. Consequently, ABL001 is specific for the latter three 
enzymes.
ABL001 potently and selectively inhibits the proliferation of cell lines that express BCR-
ABL1. By virtue of ABL001 not interacting with the ATP-binding site, the drug maintains 
activity against cells expressing clinically observed ATP-binding TKI resistance mutations.
1.2.1.1
Non-clinical experience
In vitro and in vivo pharmacology data
ABL001 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 


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observed at doses of 7.5mg/kg BID and above when ABL001 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 ABL001 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 ABL001. In contrast, 
animals treated upfront with the combination of ABL001 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.
Figure 1-1
KCL-22 CML Xenograft
These data are consistent with ABL001 being active against nilotinib-resistant mutations and 
nilotinib being active against ABL001-resistant mutations. Consequently, the findings support 
development of ABL001 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 ABL001 specifically targeting the ABL kinase family (ABL1, ABL2, 
BCR-ABL), ABL001 offers the potential for improved safety and tolerability when 
administered as monotherapy when compared to TKIs binding to the ATP site of BCR-ABL, 
which are less specific towards ABL. Thus, there is the potential for an improved safety 
profile of ABL001 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 ABL001 is not expected to cause effects on the 
vital functions of the CNS, and the respiratory systems. The IC50 for ABL001 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 200 mg/kg or the invasive telemetry 


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cardiovascular safety study up to 60 mg/kg. Furthermore, no ECG related findings were noted 
in the 4 week GLP dog toxicology study at the end of treatment or recovery.
ABL001 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) and to use sunscreen.
In the embryofetal development study in rats, results indicate a risk of fetal malformations 
and/or visceral and skeletal variants. In the fertility study, administration of ABL001 by daily 
oral gavage at doses of 10, 50 and 200 mg/kg/day to males and females there was no evidence 
of effects on reproductive function (mean day to mating, mating and fertility indices) at any 
dose. There was evidence of a slight effect on male sperm motility and/or sperm count in 
individual animals and an embryo-lethal effect at 200 mg/kg/day. Based on these results, the 
no-observed-adverse-effect level (NOAEL) for paternal and maternal toxicity was considered 
to be 200 mg/kg/day and the no-observed-effect level (NOEL) for reproductive function and 
early embryo-fetal development was considered to be 50 mg/kg/day.
Repeat dose toxicity studies have been performed in rats, dogs and monkeys up to 26, 4 and 
13 weeks duration, respectively. Rat and dog toxicology studies identified pancreas, liver, 
adrenal and harderian gland as potential target tissues. The cynomolgus monkey did not 
recapitulate in short or long-term studies the pancreatic changes observed in the dog or the rat 
hepatic changes. All findings thus far have demonstrated a partial to complete reversibility 
during a 4-week recovery phase, and can be readily monitored in preclinical and clinical 
settings. The maximal doses evaluated in the 13/26-week general toxicity studies was 200 
mg/kg in rats and 100 mg/kg in monkey and provide substantive safety margins over the 40 
mg BID clinical dose exposures.
Please refer to the latest [ABL001 Investigator’s Brochure] for more details.
Non-clinical pharmacokinetics and metabolism
The preclinical pharmacokinetic profile of ABL001 has been investigated in three species: 
mouse, rat and dog. In these species, ABL001 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.
ABL001 displayed high plasma protein binding across all tested species (2-6% free fraction).
The metabolite profile of ABL001 has been examined in vitro using rat, dog, monkey and 
human hepatocytes. Interspecies differences were observed. Direct glucuronidation occurred 
more readily in human and dog than in 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 ABL001 has also been examined in vivo in rats. Following 
intravenous and oral administration of [14C-ABL001] to intact rats, ABL001 was found to be 
the predominant component of plasma, accounting for ~86 - 91% of radioactivity from 0 - 8 h. 
ABL001 was excreted primarily in the feces, with ~90% of radioactivity detected in the feces 


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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 ABL001, 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 ABL001 was found to be 
glucuronidation, followed by oxidative metabolism, consistent with findings from human 
hepatocytes. Several UGT enzymes were found to be capable of ABL001 glucuronidation 
(UGT1A3, UGT1A4, UGT2B7, and UGT2B17). The oxidative metabolism of ABL001 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 ABL001 concentration. Therefore, strong inhibitors of CYP3A4/5 should be avoided
and are prohibited in this study. Strong inducers of CYP3A4/5 have the potential to reduce 
ABL001 concentrations. Therefore, the use of strong inducers of CYP3A4/5 or UGT1A/2B is 
prohibited in this trial.
Transporter phenotyping studies have identified ABL001 to be a substrate of Breast Cancer 
Resistant Protein (BCRP) and Permeability glycoprotein (P-gp). While inhibition of BCRP is 
not expected to result in any clinical relevant changes, inhibitors of P-gp may increase 
ABL001 concentrations significantly and are prohibited in this study.
There is a potential for DDIs with co-medications metabolized by CYP3A4/5, CYP2C8 and 
CYP2C9 at the anticipated human efficacious dose. Therefore, narrow therapeutic index 
substrates of CYP3A4/5, CYP2C8 and CYP2C9 are prohibited. All other substrates of 
CYP3A4/5, CYP2C8 and CYP2C9 should be used with caution.
Please refer to the latest [ABL001 Investigator Brochure] version for more details.
1.2.1.2
Clinical experience
ABL001 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 ABL001 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 
ABL001 BID single agent only.
In this study, 101 patients have been enrolled as of 2 May 2016, and recruitment is still 
ongoing. For the most recent data cut-off of 2 May 2016, 67 CML patients had been treated 
with twice-daily (BID) doses of ABL001 of 10 mg (1 patient), 20 mg (14 patients), 40 mg (26 
patients), 80 mg (12 patients), 150 mg (9 patients), and 200 mg (5 patients). Of note, 66 of 


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those 67 patients had CML-CP, while one of the patients from the 40 mg cohort was in AP. 
This CML-AP patient discontinued after 20 days of treatment without any post screening 
efficacy assessment.
The dose of ABL001 40mg BID has been selected for the proposed Phase 3 study based on 
preliminary MMR and CCyR results from the ongoing FIH study [CABL001X2101], as well 
as overall ABL001 safety and pharmacokinetic information.
Efficacy:
Preliminary data from the ongoing Phase 1 FIH study [CABL001X2101] indicate that 
ABL001 has single-agent activity in patients with CML who have failed, relapsed, or are 
refractory or intolerant after at least two prior TKIs, as demonstrated by reduction in the BCR-
ABL transcript. ABL001 resulted in molecular and cytogenetic responses at doses ≥10 mg 
BID. In reporting the activity of ABL001, the denominator at each time point represents the 
number of patients who, by that time point have either, achieved the endpoint, discontinued 
treatment, acquired an intra-patient dose escalation (ignoring assessments after escalation), or 
have sufficient exposure.
Overall at any dose of ABL001 BID, in patients without T315I mutation:
Molecular response:
In the subset of the n=47 patients treated at a dose level between 10mg - 200mg BID who 
were not in MMR at screening:

6 out of 42 (14.3%) patients achieved MMR by 3 months

10 out of 31 (32.3%) patients achieved MMR by 6 months

12 out of 31 (38.7%) patients achieved MMR by 9 months

13 out of 30 (43.3%) patients achieved MMR by 12 months

At the dose of 40 mg BID, MMR was achieved in 1 out of 17 (5.9%) patients by 3 months, 
4 out of 11 (36.4%) patients by 6 months, 5 out of 11 (45.5%) patients by 9 and 12 months
Cytogenetic response:

22 patients had >35% Ph+ metaphases at screening. Of these 22 patients, 5 patients were 
evaluable with 2 PCyR and 3 CCyR by 3 months. By 6, 9 and 12 months, 7 patients were 
evaluable with 1 minor cytogenetic response and 5 CCyR.

33 patients did not have CCyR at screening. Of these 33 patients, 7 patients were 
evaluable with 3 PCyR and 4 CCyR by 3 months. By 6, 9 and 12 months, 10 patients were 
evaluable with 1 minor cytogenetic response, 1 PCyR and 7 CCyR.

15 of the above 33 patients who did not have CCyR at screening were treated at the dose 
of 40mg BID. Of these 15 patients, 3 patients were evaluable and with PCyR by 3 months. 
By 6, 9 and 12 months 4 patients were evaluable with 1 PCyR and 2 CCyR.
Please refer to the latest [ABL001 Investigator’s Brochure] for more details.


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Safety:
ABL001 was generally well tolerated in heavily pre-treated CML patients resistant to or 
intolerant of prior TKIs. By data cutoff of 2 May 2016, 67 CML patients, including those with 
a T315I mutation (n=9), have been treated at any dose of the ABL001 BID regimen.
There were no study drug related deaths reported. One death was reported due to general 
physical health deterioration unrelated to the study drug. Overall, 43 SAEs were reported in 
20 patients of the 67 patients. Six patients (9%) discontinued ABL001 due to adverse events 
Dose limiting toxicities in the study included acute cardiac syndrome, lipase increase, 
arthralgia/myalgia, and bronchospasm in 1 patient each.
Overall of 67 CML patients, almost all (94%) patients reported at least one AE, including 45% 
reported grade 3/4 AEs. The most common AEs (>10%), regardless of study drug-relationship, 
were headache, increased lipase (23.9%), rash (20.9), arthralgia, vomiting (both 19.4%), 
diarrhea, fatigue (both 17.9%), abdominal pain, pruritus (both 16.4%), constipation, myalgia, 
nausea, upper respiratory tract infection (all 14.9%), thrombocytopenia (13.4%), peripheral 
edema (11.9%), increased amylase, dizziness, musculoskeletal pain (all 10.4%).
At 40 mg BID dose (n=26), the most common adverse events (>10%), regardless of study 
drug-relationship, were: increased lipase (30.8%), rash (26.9%), abdominal pain, fatigue, 
vomiting (all 23.1%), arthralgia, diarrhea (both 19.2%), increased amylase, upper respiratory 
tract infection (both 15.4%), cough, bone pain, pruritus, increased weight, abdominal 
discomfort, anemia, constipation, dyspnea, ear pain, non-cardiac chest pain, and 
thrombocytopenia (all 11.5%).
Please refer to the latest [ABL001 Investigator’s Brochure] for more details.
Pharmacokinetics:
PK data from 61 patients (1 in 10 mg BID; 14 in 20 mg BID; 20 in 40 mg BID; 12 in 80 mg 
BID; 9 in 150 mg BID; 5 in 200 mg BID) were available from the [CABL001X2101] study, 
as of 2 May 2016.
Based on the available PK data, ABL001, 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 ABL001, 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 %) of 34 to 50% for Cycle 1 Day 1 AUC last and 36 to 60% for Cycle 1 Day 1 Cmax. 
With the twice daily dosing regimen, median plasma ABL001 accumulation ratios ranged 
from 1.4 to 2.4. The median accumulation half-life was estimated to be 7 to 15 hours.
The emerging data of the hADME study [CABL001A2102] show that the relative 
contribution of the glucuronidation pathway to the total clearance of ABL001 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 ABL001 via the oxidative pathway while UGT2B7 and UGT2B17 were 
responsible for the clearance of ABL001 via the glucuronidation pathway. There was no 


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metabolite detected with mean contribution to plasma radioactivity AUC0-24hours ≥ 10%. 
ABL001 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 [ABL001 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 02May-2016). The time course of molecular response 
(change in BCR-ABL 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 ABL001 population PK model revealed that a dose of 40 mg 
BID maintains Ctroughss 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 ABL001 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-ABL 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.
Food effect
The effect of food on ABL001 PK was characterized in a Phase I study [CABL001A2101] in 
healthy volunteers. Food was found to influence the pharmacokinetics of ABL001. When 
administered with a low-fat meal, the exposure (AUC) decreased by approximately 30%. The 
overall exposure decreased by approximately 65% when administered with a high-fat meal.
Therefore, ABL001 will be administered in a fasted state.
1.2.2
Overview of bosutinib
Bosutinib (Bosulif®) is indicated for the treatment of adult patients with chronic, accelerated, 
or blast phase Ph+ chronic myelogenous leukemia (CML) with resistance or intolerance to 
prior therapy [Bosulif® USPI], and in Europe for the treatment of adult patients with chronic 
phase (CP), accelerated phase (AP), and blast phase (BP) Philadelphia chromosome positive 


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chronic myelogenous leukemia (Ph+ CML) previously treated with one or more tyrosine 
kinase inhibitor(s) and for whom imatinib, nilotinib and dasatinib are not considered 
appropriate treatment options [EU SmPC]. Bosutinib has been evaluated in patients treated 
with one or more prior TKIs.
For patients treated only with prior imatinib, the MMR rate is approximately 15% at 24 weeks 
overall, and approximately 10% in resistant patients and 20% in intolerant patients 
(Gambacorti-Passerini 2014). The cytogenetic, molecular, and hematological response rates 
did not appear to differ greatly between patients who were imatinib-resistant or imatinib-
intolerant (Gambacorti-Passerini 2014).
When treated with bosutinib, the majority of patients with CML-CP previously treated with at 
least 2 TKIs did not achieve Major Cytogenetic Response (MCyR); there was a 27% MCyR 
rate by Week 24 [Bosulif® USPI]. For patients previously treated with imatinib and either 
dasatinib or nilotinib, after a median of 28.5 months follow-up, the cumulative rate of Major 
Molecular Response (MMR) is 15% (Khoury 2012). The cytogenetic, molecular, and 
hematological response rates appeared to be lower in patients who were resistant to dasatinib 
after imatinib treatment as compared to patients who were intolerant to dasatinib after 
imatinib treatment (Khoury 2012). In a small (30 patient) compassionate use trial of patients 
previously treated with imatinib, dasatinib and nilotinib, after a median duration of treatment 
of 9.3 months, the cumulative MMR rate was 14% (García-Gutiérrez 2015). Based on these 
data, the MMR rate at 6 month with bosutinib treatment in patients treated with at least 2 prior 
TKIs is estimated to be approximately 10-15%.
Bosutinib has no activity against the T315I and V299L mutant form of BCR-ABL. 
Accordingly, the pivotal trial leading to the registration in the 3rd line setting excluded patients 
with a known history of the T315I or V299L mutation [Bosulif® USPI].
2
Rationale
2.1
Study rationale and purpose
ABL001 is an agent intended to be evaluated for the treatment of patients with CML. In the 
ongoing study [CABL001X2101] study, ABL001 was found to produce clinically meaningful 
and durable responses in patients who have had treatment failure after a minimum of 2 prior 
ATP-binding site TKIs, with an acceptable safety and tolerability profile.
The purpose of this pivotal study is to compare the efficacy of ABL001 with that of bosutinib 
in the treatment of patients with CML-CP having previously been treated with a minimum of 
two prior ATP-binding site TKIs with BCR-ABL ratios ≥1% IS at screening.
Imatinib, nilotinib and dasatinib are indicated for the treatment of patients with newly 
diagnosed CML. Multiple agents, including nilotinib, dasatinib, ponatinib, bosutinib, 
radotinib (Korea) and omacetaxine (USA, Canada) are approved for patients with CML-CP 
previously treated with prior therapy. Imatinib is a first generation TKI; nilotinib, dasatinib, 
bosutinib, ponatinib and radotinib are considered second generation TKIs and have activity in 
patients previously treated with imatinib. The activity of nilotinib or dasatinib in patients 
previously treated with a second generation TKI is not known. All the currently approved 


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BCR-ABL TKIs are enzymatic site inhibitors, in distinction to ABL001 which is an allosteric 
TKI. Omacetaxine is a cytotoxic chemotherapeutic agent.
2.2
Rationale for the study design
ABL001 is an orally bioavailable specific BCR-ABL1 inhibitor with a novel mechanism of 
action. In contrast to other TKIs that bind within the ATP-binding site of the ABL kinase 
domain, ABL001 inhibits ABL tyrosine kinase activity by binding to a particular allosteric 
site on the kinase domain that is utilized by a myristate group to auto-regulate the native 
ABL1 kinase. With allosteric inhibition of BCR-ABL being a novel mechanism of action, 
ABL001 produces clinically meaningful and durable responses in patients who have had 
treatment failure after a minimum of 2 prior ATP-binding site TKIs, with an acceptable safety 
and tolerability profile as demonstrated in study [CABL001X2101].
The development of ABL001, presents an opportunity to evaluate the beneficial effects of 
inhibition of BCR-ABL in the treatment of patients with CML. The proposed study design is 
expected to adequately allow an assessment of the efficacy, safety and tolerability of ABL001 
in a population of patients with continuing medical need i.e., patients who have been treated 
with at least two prior TKIs and are in the need for further therapeutic intervention.
Bosutinib is one of the TKIs with proven clinical benefit in CP-CML patients previously 
treated with one or more tyrosine kinase inhibitor(s) and is currently approved for this 
indication in many countries, including the European Union. The proposed study will evaluate 
ABL001 in comparison to bosutinib at the approved doses in the targeted population.
This study is not being conducted as a blinded study; the conditions for drug administration 
being distinct for the two treatments arms makes blinding complex and increases the 
likelihood of dosing errors. Bosutinib needs to be taken with food, whereas ABL001 needs to 
be taken fasted. The difference in administration of the two treatments, requiring double 
dummy treatments, makes blinding difficult to put in place in practice and carries inherent 
risks of dosing errors and reduces patient compliance. Additionally, the characteristic adverse 
event profile of bosutinib (frequent gastrointestinal AEs of diarrhea and vomiting in 78.5% 
and 37.1% patients, respectively) further preclude effective blinding. Randomization and use 
of objective efficacy endpoints mitigate the risks of an open label study design.
The study design incorporates a 2:1 randomization, allocating more patients to the ABL001 
arm in order to learn more about the safety profile of the experimental therapy, whereas the 
safety of bosutinib therapy is well documented.
Treatment duration for each patient in the present study is for up to 96 weeks after the last 
patient received the first dose, which should be adequate to address both the primary objective 
of the study, i.e. determination of the MMR rate at 24 weeks, as well as secondary efficacy 
and safety objectives. Blood Samples will be taken in this study from all patients randomized 
to ABL001 in order to describe the pharmacokinetics and possibly identify the sources of 
variabilities. Exploratory analysis may be performed to establish the relationship between 
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With respect to overall exposure, the dose of 40 mg BID is 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).
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-ABL 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 ABL001 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-ABL mRNA transcript levels from baseline at 6 months, and 53% (CI95%: 43-63%) 
at 12 months, and predicting higher probability of achieving BCR-ABL 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 ABL001 were conducted (Section 1.2.1.2). The efficacy measure used was 
Molecular Response (MR) which is defined as a decline in BCR-ABL transcript levels in 
clinical blood samples of patients with Chronic Myeloid Leukemia (CML). MR was evaluated 
as both a continuous variable (BCR-ABL transcript levels) and categorical variable (whether 
or not adequate decline in BCR-ABL was achieved). The safety measures used were 
occurrence of Common Toxicity Criteria (CTC) grade 2, 3 or 4 laboratory values for lipase 
and amylase.
Reviewing the totality of the efficacy, safety, and pharmacokinetic data derived from the 
[CABL001X2101] study, the recommended dose for ABL001 in this phase 3 study is 40 mg 
BID. Of note, the dose of ABL001 single agent BID is further being evaluated in patients with 
the T315I mutation. At present the recommended dose of 40 mg BID is for patients without 
the T315I mutation. For this reason, patients with the T315I mutation are excluded from this 
study.
2.4
Rationale for choice of combination drugs
Not Applicable.
2.5
Rationale for choice of comparators drug bosutinib
The guidance provided by the NCCN and the ELN (Bacarrani 2013), recommends bosutinib 
as a treatment in CML-CP patients who fail first-line or second-line treatment with imatinib or 
nilotinib or dasatinib. Consistent with these recommendations and clinical practice, bosutinib 
was selected to be an appropriate comparator in a study of 3 rd line CML-CP patients after 
failure of at least 2 prior TKIs, and is the comparator that will be used in the present study.
It is to be noted that bosutinib has no activity against the T315I and V299L mutant form of 
BCR-ABL. Patients who have the T315I or V299L mutations documented in their medical 
record will already be excluded from this study. Bosutinib is known to be active against 


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E255K/V, F317L/V/I/C, F359V/C/I, T315A, and Y253H and therefore, these mutations are 
not considered in the exclusion criteria for the current study.
Ponatinib is not selected as the comparator in the present clinical trial, because the comparator 
in this study needs to be an approved agent administered at the approved dose. Currently, the 
ponatinib dose is being evaluated in a randomized trial as a post-approval commitment due to 
the occurrence of vascular risks at the current approved dose of ponatinib. The dose of 
ponatinib that will be approved and will be used in practice at the completion of the present 
study may not be the approved dose at the time of initiation of the present study.
2.6
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 6.3. 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 experimental arm of the study with 
ABL001 will be that this agent may be ineffective. However, the evidence to date at the doses 
to be administered in a similar population of patients in the study [CABL001X2101] suggests 
that ABL001 is an active agent. Further, the adverse event profile of ABL001 is similar 
qualitatively to that observed with other TKIs targeting BCR-ABL1 (Section 1.2.1.2). The 
risk of ABL001 not being effective has been mitigated in that patients will be observed 
closely for evidence of efficacy, based on assessment of hematologic, cytogenetic and 
molecular response data, which will permit rapid decision making as to discontinuation of 
therapy if necessary.
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 ABL001 which could be serious. Refer to the latest 
[ABL001 Investigator’s Brochure] for additional details.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To compare the MMR rate at 24 weeks of ABL001 versus 
bosutinib 
Major Molecular Response (MMR) rate at 24 weeks
Refer to Section 10.4
Key secondary
To compare additional parameters of the efficacy of ABL001 
versus bosutinib 
MMR rate at 96 weeks
Refer to Section 10.5.1
Other secondary
To compare additional parameters of the efficacy of ABL001 
versus bosutinib
●
cytogenetic response rate (Complete, Partial, Major, Minor, Minimal, 
no response) at and by all scheduled data collection time points including 
24, 48 and 96 weeks
●
MMR rate at all scheduled data collection time points (except 24 and 
96 weeks which are already covered by primary and key secondary 
endpoints)
●
MMR rate by all scheduled data collection time points including 24, 48 
and 96 weeks
●
Time to MMR
●
Duration of MMR
●
Time to CCyR
●
Duration of CCyR
●
Time to treatment failure
●
Progression free survival
●
Overall survival
Refer to Section 10.5.2
To compare the safety and tolerability profile of ABL001 versus 
bosutinib
Type, frequency and severity of adverse events,
Changes in laboratory values that fall outside the pre-determined ranges 
and clinically notable ECG and other safety data (vital signs, physical 
examination)
To characterize the PK of ABL001 in the CML-CP population
Trough plasma concentrations,
PK parameters in full PK group: Cmax, Tmax, AUC0-12h, CL/F




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4
Study design
4.1
Description of study design
The study is a phase 3, multi-center, open-label randomized study of oral ABL001 versus 
bosutinib in patients with Chronic Myelogenous Leukemia in chronic phase (CML-CP), 
previously treated with 2 or more tyrosine kinase inhibitors.
The trial is designed to compare the efficacy and safety of ABL001 with that of bosutinib in 
the treatment of patients with CML-CP having previously been treated with a minimum of 
two prior ATP-binding site TKIs with a BCR-ABL ratio-IS ≥1% at screening.
The study will also investigate secondary endpoints for efficacy, safety and PK of single-
agent ABL001 compared to bosutinib. Tolerability, PK, PRO and exploratory biomarker 
activities will also be assessed.
Patients meeting all of the inclusion and none of the exclusion criteria will be randomized into 
one of the 2 treatment arms, based on a 2:1 randomization between the ABL001 arm and the 
bosutinib arm.
The randomization will be stratified to ensure the study population is balanced between the 
arms with respect to cytogenetic response status (See Section 7.2.1.2) at screening as follows:

Major Cytogenetic response (complete or partial)

No major cytogenetic response (minor, minimal or none)
Patients will continue to receive the assigned study treatments (ABL001 or bosutinib) for up 
to 96 weeks after the last patient received the first study dose i.e., patients who are benefiting 
from their study treatment can continue to receive the treatment for up to a period of 
approximately 2 years following the completion of study enrollment. Patients who discontinue 
their study treatment at any time during the study will be followed up for survival and for 
progression to AP/BC for up to 5 years from the date the last patient received the first study 
dose.
Serial PK samples over 12 hours will be collected on Week 2 Day 1 from at least 20 CML-CP 
patients (full PK group) on the ABL001 arm, in addition to trough PK samples. These patients 
will be identified sequentially at selected sites that are capable of serial PK sampling over 12 
hours. In the remaining patients in the ABL001 arm, sparse post-dose PK samples on Week 1
Day 1 and trough PK samples will be collected (sparse PK group).


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Figure 4-1
Schematic of Study Design
4.2
Timing of interim analyses and design adaptations
Not applicable. There are no formal interim analyses or design adaptations planned for this 
study. See Section 8.6 for documentation of safety DMC.
4.3
Definition of end of study
The end of the study will occur 5 years from the date when the last patient enrolled into the 
study received the first dose of the randomized treatment.
The primary analysis (cut-off date) is defined as the date when all randomized patients have 
been on treatment for 24 weeks (Section 10.4) or discontinued early. 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 assigned study treatments (ABL001 or bosutinib) 
for up to 96 weeks after the last patient received the first study dose i.e., patients who are 
benefiting from their study treatment can continue to receive the treatment for up to a period 
of approximately 2 years following the completion of study enrollment. The end of study 
treatment analysis will be conducted with a cut-off date 30 days after last patient receives the 
last study dose to ensure all available treatment data from all patients in the study is analyzed
and summarized in a 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 Investigator 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.
Patients will be followed up for survival and progression for up to 5 years from the date the 
last patient received the first study dose. Information on subsequent treatments will also be 
collected. An updated analysis of OS and PFS will be performed at the end of the follow-up 
period.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be contacted as soon as possible and instructed to stop taking study 
medication. The end of treatment visit should be scheduled and the same assessments should 


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be performed as described in Section 7 for a discontinued or withdrawn patient. 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 patient’s interests. The investigator 
will be responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
Two-hundred and twenty-two (222) patients with CML-CP who had prior treatment with two 
or more ATP binding site TKIs will be randomized in a 2:1 fashion to receive either ABL001 
or bosutinib. No patients with a medical history of the T315I or V299L mutation at study 
entry will be included in the trial. 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 (Baccarani et al 2013), and is outlined below in the inclusion criteria.
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Male or female patients with a diagnosis of CML-CP ≥ 18 years of age
2. Patients must meet all of the following laboratory values at the screening visit:

< 15% blasts in peripheral blood and bone marrow

< 30% blasts plus promyelocytes in peripheral blood and 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
3. BCR-ABL ratio ≥1% IS according to central laboratory at the screening examination
4. Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, nilotinib, 
dasatinib, radotinib or ponatinib)
5. Failure or intolerance to the last previous TKI therapy at the time of screening (adapted 
from the 2013 ELN Guidelines Bacarrani 2013)

Failure is defined for CML-CP patients (CP at the time of initiation of last therapy) as 
follows. Patients must meet at least 1 of the following criteria.

Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases

Six months after the initiation of therapy: BCR-ABL ratio > 10% IS and/or > 65% 
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
Twelve months after initiation of therapy: BCR-ABL ratio > 10% IS and/or > 35% 
Ph+ metaphases

At any time after the initiation of therapy, loss of CHR, CCyR or PCyR

At any time after the initiation of therapy, the development of new BCR-ABL 
mutations

At any time after the initiation of therapy, confirmed loss of MMR in 2 
consecutive tests, of which one must have a BCR-ABL ratio ≥1% IS

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
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
7. Adequate end organ function as defined by (as per central laboratory tests):

Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert’s syndrome who may 
only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN

Aspartate transaminase (AST) ≤ 3.0 x ULN

Alanine transaminase (ALT) ≤ 3.0 x ULN

Serum amylase ≤ ULN

Serum lipase ≤ ULN

Alkaline phosphatase ≤ 2.5 x ULN

Creatinine clearance ≥ 50 mL/min as calculated using Cockcroft-Gault formula
8. 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.
9. Written informed consent obtained prior to any screening procedures.
10. Patients must have the following electrolyte values within normal limits (as per central 
laboratory tests) or corrected to be within normal limits with supplements prior to first 
dose of study medication:

Potassium

Magnesium

Total calcium (corrected for serum albumin)


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5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Known presence of the T315I or V299L mutation at any time prior to study entry
2. Known second chronic phase of CML after previous progression to AP/BC
3. Previous treatment with a hematopoietic stem-cell transplantation
4. Patient planning to undergo allogeneic hematopoietic stem cell transplantation
5. 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 ms (male patients), ≥460 ms (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 to prolong the QT interval and/or 
known to cause Torsades de Pointes that cannot be discontinued or replaced 7 
days prior to starting study drug by safe alternative medication.

Inability to determine the QTcF interval
6. 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)
7. History of acute pancreatitis within 1 year of study entry or past medical history of chronic 
pancreatitis
8. History of elevation in amylase or lipase (> ULN) within 1 year other than that which may 
have occurred with gallstones, trauma, or medical procedures
9. History of acute or chronic liver disease
10. Known presence of significant congenital or acquired bleeding disorder unrelated to 
cancer
11. 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
12. Known history of Human Immunodeficiency Virus (HIV), chronic Hepatitis B (HBV), or 
chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) 
and Hepatitis B core antibody (HBcAb / anti HBc) will be performed at screening


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13. 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)
14. 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

Moderate or strong inducers of CYP3A

Moderate or strong inhibitors of CYP3A and/or P-gp

Substrates of CYP3A4/5, CYP2C8, or CYP2C9 with narrow therapeutic index
15. Previous treatment with or known/ suspected hypersensitivity to ABL001 or any of its
excipients.
16. Previous treatment with or known/ suspected hypersensitivity to bosutinib or any of its
excipients.
17. Participation in a prior investigational study within 30 days prior to randomization or 
within 5 half-lives of the investigational product, whichever is longer
18. Pregnant or nursing (lactating) women
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 3 days after last dose of ABL001. 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 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.
20. 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 tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential.


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21. Sexually active males unless they use a condom during intercourse while taking the drug 
during treatment and for 3 days after stopping treatment and should not father a child in 
this period. A condom is required to be used also by vasectomized men as well as during 
intercourse with a male partner in order to prevent delivery of the drug via semen.
6
Treatment
6.1
Study treatment
The investigational treatments for this study are ABL001 (40 mg BID) and bosutinib (500 mg 
QD). Novartis will supply ABL001 to the investigational site as 20 mg and 40 mg tablets.
Bosutinib will be supplied to the investigational site as 100 mg and 500 mg tablets.
6.1.1
Dosing regimen
ABL001
ABL001 20 or 40 mg strength tablets will be administered orally twice-daily (BID), without 
food. ABL001 tablets should be ingested as follows:

ABL001 should be administered in the fasted state at least 1 h before or 2 h after a meal. 
Water is permitted during this period.

ABL001 should be taken with approximately 8 ounces (240 mL) of water.

ABL001 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 ABL001 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
Bosutinib
Bosutinib 500 mg or 100 mg tablets will be administered orally once daily (QD) with food. If 
a dose is missed beyond 12 hours, the patient should skip the dose and take the usual dose on 
the following day.
Table 6-1
Dose and treatment schedule
Study 
treatments
Pharmaceutical form 
and route of 
administration
Dose
Frequency and/or
Regimen
Fasting Condition
ABL001
Tablet for oral use
20 mga
Twice-daily 
Fasting
ABL001
Tablet for oral use
40 mg 
Twice-daily 
Fasting
Bosutinib
Tablet for oral use
100 mgb
Once-daily
Non-fasting
Bosutinib
Tablet for oral use
500 mg
Once-daily
Non-fasting
a 20 mg tablets will be dispensed to patients in the instance of dose reduction.
b 100 mg tablets will be dispensed to patients in the instance of dose modifications.


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On days when serial blood samples are collected for ABL001 PK analysis, patients will be 
instructed to bring their drug supply to the site, and take the dose in the clinic, under 
supervision of the site personnel. The exact time for dose administration and meal intake must 
be recorded in the electronic Case Report Form (eCRF).
All dosages prescribed and dispensed to the patient and all dose changes during the study
must be recorded on the Dosage Administration Record eCRF.
6.1.2
Ancillary treatments
Not applicable.
6.1.3
Rescue medication
Not applicable.
6.1.4
Guidelines for continuation of treatment
Not applicable. See Section 6.3.
6.1.5
Treatment duration
There is no fixed duration of treatment planned per patient. All patients will be given the 
opportunity to receive study treatment until the date that corresponds to 96 weeks after the last 
patient receives the first study 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.
6.2
Dose escalation guidelines
Dose escalation beyond the standard doses of 40 mg BID for ABL001 is not permitted.
Dose escalation above 500 mg QD for bosutinib is permitted in this study. Bosutinib 
escalation guidelines are as follows:
Consider dose escalation to 600 mg once daily in patients who are currently taking 500 mg 
daily, did not have Grade 3 or higher adverse events and who:

Did not reach complete hematological response (CHR) by week 8

Did not reach complete cytogenetic response (CCyR) by week 12
6.3
Dose modifications
6.3.1
Dose modification and dose delay
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” are provided to assist investigators in the event the patient experiences 
toxicity. However, deviations from “mandatory” dose interruptions and/or reductions are not 


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allowed and mandatory interruptions or reductions must be strictly followed. Re-escalation to 
ABL001 40mg 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 
on the ABL001 arm per protocol. 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 either ABL001 or bosutinib if, after treatment is 
resumed at a lower dose, the toxicity recurs with the same or worse severity (See Table 6-2). 
If a patient requires a dose interruption of > 28 days, then the patient must be discontinued 
from the study treatment. 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.


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Table 6-2
Criteria for dose reduction/interruption and re-initiation of ABL001 and bosutinib treatment for adverse drug 
reactions
Dose modifications for both ABL001 and bosutinib
Worst toxicity
CTCAE Grade 4.03
ABL001
bosutinib
Investigations (Hematologic)
Neutropenia (ANC)
Grade 1 (ANC < LLN – 1.5 x 109/L)
Recommendation: Maintain dose level
Recommendation: Maintain dose level
Grade 2 (ANC < 1.5 – 1.0 x 109/L)
Recommendation: Maintain dose level
Recommendation: Maintain dose level
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 
Mandatory: Hold dose until resolved to ≤ Grade 2 and platelets ≤ 
Grade 2 (recheck CBC 2x/week), then:
if resolved in ≤ 14 days, then maintain dose level
If resolved in > 14 days, 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 
Mandatory: Hold dose until resolved to ≤ Grade 2 and platelets ≤ 
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
Mandatory: Hold dose until resolved, then reduce dose 1 dose 
level
Thrombocytopenia
Grade 1 (PLT < LLN – 75 X 109/L)
Recommendation: Maintain dose level
Recommendation: Maintain dose level
Grade 2 (PLT < 75 - 50 x 109/L)
Recommendation: Maintain dose level
Recommendation: Maintain dose level


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Dose modifications for both ABL001 and bosutinib
Worst toxicity
CTCAE Grade 4.03
ABL001
bosutinib
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
Mandatory: Hold dose until resolved to ≤ Grade 2 and neutrophils 
≤ 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
Mandatory: Hold dose until resolved to ≤ Grade 2 and neutrophils 
≤ 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: Hold dose until resolved to ≤ Grade 2, 
then maintain current dose level
Recommendation: Hold dose until resolved to ≤ Grade 2, then 
reduce dose 1 additional 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
Recommendation: Maintain dose level
Grade 3
Mandatory: Hold dose until resolved to ≤ Grade 1, then 
reduce dose 1 dose level
Mandatory: Hold dose until resolved to ≤ Grade 2, then reduce 
dose 1 dose level, If clinically appropriate, re-escalation of the 
dose back to baseline dose level (500 mg) should be considered
Grade 4
Mandatory: Permanently discontinue patient from study 
drug treatment.
Mandatory: Hold dose until resolved to ≤ Grade 2, then reduce 
dose 1 dose level; If clinically appropriate, re-escalation of the 
dose back to baseline dose level (500 mg) should be considered
Investigations (Renal)
Serum creatinine
Grade 1 (> ULN - 1.5 x ULN)
Recommendation: Maintain dose level
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
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.
Mandatory: Permanently discontinue patient from study drug 
treatment.
Grade 4 (> 6.0 x ULN)
Mandatory: Permanently discontinue patient from study 
drug treatment.
Mandatory: Permanently discontinue patient from study drug 
treatment.


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Dose modifications for both ABL001 and bosutinib
Worst toxicity
CTCAE Grade 4.03
ABL001
bosutinib
Investigations (Hepatic)
Isolated total Bilirubin elevation
> ULN – 1.5 x ULN
Recommendation: Maintain dose level
Recommendation: Maintain dose level
> 1.5 - 3.0 x ULN
Recommendation: Hold dose. Monitor LFTsb weekly, or 
more frequently if clinically indicated, until resolved to ≤ 1.5 
x ULN:
if resolved in ≤ 14 days, then maintain dose level
if resolved in > 14 days, then reduce dose 1 dose level
Recommendation: Hold dose. Monitor LFTsb weekly, or more 
frequently if clinically indicated, until resolved to ≤ 1.5 x ULN:
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*
Mandatory: Hold dose. Monitor LFTsb weekly, or more 
frequently if clinically indicated, until resolved to ≤ 1.5 x 
ULN:
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.
Mandatory: Hold dose. Monitor LFTsb weekly, or more frequently if 
clinically indicated, until resolved to ≤ 1.5 x ULN:
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*
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.
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
> ULN - 3.0 x ULN
Recommendation: Maintain dose level
Recommendation: Maintain dose level
> 3.0 - 5.0 x ULN
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
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


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Dose modifications for both ABL001 and bosutinib
Worst toxicity
CTCAE Grade 4.03
ABL001
bosutinib
> 5.0 - 10.0 x ULN
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: Then
If resolved in ≤ 14 days, maintain dose level
If resolved in > 14 days, reduce dose 1 dose level
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 ≤ 2.5 x ULN: Then
Recommendation: If resolved in ≤ 28 days, reduce dose 1 
dose level
Recommendation: If resolved in > 28 days, Discontinue patient 
from study drug treatment
> 10.0 - 20.0 x ULN
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 ≤ baseline. Then 
reduce dose 1 dose level.
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 ≤ 2.5 x ULN. Then
Recommendation: If resolved in ≤ 28 days, reduce dose 1 
dose level maintain dose level
Recommendation: If resolved in > 28 days, Discontinue patient 
from study drug treatment.
> 20.0 x ULN
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.
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 ≤ 2.5 x ULN (then
Recommendation: If resolved in ≤ 28 days, reduce dose 1 
dose level maintain dose level
Recommendation: If resolved in > 28 days, Discontinue patient 
from study drug treatment


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Dose modifications for both ABL001 and bosutinib
Worst toxicity
CTCAE Grade 4.03
ABL001
bosutinib
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.
Mandatory: 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 
6.3.3.1 for additional follow-up evaluations as applicable.
Mandatory: Permanently discontinue patient from study drug 
treatment.
Mandatory: 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 6.3.3.1 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
Recommendation: Maintain dose level, measure 2x week
Grade 2 (> 1.5 - 2.0 x ULN)
Recommendation: Maintain dose level, measure 2x week
Recommendation: Maintain dose level, measure 2x week
Grade 3 (> 2.0 - 5.0 x ULN)
Mandatory: Hold dose until resolved to Grade ≤ 1 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).
Mandatory: Hold dose until resolved to Grade ≤ 1 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)
Mandatory: Permanently discontinue patient from study 
drug treatment. Obtain appropriate imaging (i.e., MRI, CT 
scan or ultrasound).
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 both ABL001 and bosutinib
Worst toxicity
CTCAE Grade 4.03
ABL001
bosutinib
Vascular disorders
Hypertension
CTCAE Grade 3
Mandatory: Hold dose until resolved ≤ Grade 1, then 
reduce dose 1 dose level
Mandatory: Hold dose until resolved ≤ Grade 1, then reduce dose 
1 dose level
CTCAE Grade 4
Mandatory: Permanently discontinue patient from study 
drug treatment.
Mandatory: Permanently discontinue patient from study drug 
treatment.
Gastro intestinal
Pancreatitis
Grade 2
Mandatory: If asymptomatic radiologic pancreatitis (Grade 
2 pancreatitis), hold treatment until resolved to ≤ Grade 1 
or baseline. If treatment delay is ≤ 7 days, then reduce 
dose 1 dose level. If treatment delay >7 days, 
discontinue treatment and obtain appropriate imaging (i.e., 
MRI, CT scan or ultrasound).
Mandatory: If asymptomatic radiologic pancreatitis (Grade 2 
pancreatitis), hold treatment until resolved to ≤ Grade 1 or 
baseline. If treatment delay is ≤ 7 days, then reduce dose 1 
dose level. If treatment delay >7 days, discontinue treatment and 
obtain 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).
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
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
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
Mandatory: Hold dose until recovery to ≤ grade 1. 
Recommendation: Bosutinib may then be resumed at 1 dose 
level
Grade 4
Mandatory: Permanently discontinue patient from study 
drug treatment
Mandatory: Hold dose until recovery to ≤ grade 1. 
Recommendation: Bosutinib may then be resumed at 1 dose 
level


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Dose modifications for both ABL001 and bosutinib
Worst toxicity
CTCAE Grade 4.03
ABL001
bosutinib
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)
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)
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
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.
Mandatory: Permanently discontinue patient from study drug 
treatment.
General disorders and administration site conditions
Fatigue/ Asthenia
Grade 1 or 2
Recommendation: Maintain dose level
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
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
Other adverse events
Grade 1 or 2
Recommendation: Maintain dose level
Recommendation: Maintain dose level
Grade 3
Mandatory: Hold dose until resolved within 28 days to ≤ 
grade 1 then resume at 1 dose level
Mandatory: Hold dose until resolved 1 within 28 days to ≤ grade, 
then resume at 1 dose level
Grade 4
Mandatory: Hold dose and then discontinue from study 
drug treatment
Mandatory: Hold dose and then discontinue from study drug 
treatment


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Dose modifications for both ABL001 and bosutinib
Worst toxicity
CTCAE Grade 4.03
ABL001
bosutinib
All dose modifications should be based on the worst preceding toxicity.
a Common Toxicity Criteria for Adverse Events (CTCAE Version 4.03)
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 ABL001 and bosutinib
Dose reduction*
Starting dose level – 0
Dose level - 1
ABL001 BID
40 mg tablet BID (total daily 
dose 80 mg)
20 mg tablet BID (total daily 
dose 40 mg)
*Dose reduction should be based on the worst toxicity demonstrated at the last dose.
ABL001 dose reduction below total daily 40 mg is not allowed. 20 mg tablets will be dispensed to patients in the 
instance of dose reduction.
Dose reduction*
Starting dose level – 0
Dose level - 1
Dose level – 2
Bosutinib QD
500 mg ( 1-500 mg tablet QD)
400 mg (4-100 mg tablets 
QD)
300 mg (3-100 mg 
tablets QD)
* Dose reduction should be based on the worst toxicity demonstrated at the last dose.
Bosutinib dose reduction below total daily 300 mg is not allowed. 100 mg tablets will be dispensed to patients in 
the instance of dose reduction.
6.3.2
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, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug treatment.
4. Review concomitant medication use for other causes for QT prolongation (refer to 
qtdrugs.org for known QT prolonging drugs), and for drugs with the potential to increase 
the risk of drug exposure related QT prolongation (e.g., concomitant use of CYP3A4 
inhibitors, if the study drug is a CYP3A4 substrate)
5. Check study drug dosing schedule and treatment compliance
6. Increased ECG safety monitoring is recommended during or in-between subsequent visits.
6.3.3
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.


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6.3.3.1
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with 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).
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from 
the awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
1. Laboratory tests should include ALT, AST, albumin, creatinine kinase, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.
2 . A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted.
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study.
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
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”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented.


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6.3.4
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria, as well as specific dose modification and stopping rules are 
included in this protocol. Recommended guidelines for prophylactic or supportive treatment 
for expected toxicities, including management of study-drug induced adverse events, i.e., 
hyperglycemia, skin toxicity and diarrhea are provided in Table 6-2. Refer to preclinical 
toxicity and or clinical data found in the [Investigator’s Brochure].
6.4
Concomitant medications for patients on ABL001
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.
6.4.1
Permitted concomitant therapy
Drugs that affect gastric pH
ABL001 does not have a pH-dependent solubility. Drugs that elevate gastric pH will not 
affect ABL001 absorption. All acid reducing agents are allowed.
6.4.2
Permitted concomitant therapy requiring caution and/or action
There is a potential for DDIs with co-medications metabolized by CYP3A4/5, CYP2C8 and 
CYP2C9 at the anticipated human efficacious dose. Therefore, substrates of CYP3A4/5, 
CYP2C8 and CYP2C9 should be used with caution (Section 14-Appendix).
Additionally, transporter phenotyping studies have identified ABL001 to be a substrate of 
Breast Cancer Resistant Protein (BCRP). While the effect on ABL001 exposure via BCRP 
interaction is not likely, BCRP inhibitors should be administered with caution.


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6.4.3
Prohibited concomitant therapy
Strong CYP3A4/5 and P-gp inhibitors
Every effort should be made NOT to concomitantly administer strong CYP3A4/5 and P-gp 
inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, 
telithromycin, ritonavir, mibefradil). P-gp and CYP3A4/5 inhibitors may increase absorption 
or decrease the metabolism of ABL001 and resulting in increased serum concentrations and 
increased exposure. If administration of a strong CYP3A4/5 and P-gp inhibitor cannot be 
avoided during the study and cannot be switched to an alternative therapy that does not 
strongly inhibit CYP3A4/5 or P-gp, ABL001 must be stopped.
A list of cytochrome P450 isoenzymes and CYP3A4/5 and P-gp inhibitors may be found at 
http://medicine.iupui.edu/CLINPHARM/ddis/clinical-table.
A classification of CYP3A4/5 and P-gp inhibitors can be found in Section 14-Appendix.
Further information can also be found in the following reference (Venkatakrishnan et al 2001).
Strong CYP3A4/5, and UGT1A/2B inducers
Every effort should be made NOT to concomitantly administer strong CYP3A4 inducers 
during the study.
Additionally, the use of strong inducers of UGT1A/2B is prohibited during the study.
NTI substrates of CYP3A4/5, CYP2C8 and CYP2C9
Based on the in vitro results, there is a potential for DDIs with co-medications metabolized by 
CYP3A4/5, CYP2C8 and CYP2C9 at the anticipated human efficacious dose. Therefore, 
narrow therapeutic index substrates of CYP3A4/5, CYP2C8 and CYP2C9 are prohibited
QT prolonging agents
Every effort should be made NOT to administer a QT prolonging agent. If during the course 
of the study, concomitant administration of an agent known to prolong the QT interval is 
required and cannot be switched to an alternative therapy, ABL001 must be permanently 
discontinued.
Please see: http://www.torsades.org/medical-pros/drug-lists/printable-drug-
list.cfmcrediblemeds.org/everyone/composite-list-all-qtdrugs/ for a list of agents that prolong
the QT.
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.


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6.4.4
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 6.4.2 and Section 14.1/Appendix 1).
Bisphosphonates
The use of bisphosphonates regardless of indication is allowed.
Contraceptives
Hormonal contraceptives are allowed as contraception methods. Highly effective 
contraception should be maintained throughout the study and for 3 days after study treatment 
discontinuation.
Anticoagulation agents
All anticoagulants or anti-aggregation agents may be administered under the discretion of the 
investigator.
Therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative 
anticoagulants should be used with caution and fully avoided whenever possible because of its 
known interaction with many commonly used medications and certain foods. As warfarin has 
a narrow therapeutic range, and ABL001 is possibly an 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 ABL001 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 ABL001 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 ABL001. Alternatively, therapeutic anticoagulation 
may be accomplished using low-molecular weight heparin.
6.5
Concomitant medications for patients on Bosutinib
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) 


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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
6.5.1
Prohibited concomitant medications
Concomitant use with CYP3A inhibitors
Avoid the concomitant use of strong or moderate CYP3A inhibitors as an increase in 
bosutinib plasma concentration is expected. Strong CYP3A inhibitors include boceprevir, 
clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, 
nefazodone, 
nelfinavir, 
posaconazole, 
ritonavir, 
saquinavir, 
telaprevir, 
telithromycin, and voriconazole.
Moderate CYP3A inhibitors include amprenavir, aprepitant, atazanavir, ciprofloxacin, 
crizotinib, 
darunavir/ritonavir, 
diltiazem, 
erythromycin, 
fluconazole, 
fosamprenavir, 
grapefruit products, imatinib and verapamil) [Bosulif® USPI]. If administration of a strong or 
moderate CYP3A4/5 inhibitor cannot be avoided during the study and cannot be switched to 
an alternative therapy, bosutinib must be stopped.
Concomitant use with CYP3A inducers
Avoid the concomitant use of strong or moderate CYP3A inducers as a large reduction in 
exposure is expected (strong CYP3A inducers include carbamazepine, phenytoin, rifampin 
and St. John's Wort. Moderate CYP3A inducers include bosentan, efavirenz, etravirine, 
modafinil and nafcillin) [Bosulif® USPI]. If administration of a strong or moderate CYP3A4/5 
inducer cannot be avoided during the study and cannot be switched to an alternative therapy, 
bosutinib must be stopped.
P-gp Inhibitors
Avoid the concomitant use of P-gp inhibitors with BOSULIF as an increase in bosutinib 
plasma concentration is expected [Bosulif® USPI].
pH Altering Medications
Bosutinib displays pH-dependent aqueous solubility, in vitro. In a cross-over trial in 23 
healthy volunteers, a single oral dose of 400 mg of bosutinib was either administered alone or 
in combination with multiple-oral doses of 60 mg of lansoprazole (PPI) under fasting 
conditions. Lansoprazole decreased bosutinib Cmax and AUC by 46% and 26%, respectively.


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Concomitant administration with PPIs is not allowed.
Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in 
bosutinib exposure. Separate antacid or H2 blocker dosing by more than 2 hours [Bosulif®
USPI].
6.6
Patient numbering, treatment assignment or randomization
6.6.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned 
when the patient is first enrolled for screening and is retained as the primary identifier for the 
patient throughout his/her entire participation in the trial. The Subject No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential patient number suffixed to it, so that each subject is numbered uniquely across the 
entire database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Subject No. available to the investigator through the Oracle Clinical RDC interface.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be 
changed, even if the patient is re-screened. If the patient fails to be randomized or start 
treatment for any reason, the reason will be entered into the Screening Disposition page. IRT 
must be notified within 2 days that the patient was not randomized.
6.6.2
Treatment assignment or randomization
Patients will be assigned to one of the 2 treatment arms (Section 4.1 and Section 6.1) in a ratio 
of 2:1. Randomization will be stratified by cytogenetic response status at screening.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication randomization 
list will be produced by or under the responsibility of Novartis Drug Supply Management 
using a validated system that automates the random assignment of medication numbers to 
medication packs containing each of the study treatments.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the patient. The randomization number will not be communicated 
to the caller.


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6.6.3
Treatment blinding
Not applicable.
6.7
Study drug 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.
6.7.1
Study treatment packaging and labeling
Study treatment, ABL001 and bosutinib tablets, will be provided as global clinical open-label 
supply and will be packed and labeled under the responsibility of Novartis, Drug Supply 
Management.
Study treatment labels will comply with the legal requirements of each country and will 
include storage conditions, a unique medication number (corresponding to study treatment 
and strength). Responsible site personnel will identify the study treatment package(s) to 
dispense by the medication number(s) assigned by IRT to the patient. Site personnel will add 
the patient number on the label. If the label has 2-parts (base plus tear-off label), immediately 
before dispensing the package to the patient, site personnel will detach the outer part of the 
label from the package and affix it to the patient’s source document.
Table 6-4
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
ABL001 (20 mg and 40 mg)
Tablets in bottle
Labeled as ‘ABL001 20 mg/ABL001 40 
mg’(BID)
bosutinib (100 mg or 500 mg)
Tablets in bottle or tablets in 
blister
Labeled as ‘bosutinib 100 mg or bosutinib 
500 mg’(QD)
6.7.2
Drug supply and storage
Study treatments must be received by designated personnel 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, the ABL001 and bosutinib should be 
stored according to the instructions specified on the drug labels.
6.7.3
Study drug compliance and accountability
6.7.3.1
Study drug compliance
Total daily dose of study treatment administered with start and end date will be collected on 
the Dose Administration Record eCRF page. Name, start and end dates of any Concomitant 
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 


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Accountability Form. This information must be captured in the source document at each 
patient visit.
6.7.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and 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.
6.7.3.3
Handling of other study treatment
Not applicable.
6.7.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, or at the site only if permitted by local regulations and authorized by Novartis in a 
prior agreement.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. Patients can be consented for study participation prior to study day -21.
No eCRF will be used as a source document.
(S) is defined as “Source”
(D) is defined as “Data Based”




















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7.1.1
Molecular pre-screening
Not applicable.
7.1.2
Screening
Written informed consent must be obtained before any study specific medical procedures are 
performed (Day -42). All screening/baseline assessments (with the exception of Bone Marrow 
Aspirates) should occur within 21 days before randomization.
The screening visit window for bone marrow assessments is 42 days prior to randomization.
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 RQ-PCR and the bone marrow aspirate must be available prior to randomization and first 
dose of study treatment
For details of assessments required during screening please refer to Table 7-1.
Laboratory baseline assessments (including hematology, chemistry, coagulation 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 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, the patient ID number will remain the same. All required 
screening activities must be performed when the patient is re-screened for participation in the 
study. An individual patient may only be re-screened once 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.


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7.1.2.1
Eligibility screening
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be managed via IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
7.1.2.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure. The reason for not being started on treatment will be entered on 
the Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details). If the patient fails to be randomized, the IRT must be notified within 2 days 
of the screen fail that the patient was not randomized.
7.1.2.3
Patient demographics and 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, 
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 and the bone 
marrow aspirate must be available prior to randomization and first dose of study treatment to 
evaluate eligibility and to stratify the patient.
7.1.2.4
Local recruitment procedures-Japan
Given the limited safety data available in Japanese patients, specific recruitment and data 
monitoring procedures will be put in place for Japanese patients randomized to ABL001.
Randomization of these patients will be staggered to avoid enrollment of more than one 
patient on the same day. Safety parameters from a minimum of 2 patients treated on the 
ABL001 arm will be reviewed for determining the appropriateness of continuing patient 
enrollment in Japan.
7.1.3
Run-in period
Not applicable.


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7.1.4
Treatment period
There is no fixed duration of treatment planned per patient. All patients will be given the 
opportunity to receive study treatment until the date that corresponds to 96 weeks after the last 
patient receives the first study dose.
During the treatment phase, the patients will receive either ABL001 treatment 40 mg BID or 
bosutinib 500mg QD according to randomization. The dose can be modified, if required from 
the perspective of tolerance, following the guidance in Section 6.2 and Section 6.3. Treatment 
is ongoing until patient experiences 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).
7.1.5
Visit windows
Study visits from Day 1 to Week 16 should be completed every 2 weeks on the designated 
date [with an allowed “visit window” of +/- 1 day]
Study visits from Week 16 to Week 96 should be completed every 4 weeks on the designated 
date [with an allowed “visit window” of +/- 2 days]
Study visits from Week 96 to EOT should be completed every 12 weeks on the designated 
date [with an allowed “visit window” of +/- 7 days]
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.
7.1.6
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If
a patient decides to discontinue from the study treatment, the investigator should make a  
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this
decision and record this information in the patient’s chart and on the appropriate eCRF pages.
They may be considered withdrawn if they state an intention to withdraw, fail to return for
visits, or become lost to follow-up for any other reason.
The investigator should discontinue study treatment for a given patient if, he/she believes that
continuation would be detrimental to the patient’s well-being. Patients who discontinue study 
treatment should undergo an end of study visit.
For patients who discontinue treatment for reasons other than death, lost to follow-up, or 
withdrawal of consent, the patient should enter the survival follow-up phase. Survival visit
assessments (survival, antineoplastic therapies, stem cell transplant and progression) should 
be performed every 12 weeks until documented death, lost to follow-up, or withdrawal of 
consent.
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 
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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

pregnancy during treatment phase

use of prohibited treatment refer to Appendix 1.

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 treatment failure the patient must be discontinued from the study treatment. 
The following events will constitute ‘treatment failure’, and are based on the ELN criteria
(Bacarrani 2013) defining failure of a second line treatment:

No CHR or > 95% Ph+ metaphases at three months after randomization or thereafter

BCR-ABL ratio > 10% IS and/or > 65% Ph+ metaphases at six months after 
randomization or thereafter

BCR-ABL ratio > 10% IS and/or > 35% Ph+ metaphases at 12 months after 
randomization or thereafter

Loss of CHR, CCyR or PCyR at any time after randomization

Detection of new BCR-ABL mutations at any time after randomization

Confirmed loss of MMR in 2 consecutive tests, of which one must have a BCR-ABL ratio 
≥ 1% IS 6 months after randomization

New clonal chromosome abnormalities in Ph+ cells: CCA/Ph+: at any time after 
randomization
In the event of disease progression the patient must be discontinued from the study treatment. 
The following events are considered disease progression.
1. 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)
2. Accelerated phase (AP) as defined by any of the following:

≥ 15% blasts in the peripheral blood or bone marrow aspirate, but < 30% blasts in 
both the peripheral blood and bone marrow aspirate

≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow aspirate

≥ 20% basophils in the peripheral blood

Thrombocytopenia (<100 x 109/L) that is unrelated to therapy


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3. Blast crisis (BC) as defined by any of the following:

≥ 30% blasts in peripheral blood or bone marrow aspirate

Appearance of extramedullary involvement other than hepatosplenomegaly proven by 
biopsy (i.e., chloroma).
7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Molecular response
Molecular response (MR) will be assessed in all patients randomized to each treatment arm.
Levels of BCR-ABL 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-
ABL transcripts levels from the standardized baseline value, or the percent ratio of BCR-ABL 
transcripts versus control gene (ABL) transcripts converted to a reference standard, 
international scale (Hughes and Branford 2006), will be calculated for each sample.
Major molecular response 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-ABL transcripts compared to the standardized baseline equivalent to ≤ 
0.1 % BCR-ABL/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 randomization 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.
Loss of MMR is defined as confirmed loss of a greater than or equal to 3.0 log reduction in 
BCR-ABL transcript levels compared to the standardized baseline value, or confirmed loss of 
a less than or equal to 0.1% BCR-ABL/ABL by international scale in association with a ≥ 5-
fold rise in BCR-ABL from the lowest value achieved on study treatment confirmed by a 
duplicate analysis of the same sample. This result has to be confirmed by a subsequent sample 
within 4-6 weeks unless it is associated with confirmed loss of CHR or loss of CCyR or 
progression to AP/BC or CML-related death.
Mutational analysis will be performed at a Novartis designated laboratory by Sanger 
sequencing at baseline and at end of treatment. If the result at baseline is positive for a 
mutation, analysis will be performed every 12 weeks.
The blood samples will be taken as described in Table 7-1 and Table 7-2.


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Table 7-2
Blood samples (efficacy primary endpoint)
Sample Type
Volume
Visit
Time point
Blood for BCR-ABL
quantification by RQ-PCR
20 mL
Screening/Baseline
Pre-dose
20 mL
Week 4
Pre-dose
20 mL
Week 8
Pre-dose
20 mL
Week 12
Pre-dose
20 mL
Week 16
Pre-dose
20 mL
Week 24
Pre-dose
20 mL
Week 36
Pre-dose
20 mL
Week 48
Pre-dose
20 mL
Week 60
Pre-dose
20 mL
Week 72
Pre-dose
20 mL
Week 84
Pre-dose
20 mL
Week 96
Pre-dose
20 mL
Every 12 weeks thereafter 
(W108,W120,W132, 
W144,W156,W168)
Pre-dose
20 mL
End of Treatment
Anytime
Blood for BCR-ABL Mutation
analysis by Sanger Sequencing
2.5 ml
Week 1 Day 1
Pre-dose
2.5 ml
End of Treatment
Anytime
Blood for BCR-ABL Mutation
analysis only for patients with
mutations at W1D1
2.5 ml
Week 12
Anytime
2.5 ml
Week 24
Anytime
2.5 ml
Week 36
Anytime
2.5 ml
Week 48
Anytime
2.5 ml
Week 60
Anytime
2.5 ml
Week 72
Anytime
2.5 ml
Week 84
Anytime
2.5 ml
Week 96
Anytime
2.5 ml
Every 12 weeks thereafter 
(W108,W120,W132, 
W144,W156,W168)
Anytime
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 [CABL001A2301 Laboratory 
Manual].
7.2.1.2
Bone marrow analysis and cytogenetics
Cytogenetic response will be assessed as the percentage of Ph+ metaphases in the bone 
marrow and is defined as the following (a review of a minimum of 20 metaphases is required):

Complete (CCyR) - 0% Ph+ metaphases

Partial (PCyR) - >0 to 35% Ph+ metaphases

Major (MCyR) - 0 to 35% Ph+ metaphases


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
Minor (mCyR) - >35 to 65% Ph+ metaphases

Minimal - >65 to 95% Ph+ metaphases

None - >95 to 100% Ph+ metaphases.
Bone marrow aspirate for cytogenetic analyses will be performed at screening/baseline
(performed up to 42 days prior to randomization), at week 24, 48, 72, 96 and at end of 
treatment. For patients on the bosutinib arm an unscheduled bone marrow assessment at week 
12 may be performed to evaluate cytogenetic response in consideration for potential dose 
escalation.
Quantification of the percentage of Ph+ chromosome metaphases, number of metaphases, 
number positive for Ph chromosome, additional chromosomal abnormalities as well as data 
from cytologic evaluation (microscopic analysis) of percentage of blasts and promyelocytes 
will be recorded on the Bone Marrow eCRF. These exams will be performed and analyzed 
locally. Fluorescent In-situ hybridization (FISH) analysis will not be accepted.
7.2.1.3
Hematologic response
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
7.2.2
Safety and tolerability assessments
Safety will be monitored by the assessments described below as well as collecting of the 
adverse events at every visit. For details on AE collection and reporting, refer to Section 8.
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.
7.2.2.1
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:

Screening

Day 1

Every 2 weeks from Week 4 to Week 16


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
Every 4 weeks from Week 16 to Week 96

Every 12 weeks from Week 96 to EOT

End of treatment visit or early discontinuation visit in case of premature discontinuation.
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)..
7.2.2.2
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:

Screening

Day 1

Every 2 weeks from Week 2 to Week 16

Every 4 weeks from Week 16 to Week 96

Every 12 weeks from Week 96 to EOT

End of treatment visit or early discontinuation visit in case of premature discontinuation.
7.2.2.3
Height and weight
Height in centimeters (cm) will be measured at screening only.
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured at screening and at subsequent time points as specified in Table 7-1:

Screening

Every 2 weeks from Week 4 to Week 16

Every 4 weeks from Week 16 to Week 96

Every 12 weeks from Week 96 to EOT

End of treatment visit or early discontinuation visit in case of premature discontinuation.
7.2.2.4
Performance status
ECOG Performance status scale (Table 7-2) will be used as described in the Table 7-1.

Screening

Day 1

Every 2 weeks from Week 4 to Week 16

Every 4 weeks from Week 16 to Week 96

Every 12 weeks from Week 96 to EOT

End of treatment visit or early discontinuation visit in case of premature discontinuation.


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More frequent examinations may be performed at the investigator’s discretion, if medically 
indicated.
Table 7-3
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
7.2.2.5
Laboratory evaluations
Central laboratory will be used for analysis of hematology, biochemistry, coagulation, serum 
pregnancy and hepatitis marker specimens collected (safety monitoring). Details on the 
collections, shipment of the samples and reporting of results by the central laboratory are 
provided to investigators in the [CABL001A2301 Laboratory Manual]. The time windows 
granted for laboratory evaluations are identical with the corresponding visit time windows for 
each visit (see Section 7.1.5).
Table 7-4
Central 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 2 weeks from week 4 up to 
week 16, every 4 weeks up to week 96, 
and every 12 weeks thereafter, EOT and 
as clinically indicated
Chemistry
Hemoglobin A1c
Screening/Baseline, Week 12 and as 
clinically indicated
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), 
AST (SGOT), Total Calcium, Creatinine, 
Creatinine kinase, Potassium, Magnesium, 
Sodium, Phosphorus, Direct Bilirubin, Indirect 
Bilirubin, Total Bilirubin, Total Cholesterol, 
LDL, HDL, Total Protein, Triglycerides, Blood 
Urea or Nitrogen (BUN), Uric Acid, Amylase, 
Lipase, Glucose (fasting)
Screening/Baseline, week 1 Day 1, week 
2 Day 1, every 2 weeks from week 4 up to 
week 16, every 4 weeks up to week 96, 
and every 12 weeks thereafter, EOT, and 
as clinically indicated
Coagulation
International normalized ratio (INR)
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 96, and every 12 weeks thereafter,
EOT, unscheduled


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7.2.2.5.1 Hematology
Hematology labs are to be analyzed at each scheduled visit by a central laboratory. 
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 7-4).
7.2.2.5.2 Clinical chemistry
Blood chemistry labs are to be analyzed at each scheduled visits by a central laboratory. 
Chemistry includes albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), total calcium, 
creatinine, creatinine kinase, potassium, magnesium, sodium, phosphorus, direct bilirubin, 
indirect bilirubin, total bilirubin, total cholesterol, LDL, HDL, total protein, triglycerides, 
blood urea or nitrogen (BUN), uric acid, amylase, lipase and fasting glucose. In addition the 
coagulation parameter INR is analyzed at each scheduled visit.
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 7-4).
7.2.2.5.3 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 
7-1 of the Visit evaluation schedule. Serum pregnancy test will be performed by a central 
laboratory.
After Week 96 monthly urine pregnancy test must be performed by all women of child-
bearing potential between the three monthly visits (beginning at Week 100). Urine pregnancy 
tests may be performed at the investigational site or at home. Test results performed at home 
should be recorded onto a patient diary and brought to each scheduled visit for the site to 
review. If a test result indicates a pregnancy, the patient must contact the investigator 
immediately.
All pregnancies (including female partners of male patients) should be recorded on a Clinical 
Trial Pregnancy Form and reported by the investigator to the Oncology Novartis Drug Safety 
and Epidemiology Department (DS&E).
During the whole study, women of childbearing potential should employ the use of highly 
effective contraception. Highly effective contraception methods are defined in Section 5.3.
Sexually active males 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 in this period. A condom is 
required to be used also by vasectomized men in order to prevent delivery of the drug via 
seminal fluid.


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7.2.2.6
Cardiac assessments
7.2.2.6.1 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 7-5 and Table 7-6. Blood samples for 
PK scheduled at the same time point should be taken after the ECGs are completed.
Table 7-5
Central ECG collection (all patients)
Week (or Day)
Number of ECGs (per visit)
Time of ECG
Day -21 to -1
3
3 serial ECGs at the screening visit
Week 1 Day 1
3
3 serial ECGs at 2 h post dose
Week 2 Day 1
12
3 serial ECGs pre-dose and at 2, 3, 4 h post-
dose
Week 4
3
3 serial ECGs pre-dose
Week 12
3
3 serial ECGs pre-dose
Week 24
3
3 serial ECGs pre-dose
Week 96
3
3 serial ECGs 30 min* post-dose
Unscheduled
3
3 serial ECGs 30 min* post-dose
* 30 min +/- 5min allowed
Table 7-6
Central ECG collection plan for patients in full PK ABL001 group
Week (or Day)
Number of ECGs (per visit)
Time of ECG
Day -21 to -1
3
3 serial ECGs at the screening visit
Week 1 Day 1
3
3 serial ECGs at 2 h post dose
Week 2 Day 1
24
3 serial ECGs pre-dose and at 1, 2, 3, 4, 6, 8, 12 
h post-dose
Week 4
3
3 serial ECGs pre-dose
Week 12
3
3 serial ECGs pre-dose
Week 24
3
3 serial ECGs pre-dose
Week 96
3
3 serial ECGs 30 min post-dose
Unscheduled
3
3 serial ECGs 30 min post-dose
* 30 min +/- 5min allowed
All ECGs performed will be independently reviewed. Instructions for the collection and 
transmission of these ECGs to the independent central reader (eRT) will be provided in the 
[CABL001A2301 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 eRT. 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 ≥450msec (male) or ≥ 460msec (female) by automated reading, an immediate manual 
central reading must be requested by calling eRT. The patient may not be dosed if the average 
of the manually read ECGs confirms a QTcF ≥450msec (male) or ≥460msec (female).


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Dose adjustments in case of QT prolongation should be performed per Section 6.3.2.
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.
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.
7.2.2.6.2 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 both study treatments in the trial are TKIs (ABL001 and bosutinib), 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 
patient’s Family History.
7.2.2.6.3 Echocardiogram
Echocardiograms will be performed to monitor cardiac safety. Assessments are scheduled at 
screening/baseline, Week 20 and end of treatment visits. The echocardiogram will be 
performed and evaluated locally to assess the left ventricular ejection fraction. Any clinically 
significant findings will be collected and reported in the database (i.e. reported as adverse 
events).
7.2.2.6.4 Pulmonary function test
Pulmonary function test will be performed to monitor cardio-pulmonary safety. Assessments 
are scheduled at screening/baseline, Week 20 and end of treatment visits. 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 points. Any clinically significant findings will be collected and 
reported in the database (i.e. reported as adverse events).
7.2.3
Pharmacokinetics
Blood samples for ABL001 pharmacokinetics will be collected on all study subjects allocated 
to the ABL001 treatment arm. Blood samples for full PK profiles will be collected from at 
least 20 patients. These patients will be identified sequentially at selected sites that are 
capable of serial PK sampling over 12 hours. ABL001 should be taken for at least 3 
consecutive days without interruption or dose modification prior to full PK day.


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For the assessment of ABL001 pharmacokinetics in plasma, serial blood samples will be 
collected following ABL001 administration at several time-points (see Table 7-7 and Table 7-
8 below for further details). Remaining plasma samples may be used for identification and/or 
measurement of metabolites of ABL001.
Refer to the [CABL001A2301 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK samples.
Table 7-7
Pharmacokinetic blood collection log (Sparse PK-group-ABL001 arm)
Week
Day
Scheduled Time Point
Dose 
Reference ID
PK Sample No
Blood Volume 
(mL)
1
1
2 h (± 10 min)
101
101
2
2
1
0 h (Pre-dose)a
102/2001b
102
2
1
2 h (± 10 min)
102
103
2
1
3 h (± 15 min)
102
104
2
1
4 h (± 15 min)
102
105
2
4
Any
0 h (Pre-dose)a
103/3001b
106
2
12
Any
0 h (Pre-dose)a
104/4001b
107
2
24
Any
0 h (Pre-dose)a
105/5001b
108
2
96
Any
0 h (Pre-dose)a
106/6001 b
109
2
Unscheduled
1001+
a Pre-dose PK sample should be taken immediately prior to the next administration of ABL001. PK samples on 
Week 2 Day 1 should be taken before and after the morning dose (i.e. 1st dose of the day). PK samples on other 
weeks may be taken immediately prior to the morning dose (i.e. 1st dose of the day) or the evening dose (i.e. 2nd
dose of the day).
b The first dose reference ID refers to the first dose administered after PK sampling and the second dose 
reference ID refers to the last dose administered prior to the PK sampling.








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7.2.5
Resource utilization
The measures of healthcare Resource Utilization (RU) to be collected include: hospitalization
(H), emergency room (ER) visit, general practitioner (GP) visits, specialist (Sp) visit and 
urgent care (UC) visit. These measures will be used to derive the economic impact of 
ABL001 and bosutinib.
Hospitalization visits will also record the number of days in ward and the type of ward 
(hospital unit) and the discharge status. At each RU collection, the reason for the visit (i.e. 
related to CML, AE or other reason) will be collected in order to quantify the impact of 
ABL001 and bosutinib on healthcare resources.
The RU assessment will be completed at each scheduled clinical trial visit; the RU will be 
completed by the investigator however information with respect to the number of GP, UC, Sp 
or ER visits will be ascertained from the patient.
All attempts to collect as much information from the patient as possible should be made in 
order to minimize selection bias.
7.2.6
Patient reported outcomes
The MDASI CML, PGIC, WPAI along with EQ-5D-5L (EuroQol Group (1990), Brooks 
(1996), Herdman et al (2011)) will be used to compare data on the patient’s disease-related 
symptoms and health-related quality of life from baseline to EOT between the treatment arms. 
The WPAI will be used to assess work productivity and activity impairment related to the 
patient’s CML. All measures will assess differences between the treatment arms. All tools 
require patient’s direct completion and will be administered utilizing electronic device for 
data collection.
Patients with an evaluable baseline score and at least one evaluable post baseline score during 
the treatment period will be included in the change from baseline analyses. Missing data items 
in a scale will be handled according to the manual for each instrument. No imputation will be 
applied if the total or subscale scores are missing at a visit.
The patient should be given the questionnaire(s) to be completed at the scheduled visit before 
any clinical assessments are conducted. Patient’s refusal to complete all or any part of a 
questionnaire should be documented in the study data capture system and should not be 
captured as a protocol deviation. Patient questionnaires should be completed in the language 
most familiar to the patient.
The patient should be given sufficient space and time to complete the questionnaires and the 
administered questionnaire should be reviewed for completeness. If missing responses are 
noted, patients should be encouraged to complete any missing responses.
Completed questionnaire(s) and any unsolicited comments written by the patient should be 
reviewed and assessed by the investigator for responses which may indicate potential AEs or 
SAEs before any clinical study examinations. This assessment should be documented in study 
source records. If AEs or SAEs are confirmed, study investigators should not encourage the 
patient to change responses reported in the completed questionnaires. Study investigators 


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must follow reporting instructions outlined in Section 8 (e.g. reference “Adverse Events”
Section) of the study protocol.
MDASI-CML
The M.D. Anderson Symptom Inventory – Chronic Myeloid Leukemia (MDASI-CML) is a 
26 item self-administered questionnaire for adult CML patients. Twenty of the items measure 
the severity of disease-related symptoms and are scored from 0 (Not present) to 10 (As Bad as 
you can imagine) and 6 items that measure symptom interference with daily life scored from 0 
(Did not interfere) to 10 (Interfered completely). Descriptive statistics will be provided for the 
MDASI-CML symptom score and interference score, and the change in the MDASI-CML 
symptom score and interference score from baseline to all available time points to the end of 
study. Additional analysis may be performed and details will be described in the analysis plan.
EQ-5D-5L
EQ-5D-5L is a two-part standardized instrument for measuring health outcomes in a wide 
range of health conditions and treatments. It consists of a descriptive system and a visual 
analogue scale (EQ VAS). The descriptive system comprises the following 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension 
has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme 
problems (or unable to perform the activity). The EQ VAS records the respondent’s self-rated 
health on a vertical, visual analogue scale where the endpoints are labeled ‘Best imaginable 
health state’ and ‘worst imaginable health state’. The health states derived from the 
descriptive system can be summarized into a single index score that provides a simple 
measure of health for clinical and economic appraisal. Descriptive statistics will be provided 
for EQ-5D-5L health index score and for the EQ VAS, at each scheduled assessment time 
point. There should be only ONE response for each dimension. Missing values can be coded 
as ‘9’. Ambiguous values (e.g. 2 boxes are ticked for a single dimension) should be treated as 
missing values. Additional analysis may be performed and details will be described in a 
separate analysis plan.
WPAI
The Work Productivity and Activity Impairment Questionnaire (WPAI) is a four-item 
questionnaire which is intended to measure work and activity impairment associated with 
CML for those who self-identify as currently employed for pay. This questionnaire measures 
self-reported productivity loss associated with CML during the past seven days. It consists of 
questions about absence from work due to CML, hours spent at work, the reduction in 
productivity at work attributed to CML, and the reduction in productivity while performing 
regular activities. WPAI outcomes are expressed as impairment percentages, with higher 
numbers indicating greater impairment and less productivity, i.e., worse outcomes, Scoring 
will be done according to WPAI instrument guidance resulting in four scores including: 
Percent work time missed due to problem; percent impairment while working due to problem; 
Percent overall work impairment due to problem; and, percent activity impairment due to 
problem. Change from baseline in WPAI at each visit, where measured, will be done for each 
of the four derived scores.


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PGIC
The Patient Global Impression of Change is comprised of a single question intended to 
measure a patient’s perspective of improvement or deterioration over time relative to 
treatment. The PGIC uses a seven-point scale where one (1) equals very much improved and 
seven (7) equals very much worse. A summary of Patient Global Impression of Change 
(PGIC) at each visit, where measured will be provided.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
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.
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.
Adverse events will be assessed and graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03. 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 
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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 8.2.1
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 
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.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 


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sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.1.3
Adverse events of special interest
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 [Investigator Brochure].
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
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8.2.2
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.
8.3
Emergency unblinding of treatment assignment
Not applicable.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
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.


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Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes until delivery must be collected for the female partners of any males who
took study treatment in this study. Consent to report information regarding these pregnancy
outcomes should be obtained from the mother.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee
This study will institute a data monitoring committee (DMC) which will function 
independently of all other individuals associated with the conduct of this clinical trial, 
including the site investigators participating in the study. The DMC will be constituted prior 
to the randomization of the first patient. The DMC will be responsible to review safety data at 
approximately 6 months after the first randomized patient has started study treatment.
Subsequent reviews will be conducted approximately every 6 months on an as and when 
needed basis thereafter (ie. if significant safety findings are noted). This includes but does not 
limit the role of the DMC to evaluate these data and to provide recommendations to the 
sponsor to continue, modify or stop the study early. The DMC will be in place at least until 
the conduct of the primary analysis.
It is expected that the DMC will consist at a minimum of two physicians with appropriate 
disease area qualifications and one statistician. There will be a meeting with the DMC
describing their roles and responsibilities and discussing potential data format and process 
issues prior to the finalization of DMC charter.
It is envisioned that the DMC may make certain types of recommendations, namely:

No safety concerns, ethical to continue the study as planned

Serious safety concerns precluding further study treatment, regardless of efficacy

Recommendation to continue the study but proposing an amendment to the protocol (e.g., 
incorporate an additional safety assessments)
8.7
Steering Committee
In order to monitor study conduct, a Steering Committee (SC) will be established comprising 
investigators participating in the trial. Additionally two sponsor representatives (a physician 
and a statistician) will be active members of this committee.


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The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. Novartis will make 
final decisions on trial conduct based on SC recommendations. Together with the clinical trial 
team, the SC will review protocol amendments as appropriate, and also develop 
recommendations for publications of study results including authorship rules. The details of 
the role of the Steering Committee will be defined in a Steering Committee charter.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 


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treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient 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 recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria 
and documentation of SAEs. Additional checks of the consistency of the source data with the 
eCRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the 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 and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
Data collected by third parties (biochemistry, PCR assessments, biomarkers, PK) will be sent 
electronically to Novartis.
9.4
Database management and quality control
For studies using eCRFs, 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 WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using the Novartis Interactive Response Technology.


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For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
The data will be analyzed by Novartis and/or designated CRO. It is planned that the data from 
participating centers in this protocol will be combined, so that an adequate number of patients 
will be available for analysis.
Study data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, safety observations and measurements, and all 
relevant PK and PD measurements.
The cut-off date for the primary analysis is defined as the date when all patients have been on 
study for 24 weeks or early discontinued. The cut-off date for the final treatment phase
analysis is defined as 30 days after last patient last study drug to ensure that all available 
treatment phase data from all patients up to the last dose of study drug taken in this study, will
be analyzed and summarized in a final treatment phase CSR. Patients will be further followed 
up for survival and progression for up to 5 years from the date the last patient received the 
first study dose. An update analysis of OS and PFS will be performed at the end of the follow-
up period.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, patients will be analyzed 
according to the treatment and stratum they have been assigned to during the randomization 
procedure.
10.1.2
Safety set
The Safety Set includes all patients who received at least one dose of study treatment. 
Patients will be analyzed according to the study treatment received, where treatment received 
is defined as the randomized treatment if the patient took at least one dose of that treatment or 
the first treatment received if the randomized treatment was never received.
10.1.3
Per-Protocol set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the CSP. The PPS will be used for sensitivity analyses on the primary 
endpoint only.
Oncology standards for protocol deviations potentially leading to exclusion from the PPS are:

Type of indication different from those required by the CSP

If prior therapy does not match with CSP requirements in terms of number and types of 
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
Another anti-neoplastic therapy administered after start of study treatment and prior to 
first efficacy assessment

Study treatment received different from treatment assigned by randomization
10.1.4
Dose-determining analysis set
Not applicable.
10.1.5
Pharmacokinetic analysis set
The Pharmacokinetic analysis set (PAS) includes all patients who provide at least one 
evaluable PK concentration. For a concentration to be evaluable, patients are required to:

Take a dose of ABL001 prior to sampling,

Take the same dose of ABL001 for at least 3 consecutive days without dose interruption 
or dose modification prior to sampling,

For post-dose samples, do not vomit within 4 hours after the dosing of ABL001; For pre-
dose samples do not vomit within 4 hours after the dosing of ABL001 prior to sampling,

Have the pre-dose sample collected before the next dose administration
10.1.6
Other analysis sets
For duration of MMR and time to MMR, the MMR Responder Set will be used that includes 
patients who achieve MMR at any time.
For CCyR rates at and by scheduled time points, the CCyR Analysis Set will be used that 
includes patients who are not in CCyR at baseline.
For duration of CCyR and time to CCyR, the Cytogenetic Responder Set will be use that 
includes patients who do not have CCyR at baseline and achieve CCyR at any time.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS or the Safety Set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, by treatment group.
10.3
Treatments (study treatment, concomitant therapies, compliance)
The Safety set will be used for the analyses below.
Categorical data will be summarized as frequencies and percentages. For continuous data, 
mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
The duration of exposure in days to ABL001 and bosutinib, as well as the dose intensity 
(computed as the ratio of actual cumulative dose received and actual duration of exposure) 


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and the relative dose intensity (computed as the ratio of dose intensity and planned dose 
intensity) will be summarized by means of descriptive statistics.
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment group and all dosing data 
will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
10.4
Primary objective
The primary objective of the study is to evaluate the efficacy of ABL001 at the recommended 
dose in CML patients in chronic phase, previously treated with 2 or more tyrosine kinase 
inhibitors and to compare this efficacy profile in this population with that achieved by patients 
receiving bosutinib.
10.4.1
Variable
The primary efficacy variable of the study is the Major Molecular Response (MMR) rate at 24 
weeks. A patient will be counted as having achieved MMR at 24 weeks if he meets the MMR 
criteria (BCR-ABL ratio ≤0.1%) at 24 weeks.
10.4.2
Statistical hypothesis, model, and method of analysis
The MMR rate at 24 weeks will be calculated based on the FAS and according to the Intent 
To Treat (ITT) principle. MMR rate and its 95% confidence interval based on the Pearson-
Clopper method will be presented by treatment group. The confidence interval for the 
difference in MMR rate between treatment groups will be provided using the Wald method.
The null hypothesis is that there is no difference between the treatment groups with respect to 
MMR rate at 24 weeks. The Cochrane-Mantel-Haenszel chi-square test, stratified by the 
randomization stratification factor, i.e. major cytogenetic response status (PCyR or CCyR vs 
others) at screening, will be used to compare MMR rate between the two treatment groups, at 
the two-sided 5% level of significance. The Mantel-Haenszel estimate of the common risk 
difference and the corresponding 95% confidence interval will also be provided.
10.4.3
Handling of missing values/censoring/discontinuations
Only patients with MMR at 24 weeks are considered responders. In other words, any patient 
who achieves MMR before 24 weeks, but is no longer in MMR at 24 weeks, will be 
considered as a non-responder in this primary analysis. Patients discontinuing the randomized 
treatment prior to 24 weeks due to any reason will be considered as non-responders.
One exception to the rule above is if the 24-week PCR evaluation is missing, but both a PCR 
evaluation at 16 weeks and a PCR evaluation at 36 weeks indicate MMR, the 24-week 
assessment is imputed as a ‘Response’.


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10.4.4
Supportive and Sensitivity analyses
The analysis of the primary endpoint will also be repeated on the PPS if the PPS is different 
from the FAS.
Subgroup analyses and a logistic regression analysis will be employed. Refer to the 
exploratory objectives Section 10.6.1 for further details.
10.5
Secondary objectives
The secondary objectives in this study are as follows:

To compare additional parameters of the efficacy of ABL001 versus bosutinib, defined as:
Key secondary endpoints

MMR rate at 96 weeks
Other efficacy endpoints

Cytogenetic response (Complete, Partial, Major, Minor, Minimal, no response) rate at all 
scheduled data collection time points including24, 48 and 96 weeks.

Cytogenetic response (Complete, Partial, Major, Minor, Minimal, no response) rate by all 
scheduled data collection time points including, 24, 48 and 96 weeks.

MMR rate at all scheduled data collection time points (except 24 and 96 weeks which are 
already covered by primary and key secondary endpoints)

MMR rate by all scheduled data collection time points including 24, 48 and 96 weeks.

Time to MMR

Duration of MMR

Time to CCyR

Duration of CCyR

Time to treatment failure

Progression free survival

Overall survival

To compare the safety and tolerability profile of ABL001 versus bosutinib

To characterize the PK of ABL001 in the CML-CP population
10.5.1
Key secondary objective(s)
The key secondary endpoint to be evaluated is MMR rate at 96 weeks, which is defined as the 
proportion of patients with MMR at 96 weeks and derived in a similar fashion to MMR rate at 
24 weeks.


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10.5.1.1 Analysis for key secondary objectives
The null hypothesis is that there is no difference between the treatment groups with respect to 
MMR rate at 96 weeks. Formal statistical testing of the key secondary endpoint will be 
performed with = 0.05 (two-sided) only if the primary endpoint is significant by means of a 
gatekeeping procedure to control the overall alpha level.
MMR rate at 96 weeks will be evaluated in a similar fashion to the primary analysis of MMR 
rate at 24 weeks. The rate and the associated 95% confidence interval based on the Pearson-
Clopper method will be presented by treatment group. Confidence interval for the difference 
between treatment groups will be provided using the Wald method.
Statistical testing will be performed via CMH chi-square test stratified by the randomization 
strata. The Mantel-Haenszel estimate of the common risk difference and the corresponding 95% 
confidence interval will also be provided.
10.5.2
Other secondary efficacy objectives
Unless otherwise stated the FAS will be used for the analysis of all other secondary efficacy 
endpoints. The exceptions are using the Molecular Responder Set for duration of MMR and 
time to MMR, the CCyR Analysis Set for CCyR rates, and the Cytogenetic Responder Set for 
duration of CCyR and time to CCyR.
No statistical testing of non-key secondary efficacy endpoints will be performed, however a 
nominal p-value will be presented for exploratory purposes.
Molecular Response
MMR rates at scheduled time points (except 24 and 96 weeks which have been specified as 
primary and key secondary endpoints) will be evaluated in a similar fashion to the primary 
analysis of MMR rate at 24 weeks. Patients discontinuing the randomized treatment prior to a 
specific time point due to any reason will be considered as non-responders for that time point.
MMR rates by scheduled time points are defined as the proportion of patients who achieve 
MMR at or before the specified visit, i.e. if a patient achieves an MMR but then loses it before 
or at the visit, he/she will still be classed as achieving MMR by that time point.
For each endpoint the rate and the associated 95% confidence interval based on the Pearson-
Clopper method will be presented by treatment group. Confidence intervals for the differences 
in any response rates between treatment groups will be provided using the Wald method.
Statistical testing will be performed via CMH chi-square tests stratified by the randomization 
strata. The Mantel-Haenszel estimate of the common risk difference and the corresponding 95% 
confidence interval will also be provided.
Duration of MMR is defined in Section 7.2.1.1 as the time between the date of the first 
documented MMR and the earliest date of loss of MMR, progression to AP/BC, or CML-
related death for patients in the Molecular Responder Set. The time will be censored at the last 
molecular assessment (PCR) date on treatment for patients who have not experienced any of 
the above events.


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Duration of MMR will be analyzed by K-M method and presented by K-M plots. The 
estimated rates of patients who are still responding at various time points will also be 
provided using K-M method.
The cumulative incidence of MMR will be graphically displayed by an increasing step 
function. This curve will increase each time (after randomization) at which a new responder is 
observed and thus will increase up to the best observed response rate (e.g. up to 50% if half of 
the patients in the analysis population are able to achieve response).
Time to MMR is defined in Section 7.2.1.1 as: date of first MMR - date of randomization +1, 
for patients in the Molecular Responder Set. Descriptive statistics (range, median, quartiles, 
mean, sd) of time to MMR will be provided for the two treatment groups separately.
Cytogenetic Response
Patients in FAS will be categorized with counts and percentages provided for cytogenetic 
response (Complete, Partial, Major, Minor, Minimal, No Response) at and by (i.e. best 
response up to a specified time point) scheduled time points. Shift tables will also be 
employed to examine the changes in cytogenetic response category from baseline.
Since there are expected to be only very limited numbers who are actually in CCyR at 
baseline (due to the inclusion criteria requiring BCR-ABL ratio ≥ 1%) the analysis of CCyR 
rate at and by scheduled time points will only include patients who are not in CCyR at
baseline, i.e. the CCyR Analysis Set.
CCyR rates at and by scheduled time points etc. and the associated 95% confidence 
intervals based on the Pearson-Clopper method will be presented by treatment group with the 
analysis of these endpoints only including patients who are not in CCyR at baseline.
Confidence intervals for the differences in any response rates between treatment groups will 
be provided using the Wald method.
Statistical testing will be performed via CMH chi-square tests stratified by the randomization 
strata. The Mantel-Haenszel estimate of the common risk difference and the corresponding 95% 
confidence interval will also be provided.
Time to CCyR is defined for patients in the Cytogenetic Responder Set as: date of first CCyR 
- date of randomization +1. Descriptive statistics (range, median, quartiles, mean, sd) of time 
to CCyR will be provided for the two treatment groups separately.
The cumulative incidence of CCyR will also be graphically displayed by an increasing step 
function. This curve will increase each time (after randomization) at which a new responder is 
observed and thus will increase up to the best observed response rate.
Duration of CCyR is defined as the time between date of first documented CCyR and the 
earliest date of loss of CCyR, progression to AP/BC, or CML-related death for patients in the 
Cytogenetic Responder Set. The time will be censored at the last cytogenetic assessment date 
on treatment for patients for whom none of the above events is reported or last PCR 
evaluation on treatment indicating MMR.


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Duration of CCyR response will be analyzed by K-M method and presented by K-M plots. 
The estimated rates of patients who are still responding at various time points will also be 
provided using K-M method.
Treatment failure, disease progression and survival
Time to treatment failure (TTF) is defined as the time from date of randomization to an 
event of treatment failure. The following events will constitute ‘treatment failure’, and are 
based on the ELN criteria (Bacarrani 2013) defining failure of a second line treatment adapted 
to include discontinuation of randomized treatment as an event:

No CHR or > 95% Ph+ metaphases at three months after randomization or thereafter

BCR-ABL ratio > 10% IS and/or > 65% Ph+ metaphases at six months after 
randomization or thereafter

BCR-ABL ratio > 10% IS and/or > 35% Ph+ metaphases at 12 months after 
randomization or thereafter

Loss of CHR, CCyR or PCyR at any time after randomization

Detection of new BCR-ABL mutations at any time after randomization

Confirmed loss of MMR in 2 consecutive tests, of which one must have a BCR-ABL ratio 
≥ 1% IS 6 months after randomization

New clonal chromosome abnormalities in Ph+ cells: CCA/Ph+: at any time after 
randomization

Discontinuation from randomized treatment for any reason
For patients who have not reach treatment failure, their TTFs will be censored at the time of 
last study assessment (PCR, cytogenetic, hematologic or extramedullary).
Progression-Free-Survival (PFS) is defined as the time from the date of randomization to 
the earliest occurrence of documented disease progression to AP/BC or the date of death from 
any cause (including progressions and deaths observed during the survival follow-up period).
The time will be censored at the date of last study assessment (PCR, cytogenetic, hematologic 
or extramedullary) or last post-treatment follow-up for patients without event.
Overall survival (OS) is defined as the time from the date of randomization to the date of 
death (including the survival follow-up period). Patients who are alive at the time of the 
analysis data cutoff date will be censored at the date of last contact before the cut-off date.
TTF, PFS and OS will be estimated and graphically displayed using the K-M approach. The 
estimated rates by K-M method at various time points will be provided and the endpoints will 
be compared between the two treatment groups using stratified log-rank test stratified by the 
randomization strata. The hazard ratio and 95% confidence intervals will be computed from a 
stratified Cox model.


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10.5.3
Safety objectives
10.5.3.1 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 group.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of subject’s first informed consent to the day before first 
administration of study treatment
2. on-treatment period: from day of first administration of study treatment to 30 days after 
last actual administration of the same study treatment (including start and stop date)
3. post-treatment period: starting at day 31 after last administration of any study treatment
Summary tables for safety data will be presented for the on-treatment period. Comparative 
analysis will be performed only for the on-treatment period. Listings of safety data will 
include pre-treatment, on-treatment, and post-treatment periods, with a flag to indicate data 
collected before or after the on-treatment period.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs.
The incidence of treatment-emergent adverse events (new or worsening from baseline) 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, non-serious adverse events and adverse events of special interest
(AESI) during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre-treatment, on-
treatment and post-treatment periods) will be listed and those collected before or after the on-
treatment period will be flagged.
10.5.3.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. 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 v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following listings and summaries will be generated separately for hematology, and 
biochemistry tests:


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
Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v4.03

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline in the on-treatment period.

Shift tables using CTCAE grades to compare respective baseline to the worst on-treatment 
value
For laboratory tests where grades are not defined by CTCAE v4.03,

Shift tables using the low/normal/high/ (low and high) classification to compare respective 
baseline to the worst on-treatment value.
10.5.3.4 Other safety data
ECG
ECGs (12-lead) including PR, QRS, QT, QTcF, and HR intervals will be obtained for each 
subject during the study. ECG data will be read and interpreted centrally.
Categorical analysis of QT/QTc interval data based on the number of patients meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these patients will be produced by treatment group.
Vital signs
Data on vital signs will be tabulated and listed, notable values will be flagged.
10.5.3.5 Supportive analyses for secondary objectives
Not applicable.
10.5.3.6 Tolerability
Tolerability of each study treatment will be assessed by summarizing the number of subjects
with dose interruptions and dose reductions. Reasons for dose interruptions and dose 
reductions will be listed by subject and summarized.
10.5.4
Secondary PK objectives
The PK objective is to characterize the PK of ABL001 in CML population.
Using PAS, summary statistics (n, mean, SD, coefficient of variation (CV) for mean, 
geometric mean, CV for geometric mean, median, minimum and maximum) will be presented 
for plasma concentration at each scheduled time point. The geometric mean with mean (SD) 
and individual plasma concentration versus time profiles of ABL001 will be displayed 
graphically.
Using Safety set, concentration data will be listed. Concentration values below the limit of 
quantification (BLQ) will be set to zero by the Bioanalyst and displayed in listings as zero 


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with a flag. BLQ values will be handled as zero in any calculations of summary statistics, but 
handled as missing for the calculation of the geometric means and CVs.
Pharmacokinetic parameters will be determined by non-compartmental method(s) using the 
pharmacokinetic profile of ABL001 in patients with full PK sampling. PK parameters listed in 
Table 10-1 will be derived and reported, when feasible.
Population PK modeling may be performed and the results may be reported in a separate 
population PK report. Data from this study may be combined with data from other studies for 
this analysis.
Table 10-1
Non compartmental pharmacokinetic parameters in full PK group
AUC0-12h
The area under the plasma concentration-time curve from time zero to 12 h (mass x time x 
volume-1)a
Cmax
The maximum (peak) observed plasma drug concentration after dose administration (mass x 
volume-1)
Tmax
The time to reach maximum (peak) plasma drug concentration after dose administration (time)
CL/F
The total body clearance of drug from the plasma after oral administration (volume x time-1)
10.6
Exploratory objectives
10.6.1
Exploratory efficacy objectives

To evaluate the influence of factors such as major cytogenetic status at baseline, 
failure/intolerance to prior TKIs, line of therapy, gender, race and age on the effect of 
ABL001 with respect to the primary efficacy endpoint.

To characterize mutations in the BCR-ABL1 gene at baseline and at end of treatment and 
examine their association with molecular and cytogenetic response for ABL001 vs 
bosutinib
10.6.1.1 Data analysis of exploratory efficacy objectives
Subgroup analyses will be performed to evaluate the influence of factors such as baseline 
major cytogenetic response status, baseline BCR-ABL ATP-binding site mutation status 
(from local historical record and from Sanger Sequencing), failure/intolerance to prior TKIs, 
line of therapy, gender, race and age on the primary efficacy endpoint. In addition, a logistic 
regression analysis will incorporate the key baseline variables into the model to further 
evaluate the impact of these variables on the primary endpoint and to provide a treatment 
effect estimate which is adjusted for imbalances in the treatment groups. An adjusted odds 
ratio for the treatment effect with associated 95% confidence intervals will be presented.
Mantel-Haenszel estimates of the common odds ratio and the corresponding 95% confidence 
interval will also be provided.






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additional outpatient office visits general practitioner, specialist, and urgent care visits from 
Baseline up to End of Study. Hospitalization visits will also record the number of days on 
ward and the type of ward (hospital unit) and the discharge status. At each RU collected, the 
reason for the visit, i.e. related to CML, AE or other reason, will be collected, in order to 
quantify the impact of treatment on healthcare resources.
10.6.4.2 Patient Reported Outcomes
The MDASI CML, PGIC along with EQ-5D-5L will be used to compare data on the patient’s 
disease-related symptoms and health-related quality of life from baseline to EOT between the 
treatment arms. The WPAI will be used to assess work productivity and activity impairment 
related to the patient’s CML. All measures will assess differences between the treatment arms.
Patients with an evaluable baseline score and at least one evaluable post baseline score during 
the treatment period will be included in the change from baseline analyses. Missing data items 
in a scale will be handled according to the manual for each instrument. No imputation will be 
applied if the total or subscale scores are missing at a visit.
10.7
Interim analysis
No formal interim analysis is planned for this trial. As described in Section 10, three formal 
analyses are planned: the primary at week 24, another at the 96-week end of study treatment 
and a PFS/OS update at year 5.

24-week primary analysis: Formal testing of the primary endpoint with full alpha will be 
performed. Analyses of other efficacy endpoints at and by 24 weeks will also be 
performed.

96-week end of study treatment analysis: Formal statistical testing of the key secondary 
endpoint will be performed with = 0.05 (two-sided) only if the primary endpoint is 
significant. Analyses of other efficacy endpoints (including MMR rate at 48 weeks) will 
also be performed.

5-year PFS/OS update analysis: PFS and OS
In addition DMC safety analyses will be conducted as described in Section 8.6.
10.8
Sample size calculation
To test the null hypothesis that the response rate is equal in the two groups, based on two-
sided 5% level of significance and with 90% power, 222 patients will be needed in total (i.e. 
148 patients in the ABL001 arm and 74 patients in the bosutinib arm based on 2:1 
randomization allocation). This assumes that ABL001 leads to a 20% improvement in the 
MMR rate at 24 weeks over bosutinib from 15% to 35% which corresponds to an odds ratio 
of 3.05.
The assumed bosutinib MMR rate of 15% at 24 weeks is based on previous trials evaluating 
bosutinib therapy (Khoury 2012, Gambacorti-Passerini 2014, García-Gutiérrez 2015).


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10.9
Power for analysis of key secondary variables
If the primary analysis of MMR rate at 24 weeks is statistically significant, then the key 
secondary endpoint MMR rate at 96 weeks will be tested, with the overall alpha controlled at 
the 5% two-sided level. The testing will use a gatekeeping strategy. Full details of the testing 
strategy are provided in Section 10.5.1.
Table 10-2 below summarizes the treatment effects of the key secondary endpoint which can 
be detected with 80% and 90% power, based on the specified assumptions regarding the 
bosutinib effect. The calculations were made using the software package PASS (2008).
Table 10-2
Detectable effect sizes for key secondary endpoint
Endpoint
Anticipated effect 
with bosutinib
2-sided alpha
Power
Detectable effect 
size§
MMR rate at 96 weeks
30%*
0.05
90%
80%
≥ 23%
≥ 20%
*: Gambacorti-Passerini et al. 2014, Figure 1D.
§: Absolute difference from the anticipated effect with bosutinib.
For MMR rate at 96 weeks, if the anticipated effect with bosutinib is 30%, then the given 
sample size with 2-sided alpha=0.05 would allow to detect an absolute difference of at least 
23% (i.e. MMR rate at 96 weeks with ABL001 is at least 53%) for 90% power and of at least 
20% (i.e. MMR rate at 96 weeks with ABL001 is at least 50%) for 80% power.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. 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 Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.


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11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their eCRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication 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 requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
Additional consent form
Not applicable.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www.clinicaltrials.gov before study 
start. In addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., LPLV), those for interventional clinical trials involving 
pediatric patients within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no 
honorarium provided for such presentations.


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As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research,
please refer to www.novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study electronic case report form (eCRF) is the primary 
data collection instrument for the study. The investigator should ensure the accuracy, 
completeness, legibility, and timeliness of the data reported in the eCRFs and all other 
required reports. Data reported on the eCRF, that are derived from source documents, should 
be consistent with the source documents or the discrepancies should be explained. All data 
requested on the eCRF must be recorded. Any missing data must be explained. For electronic 
CRFs an audit trail will be maintained by the system.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.


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11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the 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/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
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/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient 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 (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.


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13
References (available upon request)
[Baccarani M, Deininger DW, Rosti G, et al (2013)] European LeukemiaNet 
recommendations for the management of chronic myeloid leukemia: 2013. Blood; 
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[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.
[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.
[Brooks R (1996)] EuroQol: the current state of play. Health Policy 37(1):53-72.
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in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science; 247(4944):824-30.
[EuroQol Group (1990)] EuroQol-a new facility for the measurement of health-related quality 
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[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.
[Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, Bonsel G, Badia X. (2011)]
Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). 
Quality of Life Research 20(10):1727-1736.
[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.
[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.
[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 
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[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.
[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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[Soverini S, Branford S, Nicolini FE, et al (2014)] Implications of BCR-ABL1 kinase 
domain-mediated resistance in chronic myeloid leukemia. Leuk Res; 38(1):10-20.
[Vardiman J.W. (2009)] Chronic Myelogenous Leukemia, BCR-ABL+. Am J Clin Pathol; 
132:250-260.
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14
Appendices
14.1
Appendix 1 List of CYP3A4 inducers, inhibitors and substrates
Table 14-1
CYP3A4 inducers
Category
Drug Names
Strong inducers 
of CYP3A41
avasimibe, carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, 
rifampin, St. John’s wort (HYPERICUM PERFORATUM)5
Moderate 
inducers of 
CYP3A42
bosentan, efavirenz, etravirine, lersivirine, lopinavir, modafinil, nafcillin, ritonavir/tipranavir, 
semagacestat4, talviraline4, thioridazine
Weak inducers 
of CYP3A43
amprenavir, aprepitant, armodafinil bexarotene, boceprevir, brivacetam, clobazam, danshen5, 
dexamethasone, echinacea5, eslicarbazepine, gingko (ginkgo biloba)5, ginseng5, glycyrrhizin5, 
honey6, quercetin6, methylprednisolone, nevirapine, oxcarbazepine, pioglitazone, pleconaril4, 
prednisone, primidone, raltegravir, ritonavir, rufinamide, sorafenib, Stribild (combo of 
elvitegravir, cobicistat, emtricitabine, and tenofovir), sulfinpyrazone, telaprevir, terbinafine, 
ticagleror, ticlopidine, topiramate, troglitazone4, vemurafenib, vicriviroc/ritonavir, vinblastine, 
yin zhi huang5
1 A strong inducer for a specific CYP is defined as an inducer that decreases the AUC of a sensitive substrate for 
that CYP by equal or more than 80%.
2 A moderate inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that 
CYP by 50-80%.
3 A weak inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that CYP 
by 20-50%.
4 Drugs not available in the US Market.
5 Herbal product.
6 Food product.
This list was based on information from the FDA’s “Guidance for Industry, Drug Interaction 
Studies”, from the Indiana University School of Medicine’s “Clinically Relevant” Table, from 
the University of Washington’s Drug Interaction Database. This list may not be 
comprehensive and may be updated periodically. Refer to Novartis Oncology Clinical 
Pharmacology Internal Memorandum, Drug-drug interactions (DDI) Database (last updated 
2016) for update or more details.


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Table 14-2
CYP3A4 inhibitors
Category
Drug Names
Strong 
inhibitors of 
CYP3A41
boceprevir, cobicistat (GS-9350), conivaptan, clarithromycin, danoprevir/ritonavir12, delalisib, 
darunavir/ritonavir12, elvitegravir/ritonavir12, grapefruit product11, indinavir, indinavir/ritonavir12, 
itraconazole, ketoconazole, LCL161, lopinavir/ritonavir12, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, saquinavir/ritonavir12, telaprevir, telithromycin, 
tipranavir/ritonavir12, troleandomycin, VIEKIRA PAK2, voriconazole
Moderate 
inhibitors of 
CYP3A42
ACT-178882, amprenavir, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, crizotinib, 
cyclosporine, Erythromycin, darunavir, diltiazem, dronedarone, FK1706Ferula asafetida resin 
(Ferula assa-foetida)4, faldaprevir, fluconazole7, imatinib, isavuconazole, netupitant, nilotinib, 
schisandra, sphenanthera, tofisopam, verapamil
Weak 
inhibitors of 
CYP3A43
almorexant, alprazolam, AMD070, amiodarone, amlodipine, atorvastatin, AZD2327, 
azithromycin, berberine, bicalutamide, blueberry juice5, chlorzoxazone, cilostazol, clotrimazole, 
cranberry juice5, daclatasvir, delavirdine, evacetrapid, everolimus, fosaprepitant (IV), 
fluvoxamine8, fostamatinib, Garden Cress seeds (Lepidium sativum)5, ginkgo4, goldenseal4, 
Guan Mai Ning13, GSK1292263, GSK2248761, isoniazid, ivacaftor, lacidipine, linagliptin, 
lomitapide, M100240, oral contraceptives, palbociclib, pazopanib, peppermint oil, propiverine, 
ranitidine, ranolazine, resveratrol, roxithromycin, Seville orange juice5, simeprevir, sitaxentan, 
suvorexant, tabimorelin, tacrolimus, teriflunomide, ticagrelor, tolvaptan, Tong Xin Luo13
1 A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by equal or more than 5-fold.
2 A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by less than 5-fold but equal to or more than 2-fold.
3 A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by less than 2-foldbut equal to or more than 1.25-fold.
4 Herbal product.
5 Food product.
6 Gemfibrozil also inhibits OATP1B1. Applicable for another class of CYP inhibitor.
7 Fluconazole is listed as a strong CYP2C19 inhibitor based on the AUC ratio of omeprazole, which is also 
metabolized by CYP3A; fluconazole is a moderate CYP3A inhibitor.
8 Fluvoxamine strongly inhibits CYP1A2 and CYP2C19, but also inhibits CYP2C8/2C9 and CYP3A.
9 Ticlopidine strongly inhibits CYP2C19, but also inhibits CYP3A, CYP2B6, and CYP1A2. The inhibition of 
CYP3A4 by ticlopidine is not strong although the actual class of its inhibition on CYP3A4 (moderate vs weak) has 
yet to be defined.
10 Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol. Applicable for another class of CYP inhibitor.
11 The effect of grapefruit product varies widely among brands and is concentration-, dose-, and preparation-
dependent. 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).
12 Combination therapy.(in some cases combinations with ritonavir have been listed as moderate inhibitors of 
CYP3A in the UW database, the have all been listed as strong in the DDI guide to avoid any potential confusion).
13 Traditional Chinese medicine.
This list is based on information from the FDA’s “Guidance for Industry, Drug Interaction 
Studies”, from the Indiana University School of Medicine’s “Clinically Relevant” Table and 
from the University of Washington’s Drug Interaction Database. Please note that this is not an 
exhaustive list. Please refer to footnotes. Refer to Novartis Oncology Clinical Pharmacology 
Internal Memorandum, Drug-drug interactions (DDI) Database (last updated 2016) for update 
or more details.


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Table 14-3
CYP3A4 substrates: Narrow therapeutic index, sensitive, and others
Category
Drug Names
Narrow Therapeutic 
index substrates of 
CYP3A41
alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfanadine, thioridazine
Sensitive substrates 
of CYP3A42
alpha-dihydroergocryptine, alfentanil, almorexant, alisoporivir, aplaviroc, aprepitant, 
atazanavir, atorvastatin, avanafil, bosutinib, brecanavir, brotizolam, budesonide, 
buspirone, capravirine, casopitant, conivaptan, danoprevir, darifenacin, darunavir, 
dasatinib, dronedarone, ebastine, eletriptan, elvitegravir, eplerenone, everolimus, 
felodipine, fluticasone, ibrutinib, indinavir, ivacaftor, levomethadyl, lomitapide, lopinavir, 
lovastatin, lumefantrine, lurasidone, maraviroc, midazolam, midostaurin, naloxegol, 
neratinib, nisoldipine, perospirone, quetiapine, ridaforolimus, saquinavir, sildenafil, 
simeprevir, simvastatin, tacrolimus, terfenadine, ticagrelor, tilidine,tipranavir, tolvaptan, 
triazolam, ulipristal, vardenafil, vicriviroc, voclosporin.
Other Substrates of 
CYP3A43
alprazolam, ambrisentan, amlodipine, antipyrine, aripiprazole, artemether, avosentan, 
boceprevir, bosentan, buprenorphine, carbamazepine, dexloxiglumide, 
dextromethorphan, diazepam, docetaxel, enzalutamide, gemigliptin, halofantrine, 
imipramine, lansoprazole, lidocaine, linagliptin, loperamide, loratadine, losartan, 
lurasidone, macitentan, methadone, mirodenafil, montelukast, morphine, nelfinavir, 
netupitant, nevirapine, nifedipine, nilotinib, nitrendipine, omeprazole, ospemifene, 
oxycodone, paclitaxel, pazopanib, pioglitazone, quinine, ranolazine, repaglinide, rifabutin, 
ritonavir, roflumilast, saxagliptin, selegiline, sertraline, sibutramine, sotrastaurine, 
telaprevir, theophylline, tirilazad, tolterodine, udenafil, ulipristal, vincristine, voriconazole
Narrow Therapeutic 
index substrates of 
CYP2C9
warfarin (also sensitive), phenytoin
Narrow Therapeutic 
index substrates of 
CYP2C8
paclitaxel
1 Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with a 
known potent inhibitor.
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades 
de Pointes).
3 Other substrates are these that have shown an in vivo ≥2-fold increase in AUC with co-administration of an 
inhibitor based on the UW database. 
This list of CYP substrates was compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table; from the FDA’s “Guidance for Industry, Drug Interaction 
Studies” and from the University of Washington’s Drug Interaction Database. This list may 
not be comprehensive and may be updated periodically. Refer to Novartis Oncology Clinical 
Pharmacology Internal Memorandum, Drug-drug interactions (DDI) Database (last updated 
2016) for update or more details.


Clinical Development
Asciminib/ABL001
Oncology Clinical Trial Protocol CABL001A2301
A phase 3, multi-center, open-label, randomized study of 
oral ABL001 (asciminib) versus bosutinib in patients with 
Chronic Myelogenous Leukemia in chronic phase (CML-
CP), previously treated with 2 or more tyrosine kinase 
inhibitors
Document type
Amended Protocol Version
EUDRACT number
2016-002461-66
Version number
03 (Clean)
Development phase
III
Document status
Final
Release date
14-Dec-2018
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 19-Nov-2015


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary:.............................................................................................................11
Amendment 3 (14-Dec-2018)............................................................................................17
Amendment 2 (13-Jul-2018) .............................................................................................23
Amendment 1 (10-Apr-2017)............................................................................................29
1
Background........................................................................................................................31
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............31
1.2
Introduction to investigational treatment...............................................................32
1.2.1
Overview of asciminib (ABL001) ........................................................32
1.2.2
Overview of bosutinib...........................................................................38
2
Rationale............................................................................................................................39
2.1
Study rationale and purpose...................................................................................39
2.2
Rationale for the study design ...............................................................................39
2.2.1
Rationale for Biomarker Assessment....................................................40
2.3
Rationale for dose and regimen selection..............................................................41
2.4
Rationale for choice of combination drugs............................................................42
2.5
Rationale for choice of comparators drug bosutinib..............................................42
2.6
Risks and benefits..................................................................................................42
3
Objectives and endpoints...................................................................................................43
4
Study design ......................................................................................................................47
4.1
Description of study design ...................................................................................47
4.1.1
Study treatment switch from bosutinib to asciminib.............................48
4.2
Timing of interim analyses and design adaptations...............................................48
4.3
Definition of end of study......................................................................................48
4.4
Early study termination..........................................................................................49
5
Population..........................................................................................................................49
5.1
Patient population..................................................................................................49
5.2
Inclusion criteria ....................................................................................................49
5.3
Exclusion criteria...................................................................................................51
6
Treatment...........................................................................................................................53
6.1
Study treatment......................................................................................................53


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6.1.1
Dosing regimen.....................................................................................53
6.1.2
Ancillary treatments..............................................................................54
6.1.3
Rescue medication ................................................................................54
6.1.4
Guidelines for continuation of treatment ..............................................54
6.1.5
Treatment duration................................................................................54
6.2
Dose escalation guidelines.....................................................................................55
6.3
Dose modifications................................................................................................55
6.3.1
Dose modification and dose delay ........................................................55
6.3.2
Dose adjustments for QTcF prolongation.............................................64
6.3.3
Follow-up for toxicities.........................................................................65
6.3.4
Anticipated risks and safety concerns of the study drug.......................66
6.4
Concomitant medications for patients on asciminib..............................................66
6.4.1
Permitted concomitant therapy .............................................................66
6.4.2
Permitted concomitant therapy requiring caution and/or action...........67
6.4.3
Prohibited concomitant therapy ............................................................67
6.4.4
Other concomitant medications.............................................................68
6.5
Concomitant medications for patients on bosutinib ..............................................69
6.5.1
Permitted concomitant therapy requiring caution.................................69
6.5.2
Prohibited concomitant therapy ............................................................70
6.6
Patient numbering, treatment assignment or randomization .................................70
6.6.1
Patient numbering .................................................................................70
6.6.2
Treatment assignment or randomization...............................................71
6.6.3
Treatment blinding................................................................................71
6.7
Study drug preparation and dispensation...............................................................71
6.7.1
Study treatment packaging and labeling ...............................................72
6.7.2
Drug supply and storage........................................................................72
6.7.3
Study drug compliance and accountability ...........................................72
6.7.4
Disposal and destruction .......................................................................73
7
Visit schedule and assessments .........................................................................................73
7.1
Study flow and visit schedule................................................................................73
7.1.1
Molecular pre-screening........................................................................92
7.1.2
Screening...............................................................................................92
7.1.3
Run-in period ........................................................................................95
7.1.4
Treatment period...................................................................................95
7.1.5
Visit windows........................................................................................95
7.1.6
Discontinuation of study treatment .......................................................96


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7.1.7
Withdrawal of consent ..........................................................................97
7.2
Assessment types...................................................................................................98
7.2.1
Efficacy assessments.............................................................................98
7.2.2
Safety and tolerability assessments.....................................................100
7.2.3
Pharmacokinetics ................................................................................107
7.2.4
Biomarkers..........................................................................................108
7.2.5
Resource utilization.............................................................................111
7.2.6
Patient reported outcomes...................................................................111
8
Safety monitoring and reporting......................................................................................113
8.1
Adverse events.....................................................................................................113
8.1.1
Definitions and reporting ....................................................................113
8.1.2
Laboratory test abnormalities..............................................................114
8.1.3
Adverse events of special interest.......................................................115
8.2
Serious adverse events.........................................................................................115
8.2.1
Definitions...........................................................................................115
8.2.2
Reporting.............................................................................................115
8.3
Emergency unblinding of treatment assignment .................................................116
8.4
Pregnancies..........................................................................................................116
8.5
Warnings and precautions....................................................................................117
8.6
Data Monitoring Committee................................................................................117
8.7
Steering Committee .............................................................................................117
9
Data collection and management.....................................................................................118
9.1
Data confidentiality .............................................................................................118
9.2
Site monitoring ....................................................................................................118
9.3
Data collection.....................................................................................................119
9.4
Database management and quality control..........................................................119
10 Statistical methods and data analysis ..............................................................................119
10.1
Analysis sets ........................................................................................................120
10.1.1
Full Analysis Set .................................................................................120
10.1.2
Safety set .............................................................................................120
10.1.3
Per-Protocol set ...................................................................................120
10.1.4
Dose-determining analysis set.............................................................120
10.1.5
Pharmacokinetic analysis set...............................................................121
10.1.6
Other analysis set ................................................................................121
10.2
Patient demographics/other baseline characteristics ...........................................121
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................121


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10.4
Primary objective.................................................................................................122
10.4.1
Variable...............................................................................................122
10.4.2
Statistical hypothesis, model, and method of analysis........................122
10.4.3
Handling of missing values/censoring/discontinuations.....................122
10.4.4
Supportive and Sensitivity analyses....................................................123
10.5
Secondary objectives ...........................................................................................123
10.5.1
Key secondary objective(s).................................................................123
10.5.2
Other secondary efficacy objectives ...................................................124
10.5.3
Safety objectives .................................................................................127
10.5.4
Secondary PK objectives.....................................................................128
10.6
Exploratory objectives.........................................................................................129
10.6.1
Exploratory efficacy objectives...........................................................129
10.6.2
Exploratory PK objectives ..................................................................130
10.6.3
Exploratory biomarker objectives.......................................................130
10.6.4
Exploratory Patient Reported Outcomes objectives ...........................131
10.7
Interim analysis....................................................................................................132
10.8
Sample size calculation........................................................................................132
10.9
Power for analysis of key secondary variables....................................................133
11 Ethical considerations and administrative procedures ....................................................133
11.1
Regulatory and ethical compliance......................................................................133
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................133
11.3
Informed consent procedures...............................................................................134
11.4
Discontinuation of the study................................................................................134
11.5
Publication of study protocol and results.............................................................134
11.6
Study documentation, record keeping and retention of documents.....................135
11.7
Confidentiality of study documents and patient records .....................................136
11.8
Audits and inspections.........................................................................................136
11.9
Financial disclosures............................................................................................136
12 Protocol adherence ..........................................................................................................136
12.1
Amendments to the protocol................................................................................136
13 References (available upon request)................................................................................137
14 Appendices ......................................................................................................................139
14.1
Appendix 1 List of concomitant medications for patients on asciminib .............139
14.2
Appendix 2 List of concomitant medications for patients on bosutinib..............141


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List of figures
Figure 1-1
KCL-22 CML Xenograft.......................................................................33
Figure 4-1
Schematic of Study Design ...................................................................48
List of tables
Table 3-1
Objectives and related endpoints ..........................................................44
Table 6-1
Dose and treatment schedule.................................................................54
Table 6-2
Criteria for dose reduction/interruption and re-initiation of 
asciminib and bosutinib treatment for adverse drug reactions..............56
Table 6-3
Dose reduction steps for asciminib and bosutinib.................................64
Table 6-4
Packaging and labeling .........................................................................72
Table 7-1
Visit evaluation schedule ......................................................................74
Table 7-2 
Visit evaluation schedule (study treatment switch phase) ....................84
Table 7-3
Blood samples (efficacy primary endpoint)..........................................99
Table 7-4
ECOG Performance status scale .........................................................102
Table 7-5
Central clinical laboratory parameters collection plan........................103
Table 7-6
Central ECG collection (all patients)..................................................105
Table 7-7
Central ECG collection plan for patients in full PK asciminib group.105
Table 7-8
Pharmacokinetic blood collection log (Sparse PK-group-asciminib 
arm/ asciminib treatment switch patients)...........................................107
Table 7-9
Pharmacokinetic blood collection log (Full PK group-asciminib 
arm) .....................................................................................................108
Table 7-10
Biomarker sample collection plan.......................................................110
Table 10-1
Non compartmental pharmacokinetic parameters in full PK group....129
Table 10-2
Detectable effect sizes for key secondary endpoint ............................133
Table 14-1
Prohibited concomitant medications for asciminib arm......................139
Table 14-2
Concomitant medications to be used with caution in asciminib arm..140
Table 14-3
Prohibited concomitant medications for bosutinib arm ......................141
Table 14-4
Concomitant medications to be used with caution in bosutinib arm ..141


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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
AP
Accelerated phase
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATP
Adenosine triphosphate
AUC
Area under the curve
AV block
Atrioventricular block
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
BMA
Bone marrow aspirate
BUN
Blood urea nitrogen
CBC
Complete Blood Count
CCA
Clonal chromosome abnormalities
CCyR
Complete Cytogenetic Response
CD8
Cluster of differentiation 8
CD34
Cluster of differentiation 34
CHR
Complete Hematological Response
CI
Confidence Interval
CMH
Cochran–Mantel–Haenszel
CML
Chronic Myelogenous Leukemia
CML-AP
Chronic Myelogenous Leukemia-Accelerated Phase
CMO&PS
Chief Medical Office and Patient Safety
CP
Chronic phase
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
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DLCO
Carbon monoxide diffusing capacity
DMC
Data Monitoring Committee
DNA
Desoxyribonucleic acid
DS&E
Drug Safety and Epidemiology
ECG
Electrocardiogram


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ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic data capture
ELN
European Leukemia Network
EOT
End of Treatment
ERT
Electronic Research Technology, Inc
EU
European Union
FAS
Full Analysis Set
FIH
First In Human
GDPR
General Data Protection Regulation
GFR
Glomerular Filtration Rate
hADME
Human ADME study (Absorption, Distribution, Metabolism and Excretion) 
HDL
High density lipoprotein
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INN
International Nonproprietary Name
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
K-M
Kaplan-Meyer
Km
Michaelis-Menten constant
LDL
Low density lipoprotein
LFT
Liver function test
LLN
Lower limit of normal
MCyR
Major Cytogenetic Response
mCyR
Minor Cytogenetic Response
MDASI-CML
MD Anderson Symptom Inventory – Chronic Myelogenous Leukemia
MMR
Major Molecular Response
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NGS
Next Generation Sequencing
NTI
Narrow Therapeutic Index
OS
Overall survival
PAS
Pharmacokinetic analysis set
PBPK
Physiologically based pharmacokinetic
PCR
Polymerase Chain Reaction
PCyR
Partial Cytogenetic Response
PD
Pharmacodynamic
PGIC
Patient Global Impression of Change
P-gp
Permeability glycoprotein


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Ph+
Philadelphia chromosome positive
PHI
Protected Health Information
PK
Pharmacokinetics
PLT
Platelets
PPS
Per-protocol set
QD
Quaque die/once a day
QT
Q to T interval (ECG)
QTcF
QTc Fredericia
REB
Research Ethics Board
RNA
Ribonucleic acid
RQ-PCR
Real time quantitative polymerase chain reaction
RU
Resource Utilization
SAE
Serious Adverse Event
SAP
The Statistical Analysis Plan (SAP) is a regulatory document which provides evidence of 
preplanned analyses
SC
Steering committee
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT 
Serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
TBIL
Total bilirubin
TdP
Torsades de Pointes
TKI
Tyrosine Kinase Inhibitor
TTF
Time to treatment failure
UGT
Uridin diPhospho-glucuronosyltransferase
ULN
Upper limit of normal
US
United States
USPI
US prescribing information
WBC
White blood cell count
WPAI
Work Productivity and Activity Impairment


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Glossary of terms
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 subject or study patient
Cycles
Number and timing or recommended repetitions of therapy are usually expressed 
as number of days (e.g. q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are 
tested in a fixed combination. Investigational treatment generally does not include 
other study treatments administered as concomitant background therapy required 
or allowed by the protocol when used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment
Subject Number (Subject 
No.)
A unique identifying number assigned to each patient/subject/healthy volunteer 
who enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Personal Data
Subject information collected by the Investigator that is transferred to Novartis for 
the purpose of the clinical trial. This data includes subject identifier information, 
study information and biological samples.
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason
Treatment group
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points
Withdrawal of study 
consent
Withdrawal of consent from the study occurs only when a subject does not want 
to participate in the study any longer, and does not allow any further collection of 
personal data


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Protocol summary:
Title
A phase 3, multi-center, open-label, randomized study of oral ABL001 (asciminib) versus 
bosutinib in patients with Chronic Myelogenous Leukemia in chronic phase (CML-CP), 
previously treated with 2 or more tyrosine kinase inhibitors
Brief title
Study of efficacy of CML-CP patients treated with asciminib versus bosutinib, previously 
treated with 2 or more TKIs
Sponsor and
Clinical Phase
Novartis
Phase 3
Investigation type
Drug 
Study type
Interventional
Purpose and 
rationale
Purpose:
The purpose of this pivotal study is to compare the efficacy of asciminib with that of 
bosutinib in the treatment of patients with CML-CP having previously been treated with a 
minimum of two prior ATP-binding site TKIs with BCR-ABL1 ratios ≥ 1% IS at screening.
Patients intolerant to the most recent TKI therapy must have BCR-ABL1 ratio > 0.1% IS 
at screening and patients failing their most recent TKI therapy must meet the definition 
of treatment failure as per the 2013 ELN guidelines (Baccarani et al 2013). No more 
than 66 patients (approximately 30% of the overall trial population) that are intolerant to 
their most recent TKI therapy with BCR-ABL1< 1% will be recruited in order to ensure 
that the CML third line patient population is adequately represented.
Rationale:
There remains an unmet need for new compounds in patients with CML who have failed 
at least two prior TKIs. Current practice suggests that a second generation TKI will have 
been used for first line therapy for about one half of patients with CML, meaning that 
most patients who have failed at least two prior TKIs will have failed at least one if not 
two second generation TKIs (such as dasatinib and/or nilotinib). Potentially, such 
patients may also have failed bosutinib and/or ponatinib (Soverini 2014). Patients having 
failed at least two TKIs may have limited sensitivity to the remaining available agents 
and, thus, there exists a need for new safe and effective therapy. In addition, mutations 
will have developed in 21 to 33% of patients that prevent the use of specific TKIs, 
increasing the need for a better and alternative compound (Soverini 2014). 
Omacetaxine, a chemotherapeutic agent, is available for patients who have failed at 
least two prior TKIs under these conditions but only in the US and Canada. This agent is 
not available for most patients globally, where a bigger unmet medical need is present. 
Thus, there remains an unmet need for patients with CML who have failed at least two 
prior TKIs despite the existence of multiple agents.
Primary Objective
and Key 
Secondary 
Objective
Primary Objective: To compare the Major Molecular Response (MMR) rate at 24 
weeks of asciminib versus bosutinib
Key Secondary Objective: To compare MMR rate at 96 weeks of asciminib versus 
bosutinib
Secondary 
Objectives
●
To compare additional efficacy parameters of asciminib versus bosutinib:
●
cytogenetic response rate (Complete, Partial, Major, Minor, Minimal, no 
response) at and by all scheduled data collection time points, including 24, 48 and 96 
weeks
●
MMR rate at all scheduled data collection time points (except 24 and 96 weeks 
which are already covered by primary and key secondary endpoints)
●
MMR rate by all scheduled data collection time points, including 24, 48 and 96 
weeks
●
Time to MMR
●
Duration of MMR
●
Time to CCyR
●
Duration of CCyR
●
Time to treatment failure


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●
Progression free survival
●
Overall survival
●
To compare the safety and tolerability profile of asciminib versus bosutinib by type, 
frequency and severity of adverse events, changes in laboratory values that fall outside 
the pre-determined ranges and clinically notable ECG and other safety data (vital signs, 
physical examination)
●
To characterize the PK of asciminib in the CML-CP population (Trough plasma 
concentrations, PK parameters in full PK group: Cmax, Tmax, AUC0-12h, CL/F)
●    To assess the safety of asciminib when administered as treatment after bosutinib 
failure according to the 2013 ELN Guidelines
Study design
This study is a randomized, phase 3, open-label, active-controlled multi-center study. 
Patients will be randomized to the novel BCR-ABL1 TKI asciminib and bosutinib in a 2:1 
ratio. The randomization is to be stratified to ensure the study population is balanced 
between the arms with respect to the patient’s cytogenetic response status at baseline 
(Major Cytogenetic response (complete or partial) vs. No major cytogenetic response 
(minor, minimal or none)).
The study design incorporates a 2:1 randomization, allocating more patients to the 
asciminib arm in order to learn more about the safety profile of the experimental therapy, 
whereas the safety of bosutinib therapy is well documented. Treatment duration for each 
patient in the present study is for up to 96 weeks after the last randomized patient 
receives the first dose, or up to 48 weeks after the last patient has switched from 
bosutinib to asciminib whichever is longer unless patients have discontinued treatment 
earlier, which should be adequate to address both the primary objective of the study, i.e. 
determination of the MMR rate at 24 weeks, as well as secondary efficacy and safety 
objectives. Patients on bosutinib will be able to switch to asciminib treatment up to 96 
weeks after the last patient has been randomized.
If patients in the bosutinib arm have documented treatment failure according to the 2013
ELN Guidelines (Baccarani et al 2013), they will have the option to receive asciminib.
Each patient who switches to asciminib after bosutinib failure can remain on asciminib 
treatment for up to 48 weeks after the last bosutinib failure patient has switched to 
asciminib during the treatment period unless patients have discontinued treatment 
earlier.
Population
Two-hundred and twenty-two (222) patients with CML-CP who had prior treatment with 
two or more ATP binding site TKIs will be randomized on a 2:1 basis to receive either 
asciminib or bosutinib. Patients with known history of T315I and/or V299L mutations at 
study entry will be excluded from the trial since bosutinib, the comparator, is not 
approved for these patients.
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Male or female patients with a diagnosis of CML-CP ≥ 18 years of age
2. Patients must meet all of the following laboratory values at the screening visit:
●
< 15% blasts in peripheral blood and bone marrow
●
< 30% blasts plus promyelocytes in peripheral blood and 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
3a. Patients intolerant to the most recent TKI therapy, BCR-ABL1 ratio > 0.1% IS 
according to central laboratory at the screening examination
4. Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, 
nilotinib, dasatinib, radotinib or ponatinib)
5. Failure (adapted from the 2013 ELN Guidelines; Baccarani et al 2013) or intolerance 
to the most recent TKI therapy at the time of screening 


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●
Failure is defined for CML-CP patients (CP at the time of initiation of last 
therapy) as follows. Patients must meet at least 1 of the following criteria.
●
Three months after the initiation of therapy: No CHR or > 95% Ph+ 
metaphases
●
Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS 
and/or > 65% Ph+ metaphases
●
Twelve months after initiation of therapy: BCR-ABL1 ratio > 10% IS 
and/or > 35% Ph+ metaphases
●
At any time after the initiation of therapy, loss of CHR, CCyR or PCyR
●
At any time after the initiation of therapy, the development of new 
BCR-ABL1 mutations which potentially cause resistance to study treatment 
●
At any time after the initiation of therapy, confirmed loss of MMR in 2 
consecutive tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS
●
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
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
7. Adequate end organ function as defined by (as per central laboratory tests):
●
Total bilirubin ≤ 1.5 x ULN) except for patients with Gilbert’s syndrome who may 
only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
●
Aspartate transaminase (AST) ≤ 3.0 x ULN
●
Alanine transaminase (ALT) ≤ 3.0 x ULN
●
Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN -  ≤ 1.5 x ULN, value must 
be considered not clinically significant and not associated with risk factors for acute 
pancreatitis
●
Alkaline phosphatase ≤ 2.5 x ULN
●
Creatinine clearance ≥ 50mL/min as calculated using Cockcroft-Gault formula
8. 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.
9. Written informed consent obtained prior to any screening procedures.
10a. 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
11. Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of 
screening which are amenable to standardized RQ-PCR quantification.
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Known presence of the T315I or V299L mutation at any time prior to study entry
2. Known second chronic phase of CML after previous progression to AP/BC


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3. Previous treatment with a hematopoietic stem-cell transplantation
4. Patient planning to undergo allogeneic hematopoietic stem cell transplantation
5. 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 TdP” 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
6. 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)
7. History of acute pancreatitis within 1 year of study entry or past medical history of 
chronic pancreatitis
9. History of acute or chronic liver disease
10. Known presence of significant congenital or acquired bleeding disorder unrelated to 
cancer
11. 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
12. Known history of Human Immunodeficiency Virus (HIV), chronic Hepatitis B (HBV), 
or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) 
and Hepatitis B core antibody (HBcAb / anti HBc) will be performed at screening
13. 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)
14a.
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
●
Moderate or strong inducers of CYP3A
●
Moderate or strong inhibitors of CYP3A 
15. Previous treatment with or known/ suspected hypersensitivity to asciminib or any of 
its excipients.
16. Previous treatment with or known/ suspected hypersensitivity to bosutinib or any of 
its excipients.
17. Participation in a prior investigational study within 30 days prior to randomization or
within 5 half-lives of the investigational product, whichever is longer
18. Pregnant or nursing (lactating) women
19a.
Women of child-bearing potential, defined as all women physiologically capable 
of becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 3 days after last dose of asciminib and one month after last dose 
of bosutinib. 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


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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.
Conditions to be 
fulfilled for 
asciminib switch
1. Failure to bosutinib treatment up to 96 weeks after the last patient received the first 
dose (adapted from the 2013 ELN Guidelines; Baccarani et al 2013). Patients must 
meet at least 1 of the following criteria. Failure is defined as follows:

Three months after the initiation of therapy or thereafter: No CHR or > 95% Ph+ 
metaphases.

Six months after the initiation of therapy or thereafter: BCR-ABL1 ratio > 10% 
IS and/or > 65% Ph+ metaphases.

Twelve months after initiation of therapy or thereafter: BCR-ABL1 ratio > 10% 
IS and/or > 35% Ph+ metaphases.

At any time after the initiation of therapy, loss of CHR, CCyR or PCyR.

At any time after the initiation of therapy, detection of new BCR-ABL1
mutations which potentially cause resistance to study treatment (asciminib or 
bosutinib).

At any time after the initiation of therapy, confirmed loss of MMR in 2 
consecutive tests.

At any time after the initiation of therapy, new clonal chromosome abnormalities 
in Ph+ cells: CCA/Ph+.
Conditions preventing patients to switch to asciminib:

Any Grade 3 or 4 toxicity which has not resolved to Grade 2 or lower within 28
days and before starting asciminib treatment.

Asymptomatic (Grade 2) pancreatitis if not resolved within 28 days 

Disease progression while on bosutinib treatment. The following events are 
considered disease progression:

Accelerated phase (AP) as defined by any of the following:

≥15% blasts in the peripheral blood or bone marrow aspirate, but < 
30% blasts in both the peripheral blood and bone marrow aspirate.

≥30% blasts plus promyelocytes in peripheral blood or bone marrow 
aspirate.

≥20% basophils in the peripheral blood.

Thrombocytopenia (< 100 x 109/L) that is unrelated to therapy.

Blast crisis (BC) as defined by any of the following:

≥30% blasts in peripheral blood or bone marrow aspirate


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
Appearance of extramedullary involvement other than 
hepatosplenomegaly proven by biopsy (i.e., chloroma).

QTcF at time of switch > 480 msec or inability to determine QTc interval
Investigational 
and reference 
therapy
Asciminib 40 mg BID
Bosutinib 500 mg QD
Efficacy 
assessments
Molecular response (RQ-PCR, mutational analysis)
Cytogenetic response (Bone Marrow Aspirate)
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
Other 
assessments
●
PK sampling (full/sparse)
●
Bone Marrow Biopsy
●
Patient Report Outcomes (MDASI-CML, PGIC, WPAI, EQ--5D-5L, resource 
utilization)
Data analysis
The primary efficacy variable of the study is the Major Molecular Response (MMR) rate 
at 24 weeks. A patient will be counted as having achieved MMR at 24 weeks if he meets 
the MMR criteria (BCR-ABL1 ratio ≤0.1%) at 24 weeks.
The MMR rate at 24 weeks will be calculated based on the FAS and according to the 
Intention To Treat (ITT) principle. MMR rate and its 95% confidence interval based on 
the Pearson-Clopper method will be presented by treatment group. Confidence interval 
for the difference in MMR rate between treatment groups will be provided using the Wald 
method.
The Mantel-Haenszel estimate of the common risk difference and the corresponding 
95% confidence interval will also be provided.
The key secondary endpoint is MMR rate at 96 weeks.
Formal statistical testing of the key secondary endpoint will be performed only if the 
primary endpoint is significant by means of a gatekeeping procedure to control the 
overall alpha level. 
Key words
Phase III, open-label, randomized trial, asciminib, bosutinib, CML-CP, prior treatment 
with 2 or more TKIs


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Amendment 3 (14-Dec-2018)
Amendment rationale 
As of 21-Nov-2018, 137 patients were screened and 86 patients were randomized in the study, 
the study is currently ongoing.
The primary purpose of the amendment is:
Modification of the inclusion criterion of BCR-ABL1 transcript threshold required at study 
entry from a BCR-ABL1 ratio ≥ 1% IS to BCR-ABL1 ratio > 0.1% IS (i.e. not in MMR) for 
patients with intolerance to most recent TKI treatment. The threshold presented in this inclusion 
criteria affects only patients who are intolerant to prior treatment, since patients failing prior 
treatment must fulfill the criteria defined by ELN guidelines (Baccarani et al 2013). Although 
the number of treatment options is increasing, especially for patients with imatinib intolerance, 
alternatives for patients with resistance and/or intolerance to at least two previous TKIs are 
limited (NCCN 2018, ELN 2013). The reason of reducing the BCR-ABL1 ratio is that in routine 
clinical practice, physicians do not wait to observe increased BCR-ABL1 levels to switch 
treatment in patients with intolerance, which may increase the risk of disease progression, 
especially in patients with only limited further treatment options. This is in line with current 
CML treatment guidelines where the switch to an alternative therapy in intolerant patients is 
not linked to a BCR-ABL1 threshold (NCCN 2018, Baccarani et al 2013 and Hochhaus et al 
2017). 
Therefore, the threshold of ≥1% BCR-ABL1 in the current trial is reduced to BCR-ABL1 ratio >
0.1% IS for patients with intolerance to most recent TKI treatment. No more than 66 patients 
(approximately 30% of the overall trial population) that are intolerant to their most recent TKI 
therapy with BCR-ABL1 < 1% will be recruited in order to ensure that the CML third line 
patient population is adequately represented. As the primary endpoint is the rate of MMR at 24 
weeks a baseline molecular response level > 0.1 % BCR-ABL1 is needed.
Patients experiencing documented treatment failure on bosutinib treatment will be allowed to 
switch to asciminib. Patients failing bosutinib treatment will have failed at least their third TKI 
treatment, with limited remaining treatment options. With this amendment patients who have 
failed bosutinib will be offered the possibility to continue in the study by receiving asciminib, 
if investigators consider that this treatment option is in the best interest of the patient. As of 15-
Oct-2018, 4 patients could have potentially benefited from this option. Treatment failure during 
study treatment is assessed by measureable and pre-specified milestones defined by ELN 
criteria (Baccarani et al 2013), which are also used to define treatment failure as entry criteria 
for the study. Only documented treatment failure in the bosutinib arm will be considered for a 
treatment switch. For the purpose of the primary and secondary endpoint analyses, any patient 
meeting the ELN failure criteria while receiving study treatment, (either before or by the time 
of conducting the analysis and irrespective of treatment arm), will be considered as non-
responders for the specific time point and for any subsequent time point. The switch to 
asciminib in case of bosutinib treatment failure is not expected to introduce bias as those 
patients will be regarded as non-responders irrespective of treatment switch and the disease 
burden will certainly not improve without further treatment. There is no option to switch 
patients failing on the asciminib treatment arm, as those patients can be offered approved 


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therapies outside of the context of the study. The efficacy data collected after the switch from 
patients switching to asciminib following bosutinib failure will be analyzed separately as 
exploratory endpoints and will not be included for primary and secondary study endpoints. In 
addition, safety data from patients receiving asciminib after bosutinib failure will be collected 
to further characterize asciminib’s safety profile.
Potassium increase of up to 6.0 mmol/L is acceptable at study entry if associated with creatinine 
clearance within normal limits. Grade 2 increase of potassium is acceptable in case of normal 
creatinine clearance as this is not considered to be a risk factor for QTc prolongation. Total 
calcium (corrected for serum albumin) increase of up to 12.5 mg/dl or 3.1 mmol/L (Grade 2) is 
acceptable at study entry if associated with creatinine clearance within normal limits as this is 
not considered to be a risk factor for QTc prolongation.
A change to creatinine clearance instead of GFR is being made in relation to the magnesium 
inclusion requirement as GFR in this study is expressed by creatinine clearance.
Exclusion criteria #19 is being modified under this amendment in order to define the duration 
of the use of highly effective methods of contraception after the last dose of bosutinib under 
this study (one month after last dose of bosutinib). This is being done in order to align with the 
latest Bosulif® USPI. 
Exclusion criteria #21 has also been removed under this amendment. In embryofetal 
development studies with asciminib, fetal malformations (cardiac malformations) and increased 
visceral and skeletal variants were observed in rats and increased incidence of resorptions 
indicative of embryo-fetal mortality and a low incidence of cardiac malformations indicative of 
dysmorphogenesis were observed in rabbits. Asciminib is not genotoxic. As published in the 
literature, small molecules can distribute to seminal fluid and the seminal accumulation 
suggested is semen/plasma ratios up to 11.3 (Klemmt and Scialli 2005). According to the FDA 
guidance, in general, there is increased concern for reproductive or developmental toxicity in 
humans for relative exposure ratios (animal: human) that are < 10 and decreased concern for 
exposure ratios > 25 (FDA Guidance for Industry 2011). The calculations for the asciminib 
safety margin were done based on Cmax (plasma) seen in patients at a dose of 200 mg BID
(Cmax 6843 ng/ml).  Safety margin calculation based on the embryo-fetal development study 
in rats was 768 and safety margin calculation based on the embryo-fetal development study in 
rabbits was 894. In conclusion, for asciminib, as outlined above, the safety margins are well 
above 25 and therefore no embryo- and fetotoxicity effects can be anticipated via seminal fluid.
Removal of male contraception is in line with the Bosutinib USPI and SmPC.
In addition, patients can be re-screened up to three times for the study, instead of once.  The 
patient population being investigated in this study is heavily pre-treated and patients might not 
have other treatment options outside the trial. There can be many intolerance-related temporary 
conditions resulting in ineligibility for the trial.
Recruitment period extension has been reflected in the VES table. Study length has changed 
with introduction of switch option for patients failing bosutinib treatment.
Patients enrolling in this trial will present a high disease burden after failure of previous 
therapies. Myelosuppression during TKI targeted treatment is a very common effect observed 
due to the suppression of the leukemic clone; this effect is also extended to hematopoiesis of 


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stem cells and progenitors (Steegmann et al 2016). For this reason, the recovery period for 
cytopenias has been extended from 28 to 42 days in order to allow for sufficient time to recover 
from suppression and to re-populate the bone marrow.
The biomarker sampling profile has been revised to remove the gene expression profile in 
leukemic stem cells in both blood and bone marrow due to technical limitations.  In addition, 
there is currently no validated assay available.
A clarification has been made to how the tests for blood urea and Blood Urea Nitrogen (BUN)
are noted. The text "blood urea, Blood Urea Nitrogen (BUN)" has been revised to “blood urea 
or Blood Urea Nitrogen (BUN)” in order to note that either test is permitted.
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.

Change of the purpose of the study by decreasing the requirement of BCR-ABL1 ratio ≥
1% IS to BCR-ABL1 ratio > 0.1% IS at the time of screening for patients with 
intolerance:

Protocol summary.

Section 2.1 Study rationale and purpose.

Section 4.1 Description of study.

Section 5.2 Inclusion criteria.

Section 10.5.2 Other secondary efficacy objectives.

Change of the study design by introducing the switch to asciminib option for patients 
experiencing treatment failure on bosutinib treatment:

Protocol summary.

Section 2.2 Rationale for the study design.

Section 4.1 Description of study.

Figure 4-1 Schematic of Study Design.

Addition of Section 4.1.1 Study treatment switch from bosutinib to asciminib

Section 4.3 Definition of end of study.

Section 6.1.5 Treatment duration

Section 6.7.3.2 Study drug accountability.

Section 7 Visit schedule and assessments:

Addition of Table 7-2 Visit evaluation schedule (study treatment switch phase).

Addition of Section 7.1.2.2 Conditions to be fulfilled for asciminib switch.

Section 7.1.5 Visit windows.

Section 7.1.6 Discontinuation of study treatment.

Section 7.2.1.1 Molecular response.

Section 7.2.1.2 Bone marrow analysis and cytogenetics

Section 7.2.2.1 Physical examination.


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
Section 7.2.2.2 Vital signs.

Section 7.2.2.3 Height and weight.

Section 7.2.2.4 Performance status.

Section 7.2.2.5 Laboratory evaluations.

Section 7.2.2.6 Cardiac assessments.

Section 7.2.3 Pharmacokinetics.

Section 7.2.4 Biomarkers.

Section 10.1.6 Other analysis sets.

Section 10.5.3.1 Analysis set and grouping for the analysis

Addition of new exploratory measure for patients that switch from bosutinib to asciminib:

Table 3-1 Objectives and related endpoints.

Section 10.1.6 Other analysis sets.

Section 10.6 Exploratory objectives:

Section 10.6.1 Exploratory efficacy objectives.

Section 10.6.1.1 Data analysis of exploratory efficacy objectives.

Reference for concomitant medications with a “known risk of TdP” has been updated to 
wwwcrediblemeds.org/

Protocol summary

Section 5.3 Exclusion criteria

Section 6.3.2 Dose adjustments for QTcF prolongation

Section 6.4.3 Prohibited concomitant therapy


Section 5.2 Inclusion criteria and protocol summary: updated inclusion criteria to reflect 
the changes below:

Inclusion Criteria #3: As referenced above, the requirement of BCR-ABL1 ratio ≥ 1% 
IS has been decreased to BCR-ABL1 ratio > 0.1% IS at the time of screening for 
patients intolerant to previous TKI.

Inclusion Criteria #10: Potassium increase of up to 6.0 mmol/L is accepted at study 
entry if associated with creatine clearance within normal limits.  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.  GFR replaced by Creatinine clearance 
(calculated using Cockcroft-Gault formula) in order to maintain consistency 
throughout the protocol as creatinine clearance is already calculated based on 
inclusion criteria #7.

Inclusion Criteria #11: As study eligibility is assessed during screening with BCR-
ABL1 PCR quantification via international scale this requirement was added as 


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clarification. Measurement according to international scale is only possible for typical 
BCR-ABL1 transcripts.

Section 5.3 Exclusion Criteria and Protocol summary: updated exclusion criteria to reflect 
the following changes:

Exclusion Criteria #14: Removal of P-gp as a moderate or strong inhibitor of CYP3A
as P-gp inhibitors are no longer prohibited per updated USPI, and SmPC

Exclusion Criteria #19: Duration of the use of highly effective methods of 
contraception after the last dose of bosutinib has been defined to align with the latest 
bosutinib USPI.

Exclusion Criteria #21 Removal of this criteria in order to align with updated pre-
clinical data.

Section 6.3.1 Dose modification and dose delay: The recovery period for cytopenias has 
been extended from 28 to 42 days in order to allow for sufficient time to recover from 
suppression and to re-populate the bone marrow.

Table 7-1 Visit evaluation schedule: updates due to inadvertent omissions in previous 
protocols and to reflect extension of study treatment period

ECOG Performance status: X has been replaced by “If needed” under Week 6, Week 
10 and Week 14.

Vital signs: added “If needed” under Week 6, Week 10 and Week 14.

Visit name: “W108, W120, W132, W144, W156” has been changed to “Every 12 
weeks up to end of study treatment” to align with new extended recruitment timelines.

Section 7.1.2 Change of patient re-screening allowance from once to up to three times.

Section 7.1.2.2 Addition of new section with screening eligibility criteria for patients 
switching from bosutinib to asciminib.

Section 7.1.4 Change of treatment duration for patients including those patients that 
switch to asciminib after failure on bosutinib. Patients can remain on asciminib treatment 
for up to 96 weeks after the last patient received the first dose in the study or up to 48
weeks after the last patient has switched to asciminib whichever is longer.

Section 7.1.6 Discontinuation of study treatment: updated to specify that the safety follow-
up visit can be conducted by telephone and replacement of “after randomization” by “after 
initiation of therapy” in the event that constitutes a treatment failure.

Section 7.2.2.5.3 Pregnancy and assessments of fertility: Change in requirement for 
reporting pregnancies under this study.  Pregnancies diagnosed in female partners of male 
participants are no longer required to be reported to CMO&PS.  Contraception use by 
sexually active males while on study treatment is no longer required.

Table 7-5 Central clinical laboratory parameters collection plan: Clarification on blood 
urea and Blood Urea Nitrogen (BUN). The text "blood urea, Blood Urea Nitrogen (BUN)" 
has been revised to “blood urea or Blood Urea Nitrogen (BUN)”.

Section 8.4 Pregnancies: removal of male contraception requirement due to new 
information of asciminib embryo and fetotoxicity.

Section 10.4.3 Handling of missing values/censoring/discontinuations: imputation rules 
updated to take in account unscheduled visits close to visit Week 24.


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
Section 10.5.1.1. Analysis for key secondary endpoints: imputation rules updated to take 
in account unscheduled visits close to visit Week 96.

Section 14 Appendices: updates to reflect that P-gp inhibitors are no longer prohibited

Section 14.2 Appendix List of concomitant medications for patients on bosutinib:

Removal of P-gp inhibitors from Table 14-3 Prohibited concomitant medications 
for bosutinib arm.

Addition of new medications to Category Torsade de pointe (TdP) TdP/QT risk: 
Known.

Addition of new category, TdP/QT risk: Possible.

Addition of new category, TdP/QT risk: Conditional.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 2 (13-Jul-2018)
Amendment rationale 
As of 29-Jun-2018, this study has been submitted in 25 and approved in 24 countries. Eighty 
five (85) sites were initiated, 67 patients were screened and 38 patients were randomized in the 
study.
The primary purposes of the amendment are:
The frequency of bone marrow aspirate (BMA) to perform cytogenetic analysis has been 
decreased in accordance with treatment guidelines (European Leukemia Network (ELN) 
Guidelines (Baccarani et al 2013), National Comprehensive Cancer Network (NCCN) (Clinical 
Practice Guidelines in Oncology-Chronic Myeloid Leukemia v4.2018). Initially BMAs were 
foreseen at screening, every 24 weeks thereafter and at end of treatment. With the protocol 
amendment BMA is no longer needed for patients that have achieved MMR during study, 
however BMA assessment is requested at the time of end of treatment for biomarker analysis. 
Toxicity studies performed in rats, dogs and cynomolgus monkeys identified the pancreas as 
potential target tissues. Therefore the assessment for laboratory parameters that are associated 
with pancreatitis were part of the inclusion criteria (amylase, lipase). Serum lipase is the 
preferred test due to its improved sensitivity, and a threshold concentration of 2-3 x ULN is 
recommended for the diagnosis of pancreatitis. There are a number of other conditions that can 
elevate lipase, including TKI pretreatment, thus the screening threshold for lipase is increased 
from ≤ULN to ≤ 1.5 x ULN (CTCAE v4.03 grade 1), as patients with history of acute 
pancreatitis within 1 year of study and history of chronic pancreatitis are excluded. Amylase is 
not a specific marker for pancreatitis, as up to 60% of total serum amylase originates from non-
pancreatic sources. Its short half-life reduces its value as a diagnostic test in the early clinical 
course. Lipase has replaced amylase as the biochemical test of choice for acute pancreatitis due 
to its higher specificity (Basnayake 2015), therefore the requirement of amylase ≤ ULN at 
screening has been removed.
Assessments for visits at weeks 6, 10 and 14 will be limited to the monitoring of the bone 
marrow function to allow for adjustments of study treatment. Assessments will comprise a 
complete blood count to detect neutropenia and thrombocytopenia which are among the most 
frequent adverse reactions [Asciminib Investigator’s Brochure, Bosutinib label]. The physical 
examination must be done at site only in case of previous or newly occurring adverse events.
The concomitant medication section has been updated to reflect the most recent clinical updates 
on asciminib as well to align with the Bosutinib label.
In addition some minor inconsistencies (discrepancies between sections, typos) have been 
corrected.
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.

ABL001 has been replaced by International Nonproprietary Name (INN) asciminib 
throughout the protocol amendment.




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
Section 6.3.1 Dose modification and dose delay: clarification made on treatment 
discontinuation.

Table 6-2 Criteria for dose reduction/interruption and re-initiation of asciminib and 
bosutinib treatment for adverse drug reactions: 

Gastro intestinal/ Pancreatitis/Grade 2: precisions provided and treatment delay 
changed from 7 to 21 days to give investigators sufficient time for re-assessment.

Removal of “other adverse event” section which was redundant with the section “non-
hematological adverse event reaction except where further specified in individual 
section”.

Mandatory instructions for grade 3 and 4 “Non-hematological adverse event reaction 
except where further specified in individual section” for bosutinib have been aligned 
with those of asciminib: dose hold until resolved to ≤ grade 1, to handle the patients 
identically independent of the treatment assigned.

Section 6.3.2 Dose adjustments for QTcF prolongation: adapting the dose adjustment
concerning QT prolonging agents to the classification known, possible or conditional risk 
for TdP, and adding the external web link to qtdrugs.org.

Section 6.4.2 Permitted concomitant therapy requiring caution and/or action: updated with 
the most clinical data available.

Section 6.4.3 Prohibited concomitant therapy (asciminib):

Section on other anticancer agent added,

Sections on strong CYP3A4/5 inhibitors and P-gp inhibitors: prohibition on P-gp 
inhibitors has been removed and moved under requiring caution and/or action section 
based on CABL001A2102 ADME study,

Section on strong CYP3A4/5, UGT1A/2B inducers updated to provide instructions on 
action to be taken in case these inducers are taken,

Section on NTI substrates of CYP3A4/5, CYP2C8 and CYP2C9 removed based on a 
most updated PBPK modeling predicting a negligible risk for sensitive CYP3A4/5, 
CYP2C8, or CYP2C9 substrates and moved under requiring caution and/or action 
section,

Section on QT prolonging agents updated to change agents known to prolong QT 
interval to agents with “known”, “possible” or “conditional” risk of Torsades de 
Pointes.

Section 6.5.1 Permitted concomitant therapy requiring caution (bosutinib): has been 
updated to reflect the bosutinib label information regarding the use of QT prolonging agents. 

Section 6.5.2 Prohibited concomitant therapy (bosutinib): 

Section on other anticancer agent added,

Concomitant use with CYP3A4/5 inhibitors/inducers: further clarifications on 
necessary actions. 

Table 7-1 Visit evaluation schedule: 

Exploratory BCR-ABL1 mutation analysis (Sanger Sequencing) for patients with 
mutations at Week 1 Day 1: rephrased to indicate that this assessment will be 
performed without any dedicated blood collection.






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
Section 10.5.2 Other secondary efficacy objectives: update of descriptive statistics 
definition and removal of presentation of p value as no formal statistical testing will be 
performed.

Section 10.6.1 Exploratory efficacy objectives and Section 10.6.3 Exploratory biomarker 
objectives: 

Correction of time points for BCR-ABL1 mutation characterization (baseline 
corrected to Week 1 Day 1, adding “upon confirmed loss of MMR, and changed 
“and” to “and/or” End of treatment).

 

Section 10.6.4.1 Resource utilization: correction on duration of resource utilization 
reporting.

Section 10.7 Interim analysis: clarification concerning the analysis of the key secondary 
endpoint at week 96 if statistical significance is not reached for primary endpoint at week 
24.

Section 14 Appendices: the lists of concomitant medications for patients on asciminib and 
bosutinib have been updated based on the internal Pharmacokinetic Sciences 
memorandum on Drug-Drug Interaction (release date: January 2018).

Some minor inconsistencies (discrepancies between sections, typos) have been corrected.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.






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1
Background
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. 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).
Multiple agents, including nilotinib, dasatinib, ponatinib, bosutinib, radotinib (Korea) and 
omacetaxine (USA, Canada) are able to combat 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 


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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.
There remains an unmet need for new compounds in patients with CML who have failed at least 
two prior TKIs. Current practice suggests that a second generation TKI will have been used for 
first line therapy for about one half of patients with CML, meaning that most patients who have 
failed at least two prior TKIs will have failed at least one if not two second generation TKIs: 
dasatinib and/or nilotinib. Potentially, such patients may also have failed bosutinib and/or 
ponatinib (Soverini 2014). Patients having failed at least two TKIs may have limited sensitivity 
to the remaining available agents and, thus, there exists a need for new safe and effective therapy. 
In addition, mutations will have developed in 21 to 33% of patients that prevent the use of 
specific TKIs, increasing the need for a better and alternative compound (Soverini 2014). 
Omacetaxine, a chemotherapeutic agent, is available for patients who have failed at least two 
prior TKIs under these conditions but only in the US and Canada. This agent is not available 
for most patients globally, where a bigger unmet medical need is present. Thus, there remains 
an unmet need for active and safe drugs in patients with CML who have failed at least two prior 
tyrosine kinase inhibitors (TKI), even in the presence of approved drugs, as described below.
1.2
Introduction to investigational treatment
1.2.1
Overview of asciminib (ABL001)
Asciminib is an orally bioavailable specific BCR-ABL1 inhibitor with a novel mechanism of 
action. In contrast to inhibitors such as imatinib, nilotinib, dasatinib and bosutinib that bind 
within the ATP-binding site of the ABL kinase domain, asciminib inhibits ABL tyrosine kinase 
activity by binding to a particular allosteric site on the kinase domain, which has only been 
identified on ABL1, ABL2 and BCR-ABL1. Consequently, asciminib is specific for the latter 
three enzymes.
Asciminib potently and selectively inhibits the proliferation of cell lines that express BCR-
ABL1. By virtue of asciminib not interacting with the ATP-binding site, the drug maintains 
activity against cells expressing clinically observed ATP-binding TKI resistance mutations.
1.2.1.1
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.


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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.
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.


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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 
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 extend 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.


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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. Therefore, strong 
inhibitors of CYP3A4/5 should be avoided and are prohibited in this study. Strong inducers of 
CYP3A4/5 have the potential to reduce asciminib concentrations. Therefore, the use of strong 
inducers of CYP3A4/5 or UGT1A/2B is prohibited in this trial.
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 
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.
1.2.1.2
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 01-Sep-2017, a total of 239 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


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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 major molecular response and reduction in the BCR-
ABL1 % IS. Asciminib has demonstrated anti-tumor activity at doses greater or equal to 10 mg 
BID as well as daily higher 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). 
Of the 62 patients with BCR-ABL1 no greater than 10 % IS at screening and without T315I 
mutation, 1-log reduction of BCRABL1 % IS was achieved in 16 of 62 (25.8%) patients by 6 
months and 19 of 62 (30.6%) patients by 12 months. For asciminib 40 mg BID dose, of the 17 
patients studied, 1-log reduction of BCRABL1 % IS was achieved in 5 of 17 (29.4%) patients 
by 6 months, and 12 months. 
Please refer to 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. All 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 was 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.


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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 %) 
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% 


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(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.
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 
overall exposure decreased by approximately 65% when administered with a high-fat meal.
Therefore, asciminib will be administered in a fasted state.
1.2.2
Overview of bosutinib
Bosutinib (Bosulif®) is indicated for the treatment of adult patients with newly-diagnosed 
chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ 
CML) and for the treatment of patients with chronic, accelerated, or blast phase Ph+ chronic 
myelogenous leukemia (CML) with resistance or intolerance to prior therapy (500 mg QD) 
[Bosulif® USPI] as well as for newly-diagnosed CML-CP (400 mg QD), and in Europe for the 
treatment of adult patients with chronic phase (CP), accelerated phase (AP), and blast phase 
(BP) Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) previously 
treated with one or more tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib and 
dasatinib are not considered appropriate treatment options [EU Summary of Product 
Characteristics (SmPC)]. Bosutinib has been evaluated in patients treated with one or more prior 
TKIs.
For patients treated with bosutinib after prior imatinib only, the MMR rate is approximately 15% 
at 24 weeks overall, and approximately 10% in imatinib-resistant patients and 20% in imatinib-
intolerant patients (Gambacorti-Passerini 2014). The cytogenetic, molecular, and hematological 
response rates did not appear to differ greatly between patients who were imatinib-resistant or 
imatinib-intolerant (Gambacorti-Passerini 2014).
Twenty seven percent of patients treated with bosutinib after at least 2 previous TKIs achieved 
MCyR rate by Week 24 [Bosulif® USPI]. For patients previously treated with imatinib and 
either dasatinib or nilotinib, after a median of 28.5 months follow-up, the cumulative rate of 
Major Molecular Response (MMR) is 15% (Khoury 2012). The cytogenetic, molecular, and 
hematological response rates appeared to be lower in patients who were resistant to dasatinib 
after imatinib treatment as compared to patients who were intolerant to dasatinib after imatinib 
treatment (Khoury 2012). In a small (30 patient) compassionate use trial of patients previously 
treated with imatinib, dasatinib and nilotinib, after a median duration of treatment of 9.3 months, 
the cumulative MMR rate was 14% (García-Gutiérrez 2015). Based on these data, the MMR 
rate at 6 month with bosutinib treatment in patients treated with at least 2 prior TKIs is estimated 
to be approximately 10-15%.
Bosutinib has no activity against the T315I and V299L mutant form of BCR-ABL1. 
Accordingly, the pivotal trial leading to the registration in the 3rd line setting excluded patients 
with a known history of the T315I or V299L mutation [Bosulif® USPI].


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2
Rationale
2.1
Study rationale and purpose
Asciminib is an agent intended to be evaluated for the treatment of patients with CML. In the 
ongoing study [CABL001X2101] study, asciminib was found to produce clinically meaningful 
and durable responses in patients who have had treatment failure after a minimum of 2 prior 
ATP-binding site TKIs, with an acceptable safety and tolerability profile.
The purpose of this pivotal study is to compare the efficacy of asciminib with that of bosutinib 
in the treatment of patients with CML-CP having previously been treated with a minimum of 
two prior ATP-binding site TKIs. Patients with intolerance to most recent TKI therapy must 
have BCR-ABL1 ratio >  0.1% IS at screening and patients experiencing failure to most recent
therapy must meet the definition of treatment failure as per the 2013 ELN guidelines (Baccarani 
et al 2013).
Imatinib, nilotinib and dasatinib are indicated for the treatment of patients with newly diagnosed 
CML. Multiple agents, including nilotinib, dasatinib, ponatinib, bosutinib, radotinib (Korea) 
and omacetaxine (USA, Canada) are approved for patients with CML-CP previously treated 
with prior therapy. Imatinib is a first generation TKI; nilotinib, dasatinib, bosutinib, ponatinib 
and radotinib are considered second generation TKIs and have activity in patients previously 
treated with imatinib. The activity of nilotinib or dasatinib in patients previously treated with a 
second generation TKI is not known. All the currently approved BCR-ABL1 TKIs are 
enzymatic site inhibitors, in distinction to asciminib which is an allosteric TKI. Omacetaxine is 
a cytotoxic chemotherapeutic agent.
2.2
Rationale for the study design
Asciminib is an orally bioavailable specific BCR-ABL1 inhibitor with a novel mechanism of 
action. In contrast to other TKIs that bind within the ATP-binding site of the ABL kinase 
domain, asciminib inhibits ABL tyrosine kinase activity by binding to a particular allosteric site 
on the kinase domain that is utilized by a myristate group to auto-regulate the native ABL1 
kinase. With allosteric inhibition of BCR-ABL1 being a novel mechanism of action, asciminib
produces clinically meaningful and durable responses in patients who have had treatment failure 
after a minimum of 2 prior ATP-binding site TKIs, with an acceptable safety and tolerability 
profile as demonstrated in study [CABL001X2101].
The development of asciminib, presents an opportunity to evaluate the beneficial effects of 
inhibition of BCR-ABL1 in the treatment of patients with CML. The proposed study design is 
expected to adequately allow an assessment of the efficacy, safety and tolerability of asciminib
in a population of patients with continuing medical need i.e., patients who have been treated 
with at least two prior TKIs and are in the need for further therapeutic intervention.
Bosutinib is one of the TKIs with proven clinical benefit in CP-CML patients previously treated 
with one or more tyrosine kinase inhibitor(s) and is currently approved for this indication in 
many countries, including the European Union. The proposed study will evaluate asciminib in 
comparison to bosutinib at the approved doses in the targeted population.






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Additional preliminary PK-efficacy and PK-safety analyses to assess the exposure-response 
relationship for asciminib were conducted (Section 1.2.1.2). 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 
amylase.
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. Of note, the dose of asciminib single agent BID is further being evaluated in patients with 
the T315I mutation. At present the recommended dose of 40 mg BID is for patients without the 
T315I mutation. For this reason, patients with the T315I mutation are excluded from this study.
2.4
Rationale for choice of combination drugs
Not Applicable.
2.5
Rationale for choice of comparators drug bosutinib
The guidance provided by the NCCN and the ELN (Baccarani et al 2013), recommends 
bosutinib as a treatment in CML-CP patients who fail first-line or second-line treatment with 
imatinib or nilotinib or dasatinib. Consistent with these recommendations and clinical practice, 
bosutinib was selected to be an appropriate comparator in a study of 3rd line CML-CP patients 
after failure of at least 2 prior TKIs, and is the comparator that will be used in the present study.
It is to be noted that bosutinib has no activity against the T315I and V299L mutant form of 
BCR-ABL1. Patients who have the T315I or V299L mutations documented in their medical 
record will already be excluded from this study. Bosutinib is known to be active against 
E255K/V, F317L/V/I/C, F359V/C/I, T315A, and Y253H and therefore, these mutations are not 
considered in the exclusion criteria for the current study.
Ponatinib is not selected as the comparator in the present clinical trial, because the comparator 
in this study needs to be an approved agent administered at the approved dose. Currently, the 
ponatinib dose is being evaluated in a randomized trial as a post-approval commitment due to 
the occurrence of vascular risks at the current approved dose of ponatinib. The dose of ponatinib 
that will be approved and will be used in practice at the completion of the present study may 
not be the approved dose at the time of initiation of the present study.
2.6
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 6.3. 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).


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An important potential risk for patients enrolling on the experimental arm of the study with 
asciminib will be that this agent may be ineffective. However, the evidence to date at the doses 
to be administered in a similar population of patients in the study [CABL001X2101] suggests 
that asciminib is an active agent. Further, the adverse event profile of asciminib is similar 
qualitatively to that observed with other TKIs targeting BCR-ABL1 (Section 1.2.1.2). The risk 
of asciminib not being effective has been mitigated in that patients will be observed closely for 
evidence of efficacy, based on assessment of hematologic, cytogenetic and molecular response 
data, which will permit rapid decision making as to discontinuation of therapy if necessary.
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.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To compare the MMR rate at 24 weeks of asciminib versus 
bosutinib 
Major Molecular Response (MMR) rate at 24 weeks
Refer to Section 10.4
Key secondary
To compare additional parameters of the efficacy of asciminib 
versus bosutinib 
MMR rate at 96 weeks
Refer to Section 10.5.1
Other secondary
To compare additional parameters of the efficacy of asciminib 
versus bosutinib
●
Cytogenetic response rate (Complete, Partial, Major, Minor, Minimal, 
no response) at and by all scheduled data collection time points 
including 24, 48 and 96 weeks
●
MMR rate at all scheduled data collection time points (except 24 and 
96 weeks which are already covered by primary and key secondary 
endpoints)
●
MMR rate by all scheduled data collection time points including 24, 
48 and 96 weeks
●
Time to MMR
●
Duration of MMR
●
Time to CCyR
●
Duration of CCyR
●
Time to treatment failure
●
Progression free survival
●
Overall survival
Refer to Section 10.5.2
To compare the safety and tolerability profile of asciminib versus 
bosutinib
Type, frequency and severity of adverse events,
changes in laboratory values that fall outside the pre-determined ranges 
and clinically notable ECG and other safety data (vital signs, physical 
examination)
To characterize the PK of asciminib in the CML-CP population
To assess the safety of asciminib when administered as 
treatment after bosutinib failure according to the 2013 ELN 
Guidelines
Trough plasma concentrations,
PK parameters in full PK group: Cmax, Tmax, AUC0-12h, CL/F
Type, frequency and severity of adverse events, changes in laboratory 
values that fall outside the pre-determined ranges and clinically notable 
ECG and other safety data (vital signs, physical examination)
Refer to Section 10.6




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Objective
Endpoint
Analysis

Time to MMR

Duration of MMR

Time to CCyR

Duration of CCyR

Time to treatment failure


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4
Study design
4.1
Description of study design
The study is a phase 3, multi-center, open-label randomized study of oral asciminib versus 
bosutinib in patients with Chronic Myelogenous Leukemia in chronic phase (CML-CP), 
previously treated with 2 or more tyrosine kinase inhibitors.
The trial is designed to compare the efficacy and safety of asciminib with that of bosutinib in 
the treatment of patients with CML-CP having previously been treated with a minimum of two 
prior ATP-binding site TKIs. Patients intolerant to the most recent TKI therapy must have BCR-
ABL1 ratio > 0.1% IS at screening and patients failing their most recent TKI therapy must meet 
the definition of treatment failure as per the 2013 ELN guidelines (Baccarani et al 2013). No 
more than 66 patients (approximately 30% of the overall trial population) that are intolerant to 
their most recent TKI therapy with BCR-ABL1 < 1% will be recruited in order to ensure that 
the CML third line patient population is adequately represented.
The study will also investigate secondary endpoints for efficacy, safety and PK of single-agent 
asciminib compared to bosutinib. Tolerability, PK, PRO and exploratory biomarker activities 
will also be assessed. Safety and efficacy data for patients switching to asciminib will be 
collected and analyzed separately.
Patients meeting all of the inclusion and none of the exclusion criteria will be randomized into 
one of the 2 treatment arms, based on a 2:1 randomization between the asciminib arm and the 
bosutinib arm.
The randomization will be stratified to ensure the study population is balanced between the 
arms with respect to cytogenetic response status (See Section 7.2.1.2) at screening as follows:

Major cytogenetic response (complete or partial)

No major cytogenetic response (minor, minimal or none)
Patients will continue to receive the assigned study treatments (asciminib or bosutinib) until 
the end of study treatment period as defined in Section 4.3. Patients who discontinue their study 
treatment at any time during the study will be followed up for survival and for progression to 
AP/BC for up to 5 years from the date the last randomized patient receives the first dose 
(irrespective of treatment switch for patients failing bosutinib).
Serial PK samples over 12 hours will be collected on Week 2 Day 1 from at least 20 CML-CP 
patients (full PK group) on the asciminib arm, in addition to trough PK samples. These patients 
will be identified sequentially at selected sites that are capable of serial PK sampling over 12 
hours. In the remaining patients in the asciminib arm and in patients that have switched to 
asciminib, sparse post-dose PK samples on Week 1 Day 1 and trough PK samples will be 
collected (sparse PK group).


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Figure 4-1
Schematic of Study Design
4.1.1
Study treatment switch from bosutinib to asciminib
Patients with documented treatment failure (as per the 2013 ELN guidelines; Baccarani et al 
2013) while on bosutinib treatment will have the option to switch to asciminib treatment within
96 weeks after the last patient has been randomized on study. The patients who switch to 
asciminib will be able to receive asciminib up to end of study treatment period. At the end of 
the treatment period for patients who, in the opinion of the investigator still derive clinical 
benefit, asciminib treatment will be made available through alternative options including, but 
not limited to, an expanded access/compassionate use/managed access program or access to 
commercial supplies in applicable countries. Discontinuation of asciminib for patients who
have switched over from bosutinib must follow the guidelines provided in Section 7.1.6.
Eligibility criteria for patients switching to asciminib are described in Section 7.1.
4.2
Timing of interim analyses and design adaptations
Not applicable. There are no formal interim analyses or design adaptations planned for this 
study. See Section 8.6 for documentation of safety DMC.
4.3
Definition of end of study
The patients are treated in the study up to end of study treatment period defined as up to 96 
weeks after the last patient receives the first dose or up to 48 weeks after the last patient has 
switched to asciminib treatment whichever is longer unless patients have discontinued treatment 
earlier. The end of the study, concluding the survival follow-up, will occur 5 years from the 
date when the last patient enrolled into the study receives the first dose of the randomized 
treatment.
The primary analysis (cut-off date) is defined as the date when all randomized patients have 
been on study treatment for 24 weeks (Section 10.4) or discontinued earlier. Subsequent to this 


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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 assigned study treatments (asciminib or bosutinib)
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 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.
Patients will be followed for survival and progression for up to 5 years from the date the last
randomized patient receives the first study dose (irrespective of treatment switch for patients 
failing bosutinib). Information on subsequent treatments will also be collected. An updated 
analysis of OS and PFS will be performed at the end of the follow-up period in the final study 
CSR.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be contacted as soon as possible and instructed to stop taking study 
medication. The end of treatment visit should be scheduled and the same assessments should 
be performed as described in Section 7 for a discontinued or withdrawn patient. 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 patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
Two-hundred and twenty-two (222) patients with CML-CP who had prior treatment with two 
or more ATP binding site TKIs will be randomized in a 2:1 fashion to receive either asciminib 
or bosutinib. No patients with a medical history of the T315I or V299L mutation at study entry 
will be included in the trial. 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 
(Baccarani et al 2013), and is outlined below in the inclusion criteria.
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Male or female patients with a diagnosis of CML-CP ≥ 18 years of age


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2. Patients must meet all of the following laboratory values at the screening visit:

< 15% blasts in peripheral blood and bone marrow

< 30% blasts plus promyelocytes in peripheral blood and 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
3a.  BCR-ABL1 ratio > 0.1% IS according to central laboratory at the screening examination, 
for patients intolerant to the most recent TKI therapy
4. Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, nilotinib, 
dasatinib, radotinib or ponatinib)
5. Failure (adapted from the 2013 ELN Guidelines; Baccarani et al 2013) or intolerance to 
the most recent TKI therapy at the time of screening 

Failure is defined for CML-CP patients (CP at the time of initiation of last therapy) as 
follows. Patients must meet at least 1 of the following criteria.

Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases

Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 
65% Ph+ metaphases

Twelve months after initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 
35% Ph+ metaphases

At any time after the initiation of therapy, loss of CHR, CCyR or PCyR

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 after the initiation of therapy, confirmed loss of MMR in 2 
consecutive tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS

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
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
7. Adequate end organ function as defined by (as per central laboratory tests):

Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert’s syndrome who may 
only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN


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
Aspartate transaminase (AST) ≤ 3.0 x ULN

Alanine transaminase (ALT) ≤ 3.0 x ULN

Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN -  ≤ 1.5 x ULN, value must be 
considered not clinically significant and not associated with risk factors for acute 
pancreatitis

Alkaline phosphatase ≤ 2.5 x ULN

Creatinine clearance ≥ 50 mL/min as calculated using Cockcroft-Gault formula
8. 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.
9. Written informed consent obtained prior to any screening procedures.
10a.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.
11. Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of screening 
which are amenable to standardized RQ-PCR quantification.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Known presence of the T315I or V299L mutation at any time prior to study entry
2. Known second chronic phase of CML after previous progression to AP/BC
3. Previous treatment with a hematopoietic stem-cell transplantation
4. Patient planning to undergo allogeneic hematopoietic stem cell transplantation
5. 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:


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
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
6. 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)
7. History of acute pancreatitis within 1 year of study entry or past medical history of chronic 
pancreatitis
9. History of acute or chronic liver disease
10. Known presence of significant congenital or acquired bleeding disorder unrelated to 
cancer
11. 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
12. Known history of Human Immunodeficiency Virus (HIV), chronic Hepatitis B (HBV), or 
chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) 
and Hepatitis B core antibody (HBcAb / anti HBc) will be performed at screening
13. 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)
14a. 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

Moderate or strong inducers of CYP3A

Moderate or strong inhibitors of CYP3A 
15. Previous treatment with or known/ suspected hypersensitivity to asciminib or any of its
excipients.
16. Previous treatment with or known/ suspected hypersensitivity to bosutinib or any of its
excipients.
17. Participation in a prior investigational study within 30 days prior to randomization or 
within 5 half-lives of the investigational product, whichever is longer
18. Pregnant or nursing (lactating) women
19a. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 3 days after last dose of asciminib and one month after last dose of
bosutinib. Highly effective contraception methods include:


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
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 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.
6
Treatment
6.1
Study treatment
The investigational treatments for this study are asciminib (40 mg BID) and bosutinib (500 mg 
QD). Novartis will supply asciminib to the investigational site as 20 mg and 40 mg tablets.
Bosutinib will be supplied to the investigational site as 100 mg and 500 mg tablets.
6.1.1
Dosing regimen
Asciminib
Asciminib 20 or 40 mg strength tablets will be administered orally twice-daily (BID), without 
food. 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


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
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
Bosutinib
Bosutinib 500 mg or 100 mg tablets will be administered orally once daily (QD) with food. If 
a dose is missed beyond 12 hours, the patient should skip the dose and take the usual dose on 
the following day.
Table 6-1
Dose and treatment schedule
Study 
treatments
Pharmaceutical form 
and route of 
administration
Dose
Frequency and/or
Regimen
Fasting Condition
Asciminib
Tablet for oral use
20 mga
Twice-daily 
Fasting
Asciminib
Tablet for oral use
40 mg 
Twice-daily 
Fasting
Bosutinib
Tablet for oral use
100 mgb
Once-daily
Non-fasting
Bosutinib
Tablet for oral use
500 mg
Once-daily
Non-fasting
a 20 mg tablets will be dispensed to patients in the instance of dose reduction.
b 100 mg tablets will be dispensed to patients in the instance of dose modifications.
On days when serial blood samples are collected for asciminib PK analysis, patients will be 
instructed to bring their drug supply to the site, and take the dose in the clinic, under supervision 
of the site personnel. The exact time for dose administration and meal intake must be recorded 
in the electronic Case Report Form (eCRF).
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
6.1.2
Ancillary treatments
Not applicable.
6.1.3
Rescue medication
Not applicable.
6.1.4
Guidelines for continuation of treatment
Not applicable. See Section 6.3.
6.1.5
Treatment duration
There is no fixed duration of treatment planned per patient. The patients are treated in the study 
up to end of study treatment period defined as up to 96 weeks after the last patient receives the 
first dose or up to 48 weeks after the last patient has switched to asciminib treatment whichever 
is longer unless patients have discontinued treatment earlier.  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.


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6.2
Dose escalation guidelines
Dose escalation beyond the standard doses of 40 mg BID for asciminib is not permitted.
Dose escalation above 500 mg QD for bosutinib is permitted in this study. Bosutinib escalation 
guidelines are as follows:
Consider dose escalation to 600 mg once daily in patients who are currently taking 500 mg 
daily, did not have Grade 3 or higher adverse events and who:

Did not reach complete hematological response (CHR) by week 8

Did not reach complete cytogenetic response (CCyR) by week 12
6.3
Dose modifications
6.3.1
Dose modification and dose delay
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” are 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 on 
the asciminib arm per protocol. 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 either asciminib or bosutinib 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. 


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Table 6-2
Criteria for dose reduction/interruption and re-initiation of asciminib and bosutinib treatment for adverse drug 
reactions
Dose modifications for both asciminib and bosutinib
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 4.03
Asciminib
Bosutinib
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
Recommendation: Maintain dose level
Grade 2 (ANC < 1.5 – 1.0 x 109/L)
Recommendation: Maintain dose level
Recommendation: Maintain dose level
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 
Mandatory: Hold dose until resolved to ≤ Grade 2 and platelets ≤ 
Grade 2 (recheck CBC 2x/week), then:
if resolved in ≤ 14 days, then maintain dose level
If resolved in > 14 days, 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 
Mandatory: Hold dose until resolved to ≤ Grade 2 and platelets ≤ 
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
Mandatory: Hold dose until resolved, then reduce dose 1 dose 
level
Thrombocytopenia
Grade 1 (PLT < LLN – 75 X 109/L)
Recommendation: Maintain dose level
Recommendation: Maintain dose level
Grade 2 (PLT < 75 - 50 x 109/L)
Recommendation: Maintain dose level
Recommendation: Maintain dose level


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Dose modifications for both asciminib and bosutinib
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 4.03
Asciminib
Bosutinib
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
Mandatory: Hold dose until resolved to ≤ Grade 2 and 
neutrophils ≤ 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
Mandatory: Hold dose until resolved to ≤ Grade 2 and 
neutrophils ≤ 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: Hold dose until resolved to ≤ Grade 2, 
then maintain current dose level. 
Recommendation: Hold dose until resolved to ≤ Grade 2, then 
reduce dose 1 additional 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
Recommendation: Maintain dose level
Grade 3
Mandatory: Hold dose until resolved to ≤ Grade 1, then 
reduce dose 1 dose level
Mandatory: Hold dose until resolved to ≤ Grade 1, then reduce 
dose 1 dose level, If clinically appropriate, re-escalation of the 
dose back to baseline dose level (500 mg) should be considered
Grade 4
Mandatory: Permanently discontinue patient from study 
drug treatment.
Mandatory: Hold dose until resolved to ≤ Grade 1, then reduce 
dose 1 dose level; If clinically appropriate, re-escalation of the 
dose back to baseline dose level (500 mg) should be considered
Investigations (Renal)
Serum creatinine
Grade 1 (> ULN - 1.5 x ULN)
Recommendation: Maintain dose level
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
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.
Mandatory: Permanently discontinue patient from study drug 
treatment.
Grade 4 (> 6.0 x ULN)
Mandatory: Permanently discontinue patient from study 
drug treatment.
Mandatory: Permanently discontinue patient from study drug 
treatment.


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Dose modifications for both asciminib and bosutinib
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 4.03
Asciminib
Bosutinib
Investigations (Hepatic)
Isolated total Bilirubin elevation
> ULN – 1.5 x ULN
Recommendation: Maintain dose level
Recommendation: Maintain dose level
> 1.5 - 3.0 x ULN
Recommendation: Hold dose. Monitor LFTsb weekly, or 
more frequently if clinically indicated, until resolved to ≤ 
1.5 x ULN:
if resolved in ≤ 14 days, then maintain dose level
if resolved in > 14 days, then reduce dose 1 dose level
Recommendation: Hold dose. Monitor LFTsb weekly, or more 
frequently if clinically indicated, until resolved to ≤ 1.5 x ULN:
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*
Mandatory: Hold dose. Monitor LFTsb weekly, or more 
frequently if clinically indicated, until resolved to ≤ 1.5 x 
ULN:
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.
Mandatory: Hold dose. Monitor LFTsb weekly, or more frequently 
if clinically indicated, until resolved to ≤ 1.5 x ULN:
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*
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.
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
> ULN - 3.0 x ULN
Recommendation: Maintain dose level
Recommendation: Maintain dose level
> 3.0 - 5.0 x ULN
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
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


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Dose modifications for both asciminib and bosutinib
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 4.03
Asciminib
Bosutinib
> 5.0 - 10.0 x ULN
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: Then
If resolved in ≤ 14 days, maintain dose level
If resolved in > 14 days, reduce dose 1 dose level
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 ≤ 2.5 x ULN: Then
Recommendation: If resolved in ≤ 28 days, reduce dose 1 
dose level
Recommendation: If resolved in > 28 days, Discontinue patient 
from study drug treatment
> 10.0 - 20.0 x ULN
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 ≤ 
baseline. Then reduce dose 1 dose level.
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 ≤ 2.5 x ULN. Then
Recommendation: If resolved in ≤ 28 days, reduce dose 1 
dose level maintain dose level
Recommendation: If resolved in > 28 days, Discontinue patient 
from study drug treatment.
> 20.0 x ULN
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.
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 ≤ 2.5 x ULN (then
Recommendation: If resolved in ≤ 28 days, reduce dose 1 
dose level maintain dose level
Recommendation: If resolved in > 28 days, Discontinue patient 
from study drug treatment


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Dose modifications for both asciminib and bosutinib
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 4.03
Asciminib
Bosutinib
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 
6.3.3.1 for additional follow-up evaluations as applicable.
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 6.3.3.1 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
Recommendation: Maintain dose level, measure 2x week
Grade 2 (> 1.5 - 2.0 x ULN)
Recommendation: Maintain dose level, measure 2x 
week
Recommendation: Maintain dose level, measure 2x week
Grade 3 (> 2.0 - 5.0 x ULN)
Mandatory: Hold dose until resolved to Grade ≤ 1 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).
Mandatory: Hold dose until resolved to Grade ≤ 1 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)
Mandatory: Permanently discontinue patient from study 
drug treatment. Obtain appropriate imaging (i.e., MRI, CT 
scan or ultrasound).
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 both asciminib and bosutinib
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 4.03
Asciminib
Bosutinib
Vascular disorders
Hypertension
CTCAE Grade 3
Mandatory: Hold dose until resolved ≤ Grade 1, then 
reduce dose 1 dose level
Mandatory: Hold dose until resolved ≤ Grade 1, then reduce 
dose 1 dose level
CTCAE Grade 4
Mandatory: Permanently discontinue patient from study 
drug treatment.
Mandatory: Permanently discontinue patient from study drug 
treatment.
Gastro intestinal
Pancreatitis
Grade 2 (radiologic findings for 
pancreatitis as per CTCAE v4.03, 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).
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).
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
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
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
Mandatory: Hold dose until recovery to ≤ grade 1. 
Recommendation: Bosutinib may then be resumed at 1 dose 
level
Grade 4
Mandatory: Permanently discontinue patient from study 
drug treatment
Mandatory: Hold dose until recovery to ≤ grade 1. 
Recommendation: Bosutinib may then be resumed at 1 dose 
level


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Dose modifications for both asciminib and bosutinib
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 4.03
Asciminib
Bosutinib
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)
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)
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
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.
Mandatory: Permanently discontinue patient from study drug 
treatment.
General disorders and administration site conditions
Fatigue/ Asthenia
Grade 1 or 2
Recommendation: Maintain dose level
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
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 4.03)
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


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Dose modifications for both asciminib and bosutinib
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 4.03
Asciminib
Bosutinib
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 and bosutinib
Dose reduction*
Starting dose level – 0
Dose level – 1
Asciminib BID
40 mg tablet BID (total daily 
dose 80 mg)
20 mg tablet BID (total daily 
dose 40 mg)
*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.
Dose reduction*
Starting dose level – 0
Dose level – 1
Dose level – 2
Bosutinib QD
500 mg (1-500 mg tablet QD)
400 mg (4-100 mg tablets 
QD)
300 mg (3-100 mg 
tablets QD)
* Dose reduction should be based on the worst toxicity demonstrated at the last dose.
Bosutinib dose reduction below total daily 300 mg is not allowed. 100 mg tablets will be dispensed to patients 
in the instance of dose reduction.
6.3.2
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, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug 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 study drug 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 and 
address clinical conditions that could potentially prolong the QT as per the ECG and 
QTc Clinical Safety Standards Guidelines Section 3.3.1. 

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 for the next treatment(s), (e.g. pre-dose and 2 hours post dose 
after one week and two weeks of treatment re-introduction): 


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
If QTcF remains ≤ 500 msec after dose reduction, continue planned ECG monitoring 
during subsequent treatment 

If QTcF > 500 msec recurs after dose reduction, discontinue patient from trial. 
6.3.3
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.
6.3.3.1
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with 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).
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
1. Laboratory tests should include ALT, AST, albumin, creatinine kinase, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.
2 . A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted.


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4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study.
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
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”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly
documented.
6.3.4
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria, as well as specific dose modification and stopping rules are 
included in this protocol. Recommended guidelines for prophylactic or supportive treatment for 
expected toxicities, including management of study-drug induced adverse events, i.e., 
hyperglycemia, skin toxicity and diarrhea are provided in Table 6-2. Refer to preclinical toxicity 
and or clinical data found in the [Asciminib Investigator’s Brochure] or bosutinib label.
6.4
Concomitant medications for patients on asciminib
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.
6.4.1
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.


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6.4.2
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 1.2.1.1). 
Therefore CYP3A4/5, CYP2C8 and CYP2C9 substrates with narrow therapeutic index (NTI) 
should be used with caution. 
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 14 appears on both the list of prohibited and the list of 
medications to be used with caution, the medication is prohibited.
6.4.3
Prohibited concomitant therapy
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 is not allowed. 
Strong CYP3A4/5 inhibitors
Every effort should be made NOT to concomitantly administer strong CYP3A4/5 inhibitors.
CYP3A4/5 inhibitors may decrease the metabolism of asciminib and resulting in increased 
serum concentrations and increased exposure. If administration of a strong CYP3A4/5 inhibitor 
cannot be avoided during the study and cannot be switched to an alternative therapy that does 
not strongly inhibit CYP3A4/5, asciminib must be interrupted.
A list of cytochrome P450 isoenzymes and CYP3A4/5inhibitors may be found at 
medicine.iupui.edu/CLINPHARM/ddis/clinical-table.
A classification of CYP3A4/5 SmPC can be found in Section 14-Appendices.
Further information can also be found in the following reference (Venkatakrishnan et al 2001).
Strong CYP3A4/5, and UGT1A/2B inducers
Every effort should be made NOT to concomitantly administer strong CYP3A4 inducers during 
the study.
Additionally, the use of strong inducers of UGT1A/2B is prohibited during the study.
If administration of a strong CYP3A4/5 inducer or 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.


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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.
6.4.4
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 6.4.2 and Section 14.1 
Appendix 1).
Bisphosphonates
The use of bisphosphonates regardless of indication is allowed.
Contraceptives
Hormonal contraceptives are allowed as contraception methods. Highly effective contraception 
should be maintained throughout the study and for 3 days after study treatment discontinuation.
Anticoagulation agents
All anticoagulants or anti-aggregation agents may be administered under the discretion of the 
investigator.
Therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative 
anticoagulants should be used with caution and fully avoided whenever possible because of its 
known interaction with many commonly used medications and certain foods. As warfarin has 
a narrow therapeutic range, and asciminib is possibly an inhibitor of CYP2C9, the major 


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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.
6.5
Concomitant medications for patients on bosutinib
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
6.5.1
Permitted concomitant therapy requiring caution
Bosutinib should be used with caution in patients who have or may develop prolongation of QT, 
including those patients who are taking medicinal products that are known to prolong the QTc 
(e.g., anti-arrhythmic medicinal products such as amiodarone, disopyramide, procainamide, 
quinidine and sotalol and other substances that may prolong QTc) (in accordance with EU 
SmPC dated 05/2018).
If a medication listed in Section 14-Appendices appears on both the list of prohibited and the 
list of medications to be used with caution, the medication is prohibited.


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6.5.2
Prohibited concomitant therapy
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 is not allowed. 
Concomitant use with CYP3A inhibitors
Avoid the concomitant use of strong or moderate CYP3A inhibitors as an increase in bosutinib 
plasma concentration is expected. Strong CYP3A inhibitors include boceprevir, clarithromycin, 
conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole.
Moderate CYP3A inhibitors include amprenavir, aprepitant, atazanavir, ciprofloxacin, 
crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit 
products, imatinib and verapamil) [Bosulif® USPI]. If administration of a strong or moderate 
CYP3A4/5 inhibitor cannot be avoided during the study and cannot be switched to an alternative 
therapy, bosutinib must be interrupted.
Concomitant use with CYP3A inducers
Avoid the concomitant use of strong or moderate CYP3A inducers as a large reduction in 
exposure is expected (strong CYP3A inducers include carbamazepine, phenytoin, rifampin and 
St. John's Wort. Moderate CYP3A inducers include bosentan, efavirenz, etravirine, modafinil 
and nafcillin) [Bosulif® USPI]. However, if administration of a strong or moderate CYP3A4/5 
inducer cannot be avoided during the study and cannot be switched to an alternative therapy, 
temporary interruption of bosutinib is NOT required.
pH Altering Medications
Bosutinib displays pH-dependent aqueous solubility, in vitro. In a cross-over trial in 23 healthy 
volunteers, a single oral dose of 400 mg of bosutinib was either administered alone or in 
combination with multiple-oral doses of 60 mg of lansoprazole (PPI) under fasting conditions. 
Lansoprazole decreased bosutinib Cmax and AUC by 46% and 26%, respectively.
Concomitant administration with PPIs is not allowed.
Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in 
bosutinib exposure. Separate antacid or H2 blocker dosing by more than 2 hours [Bosulif®
USPI].
6.6
Patient numbering, treatment assignment or randomization
6.6.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 


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throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available to the investigator through the Oracle Clinical RDC interface.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to be randomized or start treatment for any 
reason, the reason will be entered into the Screening Disposition page. IRT must be notified 
within 2 days that the patient was not randomized.
6.6.2
Treatment assignment or randomization
Patients will be assigned to one of the 2 treatment arms (Section 4.1 and Section 6.1) in a ratio 
of 2:1. Randomization will be stratified by cytogenetic response status at screening.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication randomization list 
will be produced by or under the responsibility of Novartis Drug Supply Management using a 
validated system that automates the random assignment of medication numbers to medication 
packs containing each of the study treatments.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign 
a randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the patient. The randomization number will not be communicated to the caller.
6.6.3
Treatment blinding
Not applicable.
6.7
Study drug 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.


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6.7.1
Study treatment packaging and labeling
Study treatment, asciminib and bosutinib tablets, will be provided as global clinical open-label 
supply and will be packed and labeled under the responsibility of Novartis, Drug Supply 
Management.
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to study treatment and strength).
Responsible site personnel will identify the study treatment package(s) to dispense by the 
medication number(s) assigned by IRT to the patient. Site personnel will add the patient number 
on the label. If the label has 2-parts (base plus tear-off label), immediately before dispensing 
the package to the patient, site personnel will detach the outer part of the label from the package 
and affix it to the patient’s source document.
Table 6-4
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
asciminib (20 mg and 40 mg)
Tablets in bottle
Labeled as ‘ABL001 20 mg/ABL001 40 
mg’(BID)
bosutinib (100 mg or 500 mg)
Tablets in bottle or tablets in 
blister
Labeled as ‘bosutinib 100 mg or bosutinib 
500 mg’(QD)
6.7.2
Drug supply and storage
Study treatments must be received by designated personnel 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, asciminib and bosutinib should be stored according 
to the instructions specified on the drug labels.
6.7.3
Study drug compliance and accountability
6.7.3.1
Study drug 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 
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.
6.7.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study treatment or at 
the time of study treatment discontinuation during the treatment period as well as during the 
switch treatment period with asciminib.


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At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and 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.
6.7.3.3
Handling of other study treatment
Not applicable.
6.7.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, or at the site only if permitted by local regulations and authorized by Novartis in a 
prior agreement.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. Patients can be consented for study participation prior to study day -21.
Table 7-2 lists all of the assessments required by patients that switch treatment from bosutinib 
to asciminib after documented treatment failure of bosutinib.
No eCRF will be used as a source document.
(S) is defined as “Source”
(D) is defined as “Data Based”
























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Category
Protocol 
Section 
7
Switch 
Screening 
Phase
Treatment Switch Phase
Visit name
EOT (Bosutinib)
/
S-Screening/
S-Baseline
S-Week 1 Day 1
S-Week 2 Day 1
S-Week 4
S-Week 6
S-Week 8
S-Week 10
S-Week 12
S-Week 14
S-Week 16
S-Week 20
S-Week 24
S-Week 28
S-Week 32
S-Week 36
S-Week 40
S-Week 44
S-Week 48
S-Week 52
Hematology
D
7.2.2.5.1
X
(if not done 
at EOT)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5.2
X
(if not done 
at EOT)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry-
Hemoglobin A1c
D
7.2.2.5.2
X
(if not done 
at EOT)
Week 12 and as clinically indicated
Coagulation
D
7.2.2.5.2
X
(if not done 
at EOT)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum 
Pregnancy test (if 
applicable)
D
7.2.2.5.3
X
(if not done 
at EOT)
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver 
assessments
D
as clinically indicated














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7.1.1
Molecular pre-screening
Not applicable.
7.1.2
Screening
Written informed consent must be obtained before any study specific medical procedures are 
performed. All screening/baseline assessments (with the exception of Bone Marrow Aspirates) 
should occur within 21 days before Week 1 Day 1.
The screening visit window for bone marrow assessments is 56 days prior to Week 1 Day 1.
Should bone marrow assessments have been performed before the main informed consent is 
signed but within 56 days of Week 1 Day 1, no further bone marrow sampling will be required 
at screening. At end of treatment, a bone marrow exploratory aspirate and/or biopsy must be 
collected even if the screening/baseline bone marrow exploratory aspirate and/or biopsy 
samples were not collected. 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)
and the bone marrow aspirate must be available prior to randomization and first dose of study 
treatment.
For details of assessments required during screening please refer to Table 7-1.
Laboratory baseline assessments (including hematology, chemistry, coagulation 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, the patient ID number will remain the same. All required 
screening activities must be performed when the patient is re-screened for participation in the 
study. No further bone marrow sampling will be done at re-screening if a previous assessment 
was done within 56 days of Week 1 Day 1. After 56 days, new bone marrow biopsy and 
aspirates samples for cytogenetic assessment and exploratory biomarker purpose should be re-


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collected at the time of the bone marrow assessment. 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.
7.1.2.1
Eligibility screening
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be managed via IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
7.1.2.2
Conditions to be fulfilled for asciminib switch
The eligibility assessments of patients who are candidates for asciminib switch will start with 
the bosutinib EOT visit. Assessments conducted during the EOT visit will be used to evaluate 
if all conditions for asciminib switch are fulfilled and there are no conditions preventing patients 
from receiving asciminib treatment. Therefore all efforts MUST be made to ensure that all EOT 
assessments are completed per Table 7-1. In the event that all EOT assessments cannot be 
completed during the EOT visit, they must be completed within 42 days (6 weeks) after the 
bosutinib EOT visit. For details of assessments required for patients that switch treatment from 
bosutinib to asciminib, please refer to Table 7-2. The maximum allowed time frame for patients 
failing bosutinib to start treatment with asciminib is 42 days after bosutinib EOT.
In case a patient presents with a grade 3 or 4 adverse event at the time of the EOT visit or 
develops it after the EOT visit, the adverse event must be resolved to grade 2 or lower before 
starting asciminib treatment and within 28 days of the date of occurrence of the adverse event 
as outlined in the criteria listed below. 
However, a patient who has laboratory test (peripheral blood test) results or ECG results that 
do not satisfy the treatment switch conditions may have the tests repeated multiple times during 
the treatment switch screening period. The last test performed before start of asciminib dosing 
must meet the conditions for treatment switch as listed below.
If a patient does not meet the conditions for treatment switch, they should enter the survival 
follow-up phase.
The conditions for treatment switch will be checked via the IRT system. Please refer and comply 
with detailed guidelines in the IRT manual.
Conditions to fulfill to allow the switch to asciminib:
1. Failure to bosutinib treatment up to 96 weeks after the last patient received the first dose 
(adapted from the 2013 ELN Guidelines; Baccarani et al 2013). Patients must meet at least 
1 of the following criteria. Failure is defined as follows:

Three months after the initiation of therapy or thereafter: No CHR or > 95% Ph+ 
metaphases.

Six months after the initiation of therapy or thereafter: BCR-ABL1 ratio > 10% IS 
and/or > 65% Ph+ metaphases.

Twelve months after initiation of therapy or thereafter: BCR-ABL1 ratio > 10% IS 
and/or > 35% Ph+ metaphases.


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
At any time after the initiation of therapy, loss of CHR, CCyR or PCyR.

At any time after the initiation of therapy, detection of new BCR-ABL1 mutations
which potentially cause resistance to study treatment (asciminib or bosutinib).

At any time after the initiation of therapy, confirmed loss of MMR in 2 consecutive 
tests.

At any time after the initiation of therapy, new clonal chromosome abnormalities in 
Ph+ cells: CCA/Ph+.
Conditions preventing patients to switch to asciminib

Any Grade 3 or 4 toxicity which has not resolved to Grade 2 or lower within 28 days 
and before starting asciminib treatment.

Asymptomatic (Grade 2) pancreatitis if not resolved within 28 days 

Disease progression while on bosutinib treatment. The following events are 
considered disease progression:

Accelerated phase (AP) as defined by any of the following:

≥15% blasts in the peripheral blood or bone marrow aspirate, but < 30% blasts 
in both the peripheral blood and bone marrow aspirate.

≥30% blasts plus promyelocytes in peripheral blood or bone marrow aspirate.

≥20% basophils in the peripheral blood.

Thrombocytopenia (< 100 x 109/L) that is unrelated to therapy.

Blast crisis (BC) as defined by any of the following:

≥30% blasts in peripheral blood or bone marrow aspirate

Appearance of extramedullary involvement other than hepatosplenomegaly 
proven by biopsy (i.e. chloroma).

QTcF at time of switch > 480msec or inability to determine QTc interval
7.1.2.3
Information to be collected on screening failures
Patients who sign an informed consent but fail to be randomized for any reason will be 
considered a screen failure. The reason for not being randomized will be entered on the 
Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details). If the patient fails to be randomized, the IRT must be notified within 2 days 
of the screen fail that the patient was not randomized.
7.1.2.4
Patient demographics and 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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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 and the bone 
marrow aspirate must be available prior to randomization and first dose of study treatment to 
evaluate eligibility and to stratify the patient.
7.1.2.5
Local recruitment procedures-Japan
Given the limited safety data available in Japanese patients, specific recruitment and data 
monitoring procedures will be put in place for Japanese patients randomized to asciminib.
Randomization of these patients will be staggered to avoid enrollment of more than one patient 
on the same day. Safety parameters from a minimum of 2 patients treated on the asciminib arm 
will be reviewed for determining the appropriateness of continuing patient enrollment in Japan.
7.1.3
Run-in period
Not applicable.
7.1.4
Treatment period
There is no fixed duration of treatment planned per patient. All patients will be given the 
opportunity to receive study treatment until the end of study treatment period as defined in 
(Section 4.3).
During the treatment phase, the patients will receive either asciminib treatment 40 mg BID or 
bosutinib 500 mg QD according to randomization. The dose can be modified, if required from 
the perspective of tolerance, following the guidance in Section 6.2 and Section 6.3. 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).
7.1.5
Visit windows
Study visits from Week 1 Day 1 to Week 2 Day 1 / S-Week 1 Day 1 to S-Week 2 Day 1  should 
be completed on the designated date [with an allowed “visit window” of +/- 1 day for Week 2 
Day 1 / S-Week 2 Day 1]
Study visits from Week 4 to Week 16 / S-Week 4 to S-Week 16 should be completed every 2 
weeks on the designated date [with an allowed “visit window” of +/- 1 day]


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Study visits from Week 20 to Week 96 / S-Week 20 to S-Week 96 should be completed every 
4 weeks on the designated date [with an allowed “visit window” of +/- 2 days]
Study visits from Week 108 to EOT / S-Week 108 to S-EOT should be completed every 12 
weeks on the designated date [with an allowed “visit window” of +/- 7 days]
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.
7.1.6
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a
patient decides to discontinue from the study treatment, the investigator should make a  
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this
decision and record this information in the patient’s chart and on the appropriate eCRF pages.
They may be considered withdrawn if they state an intention to withdraw, fail to return for visits,
or become lost to follow-up for any other reason.
The investigator should discontinue study treatment for a given patient if, he/she believes that
continuation would be detrimental to the patient’s well-being. Patients who discontinue study 
treatment should undergo an end of treatment visit.
For patients who discontinue treatment in treatment period or switch treatment period for 
reasons other than death, lost to follow-up, or withdrawal of consent, the patient should enter 
the survival follow-up phase. Survival visit assessments (survival, antineoplastic therapies, stem 
cell transplant and progression) should be performed every 12 weeks until documented death, 
lost to follow-up, withdrawal of consent or until the end of the study. This visit can be conducted 
by telephone.
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 14-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 T315I or V299L mutations at any time the patient must be 
discontinued from the study treatment.

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 


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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. 
Patients randomized to bosutinib treatment experiencing treatment failure may switch to 
asciminib treatment. The following events will constitute ‘treatment failure’, and are based 
on the ELN criteria (Baccarani et al 2013) defining failure of a second line treatment:

No CHR or > 95% Ph+ metaphases at three months after initiation of therapy or 
thereafter

BCR-ABL1 ratio > 10% IS and/or > 65% Ph+ metaphases at six months after 
initiation of therapy or thereafter

BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases at 12 months after 
initiation of therapy or thereafter

Loss of CHR, CCyR or PCyR at any time after initiation of therapy 

Detection of new BCR-ABL1 mutations which potentially cause resistance to study 
treatment (asciminib or bosutinib) at any time after initiation of therapy 

Confirmed loss of MMR in 2 consecutive tests (Section 7.2.1.1)

New clonal chromosome abnormalities in Ph+ cells: CCA/Ph+: at any time after 
initiation of therapy 

In the event of disease progression the patient must be discontinued from the study
treatment. The following events are considered disease progression.
1. 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)
2. Accelerated phase (AP) as defined by any of the following:

≥ 15% blasts in the peripheral blood or bone marrow aspirate, but < 30% blasts in 
both the peripheral blood and bone marrow aspirate

≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow aspirate

≥ 20% basophils in the peripheral blood

Thrombocytopenia (<100 x 109/L) that is unrelated to therapy
3. Blast crisis (BC) as defined by any of the following:

≥ 30% blasts in peripheral blood or bone marrow aspirate

Appearance of extramedullary involvement other than hepatosplenomegaly proven by 
biopsy (i.e., chloroma).
7.1.7
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data


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In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may
still be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and Rest of World: All biological samples not yet analyzed at the time of withdrawal 
will no longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements.
7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Molecular response
Molecular response (MR) will be assessed in all patients randomized to each treatment arm as 
well as in patients that switch study treatment from bosutinib to asciminib.
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.
Major molecular response 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 randomization 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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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 or loss of CCyR or progression to AP/BC or CML-
related death. Mutational analysis will be performed at a Novartis designated laboratory by 
Sanger sequencing at Week 1 Day 1, upon confirmed loss of MMR and/or at end of treatment. 
If the result at Week 1 Day 1 is positive for a mutation, analysis will be performed every 12 
weeks.
The blood samples will be taken as described in Table 7-1, Table 7-2 and Table 7-3.
Table 7-3
Blood samples (efficacy primary endpoint)
Sample Type
Volume
Visit
Time point
Blood for BCR-ABL1
quantification by RQ-PCR
20 mL
Screening/Baseline / S-Screening/S-Baseline*
Pre-dose
20 mL
Week 4 / S-Week 4
Pre-dose
20 mL
Week 8 /  S-Week 8
Pre-dose
20 mL
Week 12 /  S-Week 12
Pre-dose
20 mL
Week 16 /  S-Week 16
Pre-dose
20 mL
Week 24 /  S-Week 24
Pre-dose
20 mL
Week 36 /  S-Week 36
Pre-dose
20 mL
Week 48 /  S-Week 48
Pre-dose
20 mL
Week 60 /  S-Week 60
Pre-dose
20 mL
Week 72 /  S-Week 72
Pre-dose
20 mL
Week 84 /  S-Week 84
Pre-dose
20 mL
Week 96 /  S-Week 96
Pre-dose
20 mL
Every 12 weeks thereafter up to end of study 
treatment    
Pre-dose
20 mL
End of Treatment / S-End of Treatment
Anytime
Blood for BCR-ABL1 Mutation
analysis by Sanger 
Sequencing
5 mL
Week 1 Day 1 /S-Week 1 Day 1*
Pre-dose
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/ S-End of Treatment
Anytime
Blood for BCR-ABL1 Mutation
analysis only for patients with
mutations at Week 1 Day 1
No sample collected 
-  testing is 
performed on the 
“Blood for BCR-
ABL1 quantification 
by RQ-PCR” sample
Week 12 and every 12 weeks thereafter up to 
end of study treatment
Anytime
*Assessment does not need to be completed during the visit for patients in the treatment switch if already 
collected during the EOT or the treatment switch screening visit.


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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 [CABL001A2301 Laboratory Manual].
7.2.1.2
Bone marrow analysis and cytogenetics
Cytogenetic response will be assessed locally as the percentage of Ph+ metaphases in the bone 
marrow and is defined as the following (a review of a minimum of 20 metaphases is required):

Complete (CCyR) - 0% Ph+ metaphases

Partial (PCyR) - >0 to 35% Ph+ metaphases

Major (MCyR) - 0 to 35% Ph+ metaphases

Minor (mCyR) - >35 to 65% Ph+ metaphases

Minimal - >65 to 95% Ph+ metaphases

None - >95 to 100% Ph+ metaphases.
Bone marrow aspirate for cytogenetic analyses will be performed at screening/baseline 
(performed up to 56 days prior to Week 1 Day 1), at Week 24/S-Week 24, 48/S-48, 72/S-72, 
96/S-96 as long as patient has not achieved MMR and at end of treatment (S-end of treatment 
as specified in Table 7-1 and Table 7-2. For patients on the bosutinib arm an unscheduled bone 
marrow assessment at week 12 may be performed to evaluate cytogenetic response in 
consideration for potential dose escalation.
Quantification of the percentage of Ph+ chromosome metaphases, number of metaphases, 
number positive for Ph chromosome, additional chromosomal abnormalities as well as data 
from cytologic evaluation (microscopic analysis) of percentage of blasts and promyelocytes 
will be recorded on the Bone Marrow eCRF. These exams will be performed and analyzed 
locally. Fluorescent In-situ hybridization (FISH) analysis will not be accepted.
7.2.1.3
Hematologic response
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
7.2.2
Safety and tolerability assessments
Safety will be monitored by the assessments described below as well as collecting of the adverse 
events at every visit. For details on AE collection and reporting, refer to Section 8. 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.


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7.2.2.1
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 7-1 and Table 7-2:

Screening /S-Screening

Week 1 Day 1 / S-Week 1 Day 1

Every 2 weeks from Week 4 to Week 16 / S-Week 4 to S-Week 16. Week 6, 10 and 14 / 
S-Week 6, 10 and 14 assessments must be performed in case of previous or newly 
occurring adverse events.

Every 4 weeks from Week 16 to Week 96 / S-Week 16 to S-Week 96

Every 12 weeks from Week 96 to EOT / S-Week 96 to S-EOT

End of treatment / S-End of treatment visit or early discontinuation / S-early 
discontinuation visit in case of premature discontinuation.
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).
7.2.2.2
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 7-1 and Table 7-2:

Screening / S-Screening

Week 1 Day 1 / S-Week 1 Day 1

Week 2 Day 1 / S-Week 2 Day 1

Every 2 weeks from Week 4 to Week 16 / S-Week 4 to S-Week 16

Every 4 weeks from Week 16 to Week 96 / S-Week 16 to S-Week 96

Every 12 weeks from Week 96 to EOT/ S-Week 96 to S-EOT

End of treatment / S-End of treatment visit or early discontinuation / S-early 
discontinuation visit in case of premature discontinuation.
7.2.2.3
Height and weight
Height in centimeters (cm) will be measured at screening only.
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured at screening and at subsequent time points as specified in Table 7-1 and Table 7-2:

Screening / S-Screening


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
Week 1 Day 1 / S-Week 1 Day 1

Every 12 weeks from Week 12 to EOT / S-Week 12 to S-EOT

End of treatment visit / S-End of treatment or early discontinuation / S-early 
discontinuation visit in case of premature discontinuation.
7.2.2.4
Performance status
ECOG Performance status scale (Table 7-4) will be used as described in the Table 7-1, Table 
7-2 and Table 7-4:

Screening / S-Screening

Week 1 Day 1 / S-Week 1 Day 1

Every 2 weeks from Week 4 to Week 16 / S-Week 4 to S-Week 16

Every 4 weeks from Week 16 to Week 96 / S-Week 16 to S-Week 96

Every 12 weeks from Week 96 to EOT / S-Week 96 to S-EOT

End of treatment / S-End of treatment visit or early discontinuation / S-early 
discontinuation visit in case of premature discontinuation.
More frequent examinations may be performed at the investigator’s discretion, if medically 
indicated.
Table 7-4
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
7.2.2.5
Laboratory evaluations
Central laboratory will be used for analysis of hematology, biochemistry, coagulation, serum 
pregnancy and hepatitis marker specimens collected (safety monitoring) as specified in Table 
7-1, Table 7-2 and Table 7-5. Details on the collections, shipment of the samples and reporting 
of results by the central laboratory are provided to investigators in the [CABL001A2301 
Laboratory Manual]. The time windows granted for laboratory evaluations are identical with 
the corresponding visit time windows for each visit (see Section 7.1.5).
Local laboratory analysis are allowed if there is a clinical suspicion of abnormal laboratory
values which is supported by a reported adverse event and for hematology assessments at Week 
6, 10 and 14.


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Table 7-5
Central 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 2 weeks from week 
4 up to week 16, every 4 weeks up to 
week 96, and every 12 weeks thereafter, 
EOT and as clinically indicated / S-
Screening/S-baseline*, S-Week 1 Day 1, 
S-Week 2 Day 1, every 2 weeks from S-
week 4 up to S-week 16, every 4 weeks 
up to S-week 96, and every 12 weeks 
thereafter, S-EOT and as clinically 
indicated
Chemistry
Hemoglobin A1c
Screening/baseline, Week 12 and as 
clinically indicated / S-Screening/S-
baseline*, S-Week 12 and as clinically 
indicated
Chemistry
Creatinine clearance
Screening/baseline / 
S-Screening/S-baseline*
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 96, and every 12 weeks 
thereafter, EOT, and as clinically 
indicated / S-Screening/S-baseline*, S-
Week 1 Day 1, S-Week 2 Day 1, every 4
weeks from S-week 4 up to S-week 96, 
and every 12 weeks thereafter, S-EOT, 
and as clinically indicated
Coagulation
International Normalized Ratio (INR)
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 96, and every 12 weeks thereafter, 
EOT, unscheduled / S-Screening/S-
baseline*, every 4 weeks up to S-week 
96, and every 12 weeks thereafter, S-
EOT, unscheduled
*Assessment does not need to be completed during the screening visit for patients in the treatment switch if 
already collected during the EOT.
**Not applicable for patients being assessed for treatment switch as part of the treatment switch 
screening/baseline visit.
7.2.2.5.1 Hematology
Hematology labs are to be analyzed at each scheduled visit by a central laboratory (Week 6, 10 
and 14 assessments can be performed at site or at any peripheral local laboratory) as specified 
in Table 7-1 and Table 7-2. 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 7-5).


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7.2.2.5.2 Clinical chemistry
Blood chemistry labs are to be analyzed at each scheduled visits by a central laboratory as 
specified in Table 7-1 and Table 7-2. 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. In addition the coagulation parameter 
INR is analyzed at each scheduled visit.
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 7-5).
7.2.2.5.3 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 7-
1 and Table 7-2 of the Visit evaluation schedules. Serum pregnancy test will be performed by 
a central laboratory.
After Week 96 / S-Week 96, monthly urine pregnancy test must be performed by all women of 
child-bearing potential between the three monthly visits (beginning at Week 100 / S-Week 100).
Urine pregnancy tests may be performed at the investigational site or at home. Test results 
performed at home should be recorded onto a patient diary and brought to each scheduled visit 
for the site to review. If a test result indicates a pregnancy, the patient must contact the 
investigator immediately.
Pregnancies diagnosed in female patients participating in the study  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.
During the whole study, women of childbearing potential should employ the use of highly 
effective contraception. Highly effective contraception methods are defined in Section 5.3
7.2.2.6
Cardiac assessments
7.2.2.6.1 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 7-1, Table 7-2, Table 7-6 and Table 7-
7. ECGs should be taken before blood samples for PK if both assessments are scheduled at the 
same time point. In this case recording of ECGs should be planned according to the true time 
of blood sample for PK rather than to the scheduled time point.


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Table 7-6
Central ECG collection (all patients)
Week (or Day)
Number of ECGs (per visit)
Time of ECG
Screening/Baseline Day -21 
to -1 / S-Screening/S-
Baseline Day -42 to -1 (all 
patients)
3
3 serial ECGs at the screening visit
Week 1 Day 1 / S-Week 1 
Day 1 (all patients)
3
3 serial ECGs at 2 h post dose
Week 2 Day 1 / S-Week 2 
Day 1 (asciminib/asciminib 
switch patients)
12
3 serial ECGs pre-dose and at 2, 3, 4 h post-
dose
Week 2 Day 1 / S-Week 2 
Day 1 (bosutinib)
3
3 serial ECGs pre-dose
Week 4 / S-Week 4 (all 
patients)
3
3 serial ECGs pre-dose
Week 12 / S-Week 12 (all 
patients)
3
3 serial ECGs pre-dose
Week 24 / S-Week 24 (all 
patients)
3
3 serial ECGs pre-dose
Week 96 / S-Week 96 (all 
patients)
3
3 serial ECGs 30 min* post-dose
Unscheduled (all patients)
3
3 serial ECGs 
* 30 min +/- 5min allowed
Table 7-7
Central ECG collection plan for patients in full PK asciminib group
Week (or Day)
Number of ECGs (per visit)
Time of ECG
Day -21 to -1
3
3 serial ECGs at the screening visit
Week 1 Day 1
3
3 serial ECGs at 2 h post dose
Week 2 Day 1
24
3 serial ECGs pre-dose and at 1, 2, 3, 4, 6, 8, 
12 h post-dose
Week 4
3
3 serial ECGs pre-dose
Week 12
3
3 serial ECGs pre-dose
Week 24
3
3 serial ECGs pre-dose
Week 96
3
3 serial ECGs 30 min* post-dose
Unscheduled
3
3 serial ECGs 
* 30 min +/- 5min allowed
All ECGs performed will be independently reviewed. Instructions for the collection and 
transmission of these ECGs to the independent central reader (ERT (Electronic Research 
Technology, Inc.)) will be provided in the [CABL001A2301 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 ERT. 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 


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central reading must be requested by calling ERT. 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 6.3.2.
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.
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.
7.2.2.6.2 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 7-1 and Table 7-2. As both study treatments in the trial are TKIs 
(asciminib and bosutinib), 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 patient’s Family History.
7.2.2.6.3 Echocardiogram
Echocardiograms will be performed to monitor cardiac safety. Assessments are scheduled at 
screening/baseline, Week 20 and end of treatment visits. The echocardiogram will be performed 
and evaluated locally to assess the left ventricular ejection fraction. Any clinically significant 
findings will be collected and reported in the database (i.e. reported as adverse events). For 
patients that switch from bosutinib to asciminib treatment, an echocardiogram will no longer
be required.
7.2.2.6.4 Pulmonary function test
Pulmonary function test will be performed to monitor cardio-pulmonary safety. Assessments 
are scheduled at screening/baseline, Week 20 and end of treatment visits. 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 points. Any clinically significant findings will be collected and reported in the 
database (i.e. reported as adverse events). For patients that switch from bosutinib to asciminib
treatment, the pulmonary function testing will no longer be required.


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7.2.3
Pharmacokinetics
Blood samples for asciminib pharmacokinetics will be collected on all study subjects allocated 
to the asciminib treatment arm. Blood samples for full PK profiles will be collected from at 
least 20 patients. These patients will be identified sequentially at selected sites that are capable 
of serial PK sampling over 12 hours. Asciminib should be taken for at least 3 consecutive days 
without interruption or dose modification prior to full PK day.
Blood samples for asciminib pharmacokinetics will also be collected on patients switching from 
bosutinib to asciminib (see Table 7-8). 
For the assessment of asciminib pharmacokinetics in plasma, serial blood samples will be 
collected following asciminib administration at several time-points (see Table 7-1, Table 7-2, 
Table 7-8 and Table 7-9 below for further details). Remaining plasma samples may be used for 
identification and/or measurement of metabolites of asciminib.
Refer to the [CABL001A2301 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK samples.
Table 7-8
Pharmacokinetic blood collection log (Sparse PK-group-asciminib
arm/ asciminib treatment switch patients)
Week /
S-Week
Day
Scheduled Time 
Point
Dose 
Reference ID
PK Sample No
Blood Volume 
(mL)
1
1
2 h (± 10 min)
101
101
2
2
1
0 h (Pre-dose)a
102/2001b
102
2
1
2 h (± 10 min)
102
103
2
1
3 h (± 15 min)
102
104
2
1
4 h (± 15 min)
102
105
2
4
Any
0 h (Pre-dose)a
103/3001b
106
2
12
Any
0 h (Pre-dose)a
104/4001b
107
2
24
Any
0 h (Pre-dose)a
105/5001b
108
2
96
Any
0 h (Pre-dose)a
106/6001 b
109
2
Unscheduled
1001+
a Pre-dose PK sample should be taken immediately prior to the next administration of asciminib. PK samples 
on Week 2 Day 1 should be taken before and after the morning dose (i.e. 1st dose of the day). PK samples on 
other weeks may be taken immediately prior to the morning dose (i.e. 1st dose of the day) or the evening dose 
(i.e. 2nd dose of the day).
b The first dose reference ID refers to the first dose administered after PK sampling and the second dose 
reference ID refers to the last dose administered prior to the PK sampling.








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7.2.5
Resource utilization
The measures of healthcare Resource Utilization (RU) to be collected include: hospitalization
(H), emergency room (ER) visit, general practitioner (GP) visits, specialist (Sp) visit and urgent 
care (UC) visit. These measures will be used to derive the economic impact of asciminib and 
bosutinib.
Hospitalization visits will also record the number of days in ward and the type of ward (hospital 
unit) and the discharge status. At each RU collection, the reason for the visit (i.e. related to 
CML, AE related to CML therapy or other reason) will be collected in order to quantify the 
impact of asciminib and bosutinib on healthcare resources.
The RU assessment will be completed at each scheduled clinical trial visit as specified in Table 
7-1; the RU will be completed by the investigator however information with respect to the 
number of GP, UC, Sp or ER visits will be ascertained from the patient.
All attempts to collect as much information from the patient as possible should be made in order 
to minimize selection bias.
7.2.6
Patient reported outcomes
The MDASI CML, PGIC, WPAI along with EQ-5D-5L (EuroQol Group (1990), Brooks (1996),
Herdman et al (2011)) will be used to compare data on the patient’s disease-related symptoms 
and health-related quality of life from baseline to EOT between the treatment arms. The WPAI 
will be used to assess work productivity and activity impairment related to the patient’s CML. 
All measures will assess differences between the treatment arms. All tools require patient’s 
direct completion and will be administered utilizing an electronic device for data collection.
Patients with an evaluable baseline score and at least one evaluable post baseline score during 
the treatment period will be included in the change from baseline analyses. Missing data items 
in a scale will be handled according to the manual for each instrument. No imputation will be 
applied if the total or subscale scores are missing at a visit.
The patient should be given the questionnaire(s) to be completed at the scheduled visit before 
any clinical assessments are conducted as specified in Table 7-1. Completion of all 
questionnaires is mandatory; they cannot be skipped. In the event a patient refuses to complete 
the questionnaire(s), the patient’s refusal should be documented in the study data capture system 
and should not be captured as a protocol deviation. Patient questionnaires should be completed 
in the language most familiar to the patient.
The patient should be given sufficient space and time to complete the questionnaires and the 
administered questionnaire should be reviewed for completeness. If missing responses are noted, 
patients should be encouraged to complete any missing responses. 
Completed questionnaire(s) and any unsolicited comments written by the patient should be 
reviewed and assessed by the investigator for responses which may indicate potential AEs or 
SAEs before any clinical study examinations. This assessment should be documented in study 
source records. If AEs or SAEs are confirmed, study investigators should not encourage the 
patient to change responses reported in the completed questionnaires. Study investigators must 
follow reporting instructions outlined in Section 8 (e.g. reference “Adverse Events” Section) of 
the study protocol.


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MDASI-CML
The M.D. Anderson Symptom Inventory – Chronic Myeloid Leukemia (MDASI-CML) is a 26 
item self-administered questionnaire for adult CML patients. Twenty of the items measure the 
severity of disease-related symptoms and are scored from 0 (Not present) to 10 (As Bad as you 
can imagine) and 6 items that measure symptom interference with daily life scored from 0 (Did 
not interfere) to 10 (Interfered completely). Descriptive statistics will be provided for the 
MDASI-CML symptom score and interference score, and the change in the MDASI-CML 
symptom score and interference score from baseline to all available time points to the end of 
study. Additional analysis may be performed and details will be described in the analysis plan.
EQ-5D-5L
EQ-5D-5L is a two-part standardized instrument for measuring health outcomes in a wide range 
of health conditions and treatments. It consists of a descriptive system and a visual analogue 
scale (EQ VAS). The descriptive system comprises the following 5 dimensions: mobility, self-
care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems and extreme problems (or 
unable to perform the activity). The EQ VAS records the respondent’s self-rated health on a 
vertical, visual analogue scale where the endpoints are labeled ‘Best imaginable health state’ 
and ‘worst imaginable health state’. The health states derived from the descriptive system can 
be summarized into a single index score that provides a simple measure of health for clinical 
and economic appraisal. Descriptive statistics will be provided for EQ-5D-5L health index score 
and for the EQ VAS, at each scheduled assessment time point. There should be only ONE 
response for each dimension. Missing values can be coded as ‘9’. Ambiguous values (e.g. 2 
boxes are ticked for a single dimension) should be treated as missing values. Additional analysis 
may be performed and details will be described in a separate analysis plan.
WPAI
The Work Productivity and Activity Impairment Questionnaire (WPAI) is a four-item 
questionnaire which is intended to measure work and activity impairment associated with CML 
for those who self-identify as currently employed for pay. This questionnaire measures self-
reported productivity loss associated with CML during the past seven days. It consists of 
questions about absence from work due to CML, hours spent at work, the reduction in 
productivity at work attributed to CML, and the reduction in productivity while performing 
regular activities. WPAI outcomes are expressed as impairment percentages, with higher 
numbers indicating greater impairment and less productivity, i.e., worse outcomes, Scoring will 
be done according to WPAI instrument guidance resulting in four scores including: Percent 
work time missed due to problem; percent impairment while working due to problem; Percent 
overall work impairment due to problem; and, percent activity impairment due to problem.
Change from baseline in WPAI at each visit, where measured, will be done for each of the four 
derived scores.
PGIC
The Patient Global Impression of Change is comprised of a single question intended to measure 
a patient’s perspective of improvement or deterioration over time relative to treatment. The 


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PGIC uses a seven-point scale where one (1) equals very much improved and seven (7) equals 
very much worse. A summary of Patient Global Impression of Change (PGIC) at each visit, 
where measured will be provided.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
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.
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.
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. 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)


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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 8.2.1
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 
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.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 


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the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.1.3
Adverse events of special interest
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].
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
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 


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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.
8.3
Emergency unblinding of treatment assignment
Not applicable.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 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 on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.


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8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided asciminib 
Investigator’s Brochure or bosutinib label. Additional safety information collected between IB 
updates will be communicated in the form of Investigator Notifications. This information will 
be included in the patient informed consent and should be discussed with the patient during the 
study as needed.
8.6
Data Monitoring Committee
This study will institute a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will be constituted prior to the randomization 
of the first patient. The DMC will be responsible to review safety data at approximately 6
months after the first randomized patient has started study treatment. Subsequent reviews will 
be conducted approximately every 6 months on an as and when needed basis thereafter (i.e. if 
significant safety findings are noted). This includes but does not limit the role of the DMC to 
evaluate these data and to provide recommendations to the sponsor to continue, modify or stop 
the study early. The DMC will be in place at least until the conduct of the primary analysis.
It is expected that the DMC will consist at a minimum of two physicians with appropriate 
disease area qualifications and one statistician. There will be a meeting with the DMC 
describing their roles and responsibilities and discussing potential data format and process 
issues prior to the finalization of DMC charter.
It is envisioned that the DMC may make certain types of recommendations, namely:

No safety concerns, ethical to continue the study as planned

Serious safety concerns precluding further study treatment, regardless of efficacy

Recommendation to continue the study but proposing an amendment to the protocol (e.g., 
incorporate an additional safety assessments)
8.7
Steering Committee
In order to monitor study conduct, a Steering Committee (SC) will be established comprising 
investigators participating in the trial. Additionally two sponsor representatives (a physician 
and a statistician) will be active members of this committee.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. Novartis will make final 
decisions on trial conduct based on SC recommendations. Together with the clinical trial team, 
the SC will review protocol amendments as appropriate, and also develop recommendations for 
publications of study results including authorship rules. The details of the role of the Steering 
Committee will be defined in a Steering Committee charter.


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9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient 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 recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the 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 
and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
Data collected by third parties (biochemistry, PCR assessments, biomarkers, PK) will be sent 
electronically to Novartis.
9.4
Database management and quality control
For studies using eCRFs, 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 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using the Novartis Interactive Response Technology.
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
The data will be analyzed by Novartis and/or designated CRO. It is planned that the data from 
participating centers in this protocol will be combined, so that an adequate number of patients 
will be available for analysis.


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Study data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, safety observations and measurements, and all 
relevant PK and PD measurements.
The cut-off date for the primary analysis is defined as the date when all patients have been on 
study treatment for 24 weeks or discontinued earlier. The cut-off date for the end of study
treatment analysis is defined as 30 days after the end of study treatment period (see Section 4.3)
to ensure that all available treatment phase data from all patients up to the last dose of study 
drug taken in this study, will be analyzed and summarized in the end of study treatment phase 
CSR. Patients will be further followed  for survival and progression for up to 5 years from the 
date the last randomized patient receives the first study dose. An update analysis of OS and PFS 
will be performed at the end of the follow-up period in the final study CSR.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
by randomization. According to the intention to treat principle, patients will be analyzed 
according to the treatment and stratum they have been assigned to during the randomization 
procedure.
10.1.2
Safety set
The Safety Set includes all patients who received at least one dose of study treatment. Patients 
will be analyzed according to the study treatment received, where treatment received is defined 
as the randomized treatment if the patient took at least one dose of that treatment or the first 
treatment received if the randomized treatment was never received.
10.1.3
Per-Protocol set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the CSP. The PPS will be used for sensitivity analyses on the primary 
endpoint only.
Oncology standards for protocol deviations potentially leading to exclusion from the PPS are:

Type of indication different from those required by the CSP

If prior therapy does not match with CSP requirements in terms of number and types of 
previous therapy regimens

Another anti-neoplastic therapy administered after start of study treatment and prior to 
first efficacy assessment

Study treatment received different from treatment assigned by randomization
10.1.4
Dose-determining analysis set
Not applicable.


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10.1.5
Pharmacokinetic analysis set
The Pharmacokinetic analysis set (PAS) includes all patients who provide at least one 
evaluable PK concentration. For a concentration to be evaluable, patients are required to:

Take a dose of asciminib prior to sampling,

Take the same dose of asciminib for at least 3 consecutive days without dose interruption 
or dose modification prior to sampling,

For post-dose samples, do not vomit within 4 hours after the dosing of asciminib (this is 
the current dose); for pre-dose samples do not vomit within 4 hours after the dosing of 
asciminib prior to sampling (this is the previous dose),

Have the pre-dose sample collected before the next dose administration.
10.1.6
Other analysis set
For duration of MMR and time to MMR, the MMR Responder Set that will be used is a subset 
of FAS and includes patients who achieve MMR at any time.
For CCyR rates at and by scheduled time points, the CCyR Analysis Set that will be used is a 
subset of FAS and includes patients who are not in CCyR at baseline.
For duration of CCyR and time to CCyR, the Cytogenetic Responder Set that will be used is a 
subset of FAS and includes patients who do not have CCyR at baseline and achieve CCyR at 
any time on study treatment.
Patients who will receive at least one dose of asciminib after bosutinib failure will form the 
Switch Analysis Set which will be used for safety and exploratory efficacy endpoints defined 
on these patients. 
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS or the Safety Set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, by treatment group.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The Safety set will be used for the analyses below.
Categorical data will be summarized as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
The duration of exposure in days to asciminib and bosutinib, as well as the dose intensity 
(computed as the ratio of actual cumulative dose received and actual duration of exposure) and 


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the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity) 
will be summarized by means of descriptive statistics.
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment group and all dosing data 
will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
10.4
Primary objective
The primary objective of the study is to evaluate the efficacy of asciminib at the recommended 
dose in CML patients in chronic phase, previously treated with 2 or more tyrosine kinase 
inhibitors and to compare this efficacy profile in this population with that achieved by patients 
receiving bosutinib.
10.4.1
Variable
The primary efficacy variable of the study is the Major Molecular Response (MMR) rate at 24 
weeks. A patient will be counted as having achieved MMR at 24 weeks if he meets the MMR 
criteria (BCR-ABL1 ratio ≤0.1%) at 24 weeks.
10.4.2
Statistical hypothesis, model, and method of analysis
The MMR rate at 24 weeks will be calculated based on the FAS and according to the Intention-
ToTreat (ITT) principle. MMR rate and its 95% confidence interval based on the Pearson-
Clopper method will be presented by treatment group. The confidence interval for the difference 
in MMR rate between treatment groups will be provided using the Wald method.
The null hypothesis is that there is no difference between the treatment groups with respect to 
MMR rate at 24 weeks. The Cochrane-Mantel-Haenszel chi-square test, stratified by the 
randomization stratification factor, i.e. major cytogenetic response status (PCyR or CCyR vs.
others) at screening, will be used to compare MMR rate between the two treatment groups, at 
the two-sided 5% level of significance. The Mantel-Haenszel estimate of the common risk 
difference and the corresponding 95% confidence interval will also be provided.
10.4.3
Handling of missing values/censoring/discontinuations
Only patients with MMR at 24 week visit are considered responders. In other words, any patient 
who achieves MMR before 24 weeks, but is no longer in MMR at 24 weeks, will be considered 
as a non-responder in this primary analysis. Patients discontinuing the randomized treatment 
(having performed an EOT visit) prior to 24 weeks due to any reason will be considered as non-
responders. One exception to the rule above is if the 24-week PCR evaluation is missing, but 
both a PCR evaluation at 16 weeks and a PCR evaluation at 36 weeks indicate MMR, the 24-
week assessment is imputed as a ‘Response’. If PCR evaluations are performed at unscheduled 
visits closer to the Week 24 visit (before or after), these will be taken into account for the 
imputation.


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10.4.4
Supportive and Sensitivity analyses
The analysis of the primary endpoint will also be repeated on the PPS if the PPS is different 
from the FAS.
Subgroup analyses and a logistic regression analysis will be employed. Refer to the exploratory 
objectives Section 10.6.1 for further details.
10.5
Secondary objectives
The secondary objectives in this study are as follows:

To compare additional parameters of the efficacy of asciminib versus bosutinib, defined 
as:
Key secondary endpoints

MMR rate at 96 weeks
Other efficacy endpoints

Cytogenetic response (Complete, Partial, Major, Minor, Minimal, no response) rate at all 
scheduled data collection time points including, 24, 48 and 96 weeks.

Cytogenetic response (Complete, Partial, Major, Minor, Minimal, no response) rate by all 
scheduled data collection time points including, 24, 48 and 96 weeks.

MMR rate at all scheduled data collection time points (except 24 and 96 weeks which are 
already covered by primary and key secondary endpoints)

MMR rate by all scheduled data collection time points including 24, 48 and 96 weeks.

Time to MMR

Duration of MMR

Time to CCyR

Duration of CCyR

Time to treatment failure

Progression free survival

Overall survival

To compare the safety and tolerability profile of asciminib versus bosutinib

To characterize the PK of asciminib in the CML-CP population
10.5.1
Key secondary objective(s)
The key secondary endpoint to be evaluated is MMR rate at 96 weeks, which is defined as the 
proportion of patients with MMR at 96 weeks and derived in a similar fashion to MMR rate at 
24 weeks.


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10.5.1.1 Analysis for key secondary objectives
The null hypothesis is that there is no difference between the treatment groups with respect to 
MMR rate at 96 weeks. Formal statistical testing of the key secondary endpoint will be 
performed with = 0.05 (two-sided) only if the primary endpoint (i.e. MMR rate at 24 weeks)
is significant by means of a gatekeeping procedure to control the overall alpha level. Otherwise, 
no statistical testing will be performed, and any analysis will be considered exploratory.
MMR rate at 96 weeks will be evaluated in a similar fashion to the primary analysis of MMR 
rate at 24 weeks. The rate and the associated 95% confidence interval based on the Pearson-
Clopper method will be presented by treatment group. Confidence interval for the difference 
between treatment groups will be provided using the Wald method.
Statistical testing will be performed via CMH chi-square test stratified by the randomization 
strata. The Mantel-Haenszel estimate of the common risk difference and the corresponding 95% 
confidence interval will also be provided.
If the PCR evaluation at 96 weeks is missing, but a PCR evaluation both at 84 weeks and 108 
weeks indicate MMR, the 96 week assessment is imputed as a “response”, assuming that MMR 
is maintained between 84 and 108 weeks. If PCR evaluations are performed at unscheduled 
visits closer to the Week 96 visit (before or after), these will be taken into account for the 
imputation.
10.5.2
Other secondary efficacy objectives
Unless otherwise stated the FAS will be used for the analysis of all other secondary efficacy 
endpoints. The exceptions are using the Molecular Responder Set for duration of MMR and 
time to MMR, the CCyR Analysis Set for CCyR rates, and the Cytogenetic Responder Set for 
duration of CCyR and time to CCyR.
No statistical testing of non-key secondary efficacy endpoints will be performed, and any 
analysis will be considered exploratory.
Molecular Response
MMR rates at scheduled time points (except 24 and 96 weeks which have been specified as 
primary and key secondary endpoints) will be evaluated in a similar fashion to the primary 
analysis of MMR rate at 24 weeks. Patients discontinuing the randomized treatment prior to a 
specific time point due to any reason will be considered as non-responders for that time point.
MMR rates by scheduled time points are defined as the proportion of patients who achieve 
MMR at or before the specified visit, i.e. if a patient achieves an MMR but then loses it before 
or at the visit, he/she will still be classed as achieving MMR by that time point.
For each endpoint the rate and the associated 95% confidence interval based on the Pearson-
Clopper method will be presented by treatment group. Confidence intervals for the differences 
in any response rates between treatment groups will be provided using the Wald method.
Statistical testing will be performed via CMH chi-square tests stratified by the randomization 
strata. The Mantel-Haenszel estimate of the common risk difference and the corresponding 95% 
confidence interval will also be provided.


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Duration of MMR is defined in Section 7.2.1.1 as the time between the date of the first 
documented MMR and the earliest date of loss of MMR, progression to AP/BC, or CML-related 
death for patients in the Molecular Responder Set. The time will be censored at the last 
molecular assessment (PCR) date while on treatment for patients who have not experienced any 
of the above events.
Duration of MMR will be analyzed by K-M method and presented by K-M plots. The estimated 
rates of patients who are still responding at various time points will also be provided using K-
M method.
The cumulative incidence of MMR will be graphically displayed by an increasing step function. 
This curve will increase each time (after randomization) at which a new responder is observed 
and thus will increase up to the best observed response rate (e.g. up to 50% if half of the patients 
in the analysis population are able to achieve response).
Time to MMR is defined in Section 7.2.1.1 and calculated as: date of first MMR - date of 
randomization +1, for patients in the Molecular Responder Set. Descriptive statistics (minimum, 
maximum, median, quartiles, mean, sd) of time to MMR will be provided for the two treatment 
groups separately.
Cytogenetic Response
Patients in FAS will be categorized with counts and percentages provided for cytogenetic 
response (Complete, Partial, Major, Minor, Minimal, No Response) at and by (i.e. best response 
up to a specified time point) scheduled time points. Shift tables will also be employed to 
examine the changes in cytogenetic response category from baseline.
Since there are expected to be only limited numbers who are actually in CCyR at baseline the 
analysis of CCyR rate at and by scheduled time points will only include patients who are not in 
CCyR at baseline, i.e. the CCyR Analysis Set.
CCyR rates at and by scheduled time points etc. and the associated 95% confidence intervals 
based on the Pearson-Clopper method will be presented by treatment group with the analysis of 
these endpoints only including patients who are not in CCyR at baseline.
Confidence intervals for the differences in any response rates between treatment groups will be 
provided using the Wald method.
Statistical testing will be performed via CMH chi-square tests stratified by the randomization 
strata. The Mantel-Haenszel estimate of the common risk difference and the corresponding 95% 
confidence interval will also be provided.
Time to CCyR is defined for patients in the Cytogenetic Responder Set as: date of first CCyR 
- date of randomization +1. Descriptive statistics (minimum, maximum, median, quartiles, 
mean, sd) of time to CCyR will be provided for the two treatment groups separately.
The cumulative incidence of CCyR will also be graphically displayed by an increasing step 
function. This curve will increase each time (after randomization) at which a new responder is 
observed and thus will increase up to the best observed response rate.
Duration of CCyR is defined as the time between date of first documented CCyR and the 
earliest date of loss of CCyR, progression to AP/BC, or CML-related death for patients in the 


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Cytogenetic Responder Set. The time will be censored at the last cytogenetic assessment date 
on treatment for patients for whom none of the above events is reported or last PCR evaluation 
on treatment indicating MMR.
Duration of CCyR response will be analyzed by K-M method and presented by K-M plots. The 
estimated rates of patients who are still responding at various time points will also be provided 
using K-M method.
Treatment failure, disease progression and survival
Time to treatment failure (TTF) is defined as the time from date of randomization to an event 
of treatment failure. The following events will constitute ‘treatment failure’, and are based on 
the ELN criteria (Baccarani et al 2013) defining failure of a second line treatment adapted to 
include discontinuation of randomized treatment as an event:

No CHR or > 95% Ph+ metaphases at three months after randomization or thereafter

BCR-ABL1 ratio > 10% IS and/or > 65% Ph+ metaphases at six months after 
randomization or thereafter

BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases at 12 months after 
randomization or thereafter

Loss of CHR, CCyR or PCyR at any time after randomization

Detection of new BCR-ABL1 mutations which potentially cause resistance to study 
treatment at any time after randomization

Confirmed loss of MMR

New clonal chromosome abnormalities in Ph+ cells: CCA/Ph+: at any time after 
randomization

Discontinuation from randomized treatment for any reason
For patients who have not reached treatment failure, their TTFs will be censored at the time of 
last study assessment (PCR, cytogenetic, hematologic or extramedullary) before the cut-off date.
Progression-Free-Survival (PFS) is defined as the time from the date of randomization to the 
earliest occurrence of documented disease progression to AP/BC or the date of death from any 
cause (including progressions and deaths observed during the survival follow-up period) before 
the cut-off date.
The time will be censored at the date of last study assessment (PCR, cytogenetic, hematologic 
or extramedullary) or last post-treatment follow-up for patients without event.
Overall survival (OS) is defined as the time from the date of randomization to the date of death 
(including the survival follow-up period). Patients who are alive at the time of the analysis data 
cutoff date will be censored at the date of last contact before the cut-off date.
TTF, PFS and OS will be estimated and graphically displayed using the K-M approach on FAS. 
The estimated rates by K-M method at various time points will be provided and the endpoints 
will be compared between the two treatment groups using stratified log-rank test stratified by 
the randomization strata. The hazard ratio and 95% confidence intervals will be computed from 
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10.5.3
Safety objectives
10.5.3.1 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 group.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of subject’s first informed consent to the day before first 
administration of study treatment
2. on-treatment period: from day of first administration of study treatment to 30 days after 
last actual administration of the same study treatment (including start and stop date)
3. post-treatment period: starting at day 31 after last administration of any study treatment
Summary tables for safety data will be presented for the on-treatment period. Comparative 
analysis will be performed only for the on-treatment period. Listings of safety data will include 
pre-treatment, on-treatment, and post-treatment periods, with a flag to indicate data collected 
before or after the on-treatment period.
The same analysis will be done for patients that switch to asciminib after treatment failure on 
bosutinib. However, safety events that initiated on or after start of asciminib during the switch 
treatment phase will be included.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs.
The incidence of treatment-emergent adverse events (new or worsening from baseline) 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, non-serious adverse events and adverse events of special interest (AESI)
during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre-treatment, on-
treatment and post-treatment periods) will be listed and those collected before or after the on-
treatment period will be flagged.
10.5.3.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. 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.


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For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following listings and summaries will be generated separately for hematology, and 
biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v4.03

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline in the on-treatment period.

Shift tables using CTCAE grades to compare respective baseline to the worst on-treatment 
value
For laboratory tests where grades are not defined by CTCAE v4.03,

Shift tables using the low/normal/high/ (low and high) classification to compare respective 
baseline to the worst on-treatment value.
10.5.3.4 Other safety data
ECG
ECGs (12-lead) including PR, QRS, QT, QTcF, and HR intervals will be obtained for each 
subject during the study. ECG data will be read and interpreted centrally.
Categorical analysis of QT/QTc interval data based on the number of patients meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these patients will be produced by treatment group.
Vital signs
Data on vital signs will be tabulated and listed, notable values will be flagged.
10.5.3.5 Supportive analyses for secondary objectives
Not applicable.
10.5.3.6 Tolerability
Tolerability of each study treatment will be assessed by summarizing the number of subjects
with dose interruptions and dose reductions. Reasons for dose interruptions and dose reductions 
will be listed by subject and summarized.
10.5.4
Secondary PK objectives
The PK objective is to characterize the PK of asciminib in CML population.
Using PAS, summary statistics (n, mean, SD, coefficient of variation (CV) for mean, geometric 
mean, CV for geometric mean, median, minimum and maximum) will be presented for plasma 
concentration at each scheduled time point. The geometric mean with mean (SD) and individual 
plasma concentration versus time profiles of asciminib will be displayed graphically.


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Using Safety set, concentration data will be listed. Concentration values below the limit of 
quantification (BLQ) will be set to zero by the Bioanalyst and displayed in listings as zero with 
a flag. BLQ values will be handled as zero in any calculations of summary statistics, but handled 
as missing for the calculation of the geometric means and CVs.
Pharmacokinetic parameters will be determined by non-compartmental method(s) using the 
pharmacokinetic profile of asciminib in patients with full PK sampling. PK parameters listed in 
Table 10-1 will be derived and reported, when feasible.
Population PK modeling may be performed and the results may be reported in a separate 
population PK report. Data from this study may be combined with data from other studies for 
this analysis.
Table 10-1
Non compartmental pharmacokinetic parameters in full PK group
AUC0-12h
The area under the plasma concentration-time curve from time zero to 12 h (mass x time x 
volume-1)a
Cmax
The maximum (peak) observed plasma drug concentration after dose administration (mass x
volume-1)
Tmax
The time to reach maximum (peak) plasma drug concentration after dose administration (time)
CL/F
The total body clearance of drug from the plasma after oral administration (volume x time-1)
10.6
Exploratory objectives
10.6.1
Exploratory efficacy objectives

To evaluate the influence of factors such as major cytogenetic status at baseline, 
failure/intolerance to prior TKIs, line of therapy, gender, race and age on the effect of 
asciminib with respect to the primary efficacy endpoint.

To characterize mutations in the BCR-ABL1 gene at Week 1 Day 1, upon confirmed loss of 
molecular response and/or at end of treatment and examine their association with molecular 
and cytogenetic response for asciminib vs. bosutinib.

To assess the efficacy of asciminib when administered as treatment after bosutinib failure 
according to the 2013 ELN Guidelines.
10.6.1.1 Data analysis of exploratory efficacy objectives
Subgroup analyses will be performed to evaluate the influence of factors such as baseline major 
cytogenetic response status, baseline/Week 1 Day 1 BCR-ABL1 ATP-binding site mutation 
status (from local historical record and from Sanger Sequencing), failure/intolerance to prior 
TKIs, line of therapy, gender, race and age on the primary efficacy endpoint. In addition, a 
logistic regression analysis will incorporate the key baseline variables into the model to further 
evaluate the impact of these variables on the primary endpoint and to provide a treatment effect 
estimate which is adjusted for imbalances in the treatment groups. An adjusted odds ratio for 
the treatment effect with associated 95% confidence intervals will be presented. Mantel-
Haenszel estimates of the common odds ratio and the corresponding 95% confidence interval 
will also be provided. The effect of asciminib when administered as treatment after bosutinib 
failure will be assessed using the Switch Analysis Set to estimate response rates (cytogenetic 
and molecular response) at all scheduled time points after switch, as well as time-to and duration 






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10.6.4.2 Patient Reported Outcomes
The MDASI CML, PGIC along with EQ-5D-5L will be used to compare data on the patient’s 
disease-related symptoms and health-related quality of life from baseline to EOT between the 
treatment arms. The WPAI will be used to assess work productivity and activity impairment 
related to the patient’s CML. All measures will assess differences between the treatment arms.
Patients with an evaluable baseline score and at least one evaluable post baseline score during 
the treatment period will be included in the change from baseline analyses. Missing data items 
in a scale will be handled according to the manual for each instrument. No imputation will be 
applied if the total or subscale scores are missing at a visit.
10.7
Interim analysis
No formal interim analysis is planned for this trial. As described in Section 10, three or four
formal analyses are planned: the primary at week 24, another at the 96-week end of study 
treatment and a PFS/OS update at year 5.

24-week primary analysis: Formal testing of the primary endpoint with full alpha will be 
performed. Analyses of other efficacy endpoints at and by 24 weeks will also be 
performed.

96-week analysis: Formal statistical testing of the key secondary endpoint will be 
performed with = 0.05 (two-sided) only if the primary endpoint (i.e. MMR rate at 24 
weeks) is significant. Otherwise, no statistical testing will be performed, and any analysis
will be considered exploratory. Analyses of other efficacy endpoints (including MMR rate 
at 48 weeks) will also be performed.

End of study treatment analysis (if required) similar to the 96-week analysis without 
formal statistical testing.

5-year PFS/OS update analysis: PFS and OS
In addition DMC safety analyses will be conducted as described in Section 8.6.
10.8
Sample size calculation
To test the null hypothesis that the response rate is equal in the two groups, based on two-sided 
5% level of significance and with 90% power, 222 patients will be needed in total (i.e. 148 
patients in the asciminib arm and 74 patients in the bosutinib arm based on 2:1 randomization 
allocation). This assumes that asciminib leads to a 20% improvement in the MMR rate at 24 
weeks over bosutinib from 15% to 35% which corresponds to an odds ratio of 3.05.
The assumed bosutinib MMR rate of 15% at 24 weeks is based on previous trials evaluating 
bosutinib therapy (Khoury 2012, Gambacorti-Passerini 2014, García-Gutiérrez 2015).
No more than 66 patients (approximately 30% of the overall trial population) that are intolerant 
to their most recent TKI therapy with BCR-ABL1 < 1% will be recruited in order to ensure that 
the CML third line patient population is adequately represented.


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10.9
Power for analysis of key secondary variables
If the primary analysis of MMR rate at 24 weeks is statistically significant, then the key 
secondary endpoint MMR rate at 96 weeks will be tested, with the overall alpha controlled at 
the 5% two-sided level. The testing will use a gatekeeping strategy. Full details of the testing 
strategy are provided in Section 10.5.1.
Table 10-2 below summarizes the treatment effects of the key secondary endpoint which can 
be detected with 80% and 90% power, based on the specified assumptions regarding the 
bosutinib effect. The calculations were made using the software package PASS (2008).
Table 10-2
Detectable effect sizes for key secondary endpoint
Endpoint
Anticipated effect 
with bosutinib
2-sided alpha
Power
Detectable 
effect size§
MMR rate at 96 weeks
30%*
0.05
90%
80%
≥ 23%
≥ 20%
*: Gambacorti-Passerini et al. 2014, Figure 1D.
§: Absolute difference from the anticipated effect with bosutinib.
For MMR rate at 96 weeks, if the anticipated effect with bosutinib is 30%, then the given sample 
size with 2-sided alpha=0.05 would allow to detect an absolute difference of at least 23% (i.e. 
MMR rate at 96 weeks with asciminib is at least 53%) for 90% power and of at least 20% (i.e. 
MMR rate at 96 weeks with asciminib is at least 50%) for 80% power.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. 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 Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.


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11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their eCRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication 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 requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
Additional consent form
Not applicable.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.3.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. clinicaltrials.gov before study start. In 
addition, results of interventional
clinical trials in adult patients are posted on 
novartisclinicaltrials.com, a publicly accessible database of clinical study results within 1 year 
of study completion (i.e., LPLV), those for interventional clinical trials involving pediatric 
patients within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (icmje.org) and other specific guidelines of 
the journal or congress to which the publication will be submitted
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.


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As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study electronic case report form (eCRF) is the primary data 
collection instrument for the study. The investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported in the eCRFs and all other required reports. Data 
reported on the eCRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the eCRF 
must be recorded. Any missing data must be explained. For electronic CRFs an audit trail will 
be maintained by the system.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.


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11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
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/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
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/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
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 (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.


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13
References (available upon request)
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Research. September 2011.
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[Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, Bonsel G, Badia X. (2011)]
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Quality of Life Research 20(10):1727-1736.
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early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an 
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[Hochhaus A, Saussele S, Rosti G, et al (2017)] Chronic myeloid leukaemia: ESMO Clinical
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[Hochhaus A, O'Brien SG, Guilhot F, et al (2009)] Six-year follow-up of patients receiving 
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chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood; 
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domain-mediated resistance in chronic myeloid leukemia. Leuk Res; 38(1):10-20.
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recommendations for the management and avoidance of adverse events of treatment in 
chronic myeloid leukaemia. Leukemia; 30(8):1648-71.
[Vardiman J.W. (2009)] Chronic Myelogenous Leukemia, BCR-ABL+. Am J Clin Pathol; 
132:250-260.
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14
Appendices
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 6.4 for patients on 
asciminib and Section 6.5 for patients on bosutinib. 
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.
14.1
Appendix 1 List of concomitant medications for patients on 
asciminib
Table 14-1
Prohibited concomitant medications for asciminib arm
Category
Drug Names
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,
Strong inducers of 
CYP3A
carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, rifabutin, 
rifampicin, St. John’s wort (Hypericum perforatum)1
UGT1A1/2B7 
inducers
UGT1A1: carbamazepine, cigarette smoke, rifampicin, testosterone propiate, 
UGT2B7: Barbiturates
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 


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Category
Drug Names
(orphan drug in us), tizanidine, tolterodine, toremifene, trimipramine, vardenafil, 
vemurafenib, venlafaxine, vorinostat, zotepine
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 preparation-
dependent. 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). 
Table 14-2
Concomitant medications to be used with caution in asciminib arm
Category
Drug Names
Narrow Therapeutic 
index substrates of 
CYP2C8
Paclitaxel
Narrow Therapeutic 
index substrates of 
CYP2C9
phenytoin, warfarin (also sensitive)
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,survorexant, talinolol4, telaprevir4, 
telmisartan4, ticagrelor4, tipranavir4, tolvaptan4, valspodar, vandetanib, verapamil4, 
voclosporin, vorapaxar.
3 Evidence of in vivo DDI
4 Dual P-gp and CYP3A4 inhibitor
5 Herbal product


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Appendix 2 List of concomitant medications for patients on
bosutinib
Table 14-3
Prohibited concomitant medications for bosutinib arm
Category
Drug Names
Strong inhibitors of 
CYP3A
boceprevir, clarithromycin, cobicistat, conivaptan, grapefruit juice2, idelalisib, indinavir, 
itraconazole, ketoconazole, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, 
telaprevir, telithromycin, troleandomycin, voriconazole, atazanavir/ritonavir1, 
danoprevir/ritonavir1, darunavir/ritonavir1, elvitegravir/ritonavir1, indinavir/ritonavir1, 
lopinavir/ritonavir1, ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak)1 , 
saquinavir/ritonavir1, tipranavir/ritonavir1
Moderate inhibitors of 
CYP3A
aprepitant, amprenavir, atazanavir, cimetidine, ciprofloxacin, crizotinib, cyclosporine, 
darunavir, diltiazem, dronedarone, erythromycin, faldaprevir, fluconazole, grapefruit 
juice2, imatinib, isavuconazole, netupitant, nilotinib, tofisopam, Schisandra sphenanthera
(nan wu wei zi)3, asafoetida resin (Ferula asafoetida)3, verapamil
Strong inducers of 
CYP3A
carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, rifabutin, 
rifampicin, St. John’s wort (Hypericum perforatum)3
Moderate inducers of 
CYP3A
bosentan, efavirenz, etravirine, modafinil, nafcillin, ritonavir/tipranavir, thioridazine, 
semagacestat4, talviraline4, lopinavir, lersivirine, 
Proton pump 
inhibitors
dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole. 
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 preparation-
dependent. 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
4 Dual P-gp and CYP3A4 inhibitor
Table 14-4
Concomitant medications to be used with caution in bosutinib arm
Category
Drug Names
Torsade de pointe 
(TdP) TdP/QT risk : 
Known
amiodarone, anagrelide, arsenic trioxide, astemizole (off us mkt), azithromycin, bepridil 
(off us mkt), chloroquine, chlorpromazine, cilostazol, cisapride (off us mkt), citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone (not on us mkt), 
donepezil, dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
grepafloxacin  (off market worldwide), halofantrine, haloperidol, ibutilide, levofloxacin, 
levomethadyl (off mkt worldwide), mesoridazine (off mkt worldwide), methadone, 
moxifloxacin, ondansetron, oxaliplatin, papaverine HCl, pentamidine, pimozide, probucol 
(off mkt worldwide), procainamide (oral off us mkt), propofol, quinidine, sevoflurane, 
sotalol, sparfloxacin (off us mkt), sulpiride (not on us mkt), terfenadine (off us mkt),
thioridazine, vandetanib
TdP/QT risk: 
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 


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Category
Drug Names
(orphan drug in us), tizanidine, tolterodine, toremifene, trimipramine, vardenafil, 
vemurafenib, venlafaxine, vorinostat, zotepine
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


Clinical Development
Asciminib/ABL001
Oncology Clinical Trial Protocol CABL001A2301
A phase 3, multi-center, open-label, randomized study of 
oral ABL001 (asciminib) versus bosutinib in patients with 
Chronic Myelogenous Leukemia in chronic phase (CML-
CP), previously treated with 2 or more tyrosine kinase 
inhibitors
Document type
Amended Protocol Version
EUDRACT number
2016-002461-66
Version number
03-US.01 (Clean)
Development phase
III
Document status
Final
Release date
05-Aug-2020
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 19-Nov-2015


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary:.............................................................................................................11
Amendment 03-US.01 (05-Aug-2020)..............................................................................17
Amendment 3 (14-Dec-2018)............................................................................................18
Amendment 2 (13-Jul-2018) .............................................................................................24
Amendment 1 (10-Apr-2017)............................................................................................30
1
Background........................................................................................................................32
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............32
1.2
Introduction to investigational treatment...............................................................33
1.2.1
Overview of asciminib (ABL001) ........................................................33
1.2.2
Overview of bosutinib...........................................................................39
2
Rationale............................................................................................................................40
2.1
Study rationale and purpose...................................................................................40
2.2
Rationale for the study design ...............................................................................40
2.2.1
Rationale for Biomarker Assessment....................................................41
2.3
Rationale for dose and regimen selection..............................................................42
2.4
Rationale for choice of combination drugs............................................................43
2.5
Rationale for choice of comparators drug bosutinib..............................................43
2.6
Risks and benefits..................................................................................................43
3
Objectives and endpoints...................................................................................................44
4
Study design ......................................................................................................................48
4.1
Description of study design ...................................................................................48
4.1.1
Study treatment switch from bosutinib to asciminib.............................49
4.2
Timing of interim analyses and design adaptations...............................................49
4.3
Definition of end of study......................................................................................49
4.4
Early study termination..........................................................................................50
5
Population..........................................................................................................................50
5.1
Patient population..................................................................................................50
5.2
Inclusion criteria ....................................................................................................50
5.3
Exclusion criteria...................................................................................................52
6
Treatment...........................................................................................................................54


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6.1
Study treatment......................................................................................................54
6.1.1
Dosing regimen.....................................................................................54
6.1.2
Ancillary treatments..............................................................................55
6.1.3
Rescue medication ................................................................................55
6.1.4
Guidelines for continuation of treatment ..............................................55
6.1.5
Treatment duration................................................................................55
6.2
Dose escalation guidelines.....................................................................................56
6.3
Dose modifications................................................................................................56
6.3.1
Dose modification and dose delay ........................................................56
6.3.2
Dose adjustments for QTcF prolongation.............................................65
6.3.3
Follow-up for toxicities.........................................................................66
6.3.4
Anticipated risks and safety concerns of the study drug.......................67
6.4
Concomitant medications for patients on asciminib..............................................67
6.4.1
Permitted concomitant therapy .............................................................67
6.4.2
Permitted concomitant therapy requiring caution and/or action...........68
6.4.3
Prohibited concomitant therapy ............................................................68
6.4.4
Other concomitant medications.............................................................69
6.5
Concomitant medications for patients on bosutinib ..............................................70
6.5.1
Permitted concomitant therapy requiring caution.................................70
6.5.2
Prohibited concomitant therapy ............................................................71
6.6
Patient numbering, treatment assignment or randomization .................................71
6.6.1
Patient numbering .................................................................................71
6.6.2
Treatment assignment or randomization...............................................72
6.6.3
Treatment blinding................................................................................72
6.7
Study drug preparation and dispensation...............................................................72
6.7.1
Study treatment packaging and labeling ...............................................73
6.7.2
Drug supply and storage........................................................................73
6.7.3
Study drug compliance and accountability ...........................................73
6.7.4
Disposal and destruction .......................................................................74
7
Visit schedule and assessments .........................................................................................74
7.1
Study flow and visit schedule................................................................................74
7.1.1
Molecular pre-screening........................................................................93
7.1.2
Screening...............................................................................................93
7.1.3
Run-in period ........................................................................................96
7.1.4
Treatment period...................................................................................96
7.1.5
Visit windows........................................................................................96


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7.1.6
Discontinuation of study treatment .......................................................97
7.1.7
Withdrawal of consent ..........................................................................98
7.2
Assessment types...................................................................................................99
7.2.1
Efficacy assessments.............................................................................99
7.2.2
Safety and tolerability assessments.....................................................101
7.2.3
Pharmacokinetics ................................................................................108
7.2.4
Biomarkers..........................................................................................109
7.2.5
Resource utilization.............................................................................112
7.2.6
Patient reported outcomes...................................................................112
8
Safety monitoring and reporting......................................................................................114
8.1
Adverse events.....................................................................................................114
8.1.1
Definitions and reporting ....................................................................114
8.1.2
Laboratory test abnormalities..............................................................115
8.1.3
Adverse events of special interest.......................................................116
8.2
Serious adverse events.........................................................................................116
8.2.1
Definitions...........................................................................................116
8.2.2
Reporting.............................................................................................116
8.3
Emergency unblinding of treatment assignment .................................................117
8.4
Pregnancies..........................................................................................................117
8.5
Warnings and precautions....................................................................................118
8.6
Data Monitoring Committee................................................................................118
8.7
Steering Committee .............................................................................................118
9
Data collection and management.....................................................................................119
9.1
Data confidentiality .............................................................................................119
9.2
Site monitoring ....................................................................................................119
9.3
Data collection.....................................................................................................120
9.4
Database management and quality control..........................................................120
10 Statistical methods and data analysis ..............................................................................120
10.1
Analysis sets ........................................................................................................121
10.1.1
Full Analysis Set .................................................................................121
10.1.2
Safety set .............................................................................................121
10.1.3
Per-Protocol set ...................................................................................121
10.1.4
Dose-determining analysis set.............................................................121
10.1.5
Pharmacokinetic analysis set...............................................................122
10.1.6
Other analysis set ................................................................................122
10.2
Patient demographics/other baseline characteristics ...........................................122


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10.3
Treatments (study treatment, concomitant therapies, compliance) .....................122
10.4
Primary objective.................................................................................................123
10.4.1
Variable...............................................................................................123
10.4.2
Statistical hypothesis, model, and method of analysis........................123
10.4.3
Handling of missing values/censoring/discontinuations.....................123
10.4.4
Supportive and Sensitivity analyses....................................................124
10.5
Secondary objectives ...........................................................................................124
10.5.1
Key secondary objective(s).................................................................124
10.5.2
Other secondary efficacy objectives ...................................................125
10.5.3
Safety objectives .................................................................................128
10.5.4
Secondary PK objectives.....................................................................129
10.6
Exploratory objectives.........................................................................................130
10.6.1
Exploratory efficacy objectives...........................................................130
10.6.2
Exploratory PK objectives ..................................................................131
10.6.3
Exploratory biomarker objectives.......................................................131
10.6.4
Exploratory Patient Reported Outcomes objectives ...........................132
10.7
Interim analysis....................................................................................................133
10.8
Sample size calculation........................................................................................133
10.9
Power for analysis of key secondary variables....................................................134
11 Ethical considerations and administrative procedures ....................................................134
11.1
Regulatory and ethical compliance......................................................................134
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................134
11.3
Informed consent procedures...............................................................................135
11.4
Discontinuation of the study................................................................................135
11.5
Publication of study protocol and results.............................................................135
11.6
Study documentation, record keeping and retention of documents.....................136
11.7
Confidentiality of study documents and patient records .....................................137
11.8
Audits and inspections.........................................................................................137
11.9
Financial disclosures............................................................................................137
12 Protocol adherence ..........................................................................................................137
12.1
Amendments to the protocol................................................................................137
13 References (available upon request)................................................................................138
14 Appendices ......................................................................................................................140
14.1
Appendix 1 List of concomitant medications for patients on asciminib .............140
14.2
Appendix 2 List of concomitant medications for patients on bosutinib..............142


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List of figures
Figure 1-1
KCL-22 CML Xenograft.......................................................................34
Figure 4-1
Schematic of Study Design ...................................................................49
List of tables
Table 3-1
Objectives and related endpoints ..........................................................45
Table 6-1
Dose and treatment schedule.................................................................55
Table 6-2
Criteria for dose reduction/interruption and re-initiation of 
asciminib and bosutinib treatment for adverse drug reactions..............57
Table 6-3
Dose reduction steps for asciminib and bosutinib.................................65
Table 6-4
Packaging and labeling .........................................................................73
Table 7-1
Visit evaluation schedule ......................................................................75
Table 7-2 
Visit evaluation schedule (study treatment switch phase) ....................85
Table 7-3
Blood samples (efficacy primary endpoint)........................................100
Table 7-4
ECOG Performance status scale .........................................................103
Table 7-5
Central clinical laboratory parameters collection plan........................104
Table 7-6
Central ECG collection (all patients)..................................................106
Table 7-7
Central ECG collection plan for patients in full PK asciminib group.106
Table 7-8
Pharmacokinetic blood collection log (Sparse PK-group-asciminib 
arm/ asciminib treatment switch patients)...........................................108
Table 7-9
Pharmacokinetic blood collection log (Full PK group-asciminib 
arm) .....................................................................................................109
Table 7-10
Biomarker sample collection plan.......................................................111
Table 10-1
Non compartmental pharmacokinetic parameters in full PK group....130
Table 10-2
Detectable effect sizes for key secondary endpoint ............................134
Table 14-1
Prohibited concomitant medications for asciminib arm......................140
Table 14-2
Concomitant medications to be used with caution in asciminib arm..141
Table 14-3
Prohibited concomitant medications for bosutinib arm ......................142
Table 14-4
Concomitant medications to be used with caution in bosutinib arm ..142


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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
AP
Accelerated phase
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATP
Adenosine triphosphate
AUC
Area under the curve
AV block
Atrioventricular block
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
BMA
Bone marrow aspirate
BUN
Blood urea nitrogen
CBC
Complete Blood Count
CCA
Clonal chromosome abnormalities
CCyR
Complete Cytogenetic Response
CD8
Cluster of differentiation 8
CD34
Cluster of differentiation 34
CHR
Complete Hematological Response
CI
Confidence Interval
CMH
Cochran–Mantel–Haenszel
CML
Chronic Myelogenous Leukemia
CML-AP
Chronic Myelogenous Leukemia-Accelerated Phase
CMO&PS
Chief Medical Office and Patient Safety
CP
Chronic phase
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
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DLCO
Carbon monoxide diffusing capacity
DMC
Data Monitoring Committee
DNA
Desoxyribonucleic acid
DS&E
Drug Safety and Epidemiology
ECG
Electrocardiogram


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ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic data capture
ELN
European Leukemia Network
EOT
End of Treatment
ERT
Electronic Research Technology, Inc
EU
European Union
FAS
Full Analysis Set
FIH
First In Human
GDPR
General Data Protection Regulation
GFR
Glomerular Filtration Rate
hADME
Human ADME study (Absorption, Distribution, Metabolism and Excretion) 
HDL
High density lipoprotein
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INN
International Nonproprietary Name
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
K-M
Kaplan-Meyer
Km
Michaelis-Menten constant
LDL
Low density lipoprotein
LFT
Liver function test
LLN
Lower limit of normal
MCyR
Major Cytogenetic Response
mCyR
Minor Cytogenetic Response
MDASI-CML
MD Anderson Symptom Inventory – Chronic Myelogenous Leukemia
MMR
Major Molecular Response
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NGS
Next Generation Sequencing
NTI
Narrow Therapeutic Index
OS
Overall survival
PAS
Pharmacokinetic analysis set
PBPK
Physiologically based pharmacokinetic
PCR
Polymerase Chain Reaction
PCyR
Partial Cytogenetic Response
PD
Pharmacodynamic
PGIC
Patient Global Impression of Change
P-gp
Permeability glycoprotein


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Ph+
Philadelphia chromosome positive
PHI
Protected Health Information
PK
Pharmacokinetics
PLT
Platelets
PPS
Per-protocol set
QD
Quaque die/once a day
QT
Q to T interval (ECG)
QTcF
QTc Fredericia
REB
Research Ethics Board
RNA
Ribonucleic acid
RQ-PCR
Real time quantitative polymerase chain reaction
RU
Resource Utilization
SAE
Serious Adverse Event
SAP
The Statistical Analysis Plan (SAP) is a regulatory document which provides evidence of 
preplanned analyses
SC
Steering committee
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT 
Serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
TBIL
Total bilirubin
TdP
Torsades de Pointes
TKI
Tyrosine Kinase Inhibitor
TTF
Time to treatment failure
UGT
Uridin diPhospho-glucuronosyltransferase
ULN
Upper limit of normal
US
United States
USPI
US prescribing information
WBC
White blood cell count
WPAI
Work Productivity and Activity Impairment


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Glossary of terms
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 subject or study patient
Cycles
Number and timing or recommended repetitions of therapy are usually expressed 
as number of days (e.g. q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with
“investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are 
tested in a fixed combination. Investigational treatment generally does not include 
other study treatments administered as concomitant background therapy required 
or allowed by the protocol when used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment
Subject Number (Subject 
No.)
A unique identifying number assigned to each patient/subject/healthy volunteer 
who enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Personal Data
Subject information collected by the Investigator that is transferred to Novartis for 
the purpose of the clinical trial. This data includes subject identifier information, 
study information and biological samples.
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason
Treatment group
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points
Withdrawal of study 
consent
Withdrawal of consent from the study occurs only when a subject does not want 
to participate in the study any longer, and does not allow any further collection of 
personal data


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Protocol summary:
Title
A phase 3, multi-center, open-label, randomized study of oral ABL001 (asciminib) versus 
bosutinib in patients with Chronic Myelogenous Leukemia in chronic phase (CML-CP), 
previously treated with 2 or more tyrosine kinase inhibitors
Brief title
Study of efficacy of CML-CP patients treated with asciminib versus bosutinib, previously 
treated with 2 or more TKIs
Sponsor and
Clinical Phase
Novartis
Phase 3
Investigation type
Drug 
Study type
Interventional
Purpose and 
rationale
Purpose:
The purpose of this pivotal study is to compare the efficacy of asciminib with that of 
bosutinib in the treatment of patients with CML-CP having previously been treated with a 
minimum of two prior ATP-binding site TKIs with BCR-ABL1 ratios ≥ 1% IS at screening.
Patients intolerant to the most recent TKI therapy must have BCR-ABL1 ratio > 0.1% IS 
at screening and patients failing their most recent TKI therapy must meet the definition 
of treatment failure as per the 2013 ELN guidelines (Baccarani et al 2013). No more 
than 66 patients (approximately 30% of the overall trial population) that are intolerant to 
their most recent TKI therapy with BCR-ABL1< 1% will be recruited in order to ensure 
that the CML third line patient population is adequately represented.
Rationale:
There remains an unmet need for new compounds in patients with CML who have failed 
at least two prior TKIs. Current practice suggests that a second generation TKI will have 
been used for first line therapy for about one half of patients with CML, meaning that 
most patients who have failed at least two prior TKIs will have failed at least one if not 
two second generation TKIs (such as dasatinib and/or nilotinib). Potentially, such 
patients may also have failed bosutinib and/or ponatinib (Soverini 2014). Patients having 
failed at least two TKIs may have limited sensitivity to the remaining available agents 
and, thus, there exists a need for new safe and effective therapy. In addition, mutations 
will have developed in 21 to 33% of patients that prevent the use of specific TKIs, 
increasing the need for a better and alternative compound (Soverini 2014). 
Omacetaxine, a chemotherapeutic agent, is available for patients who have failed at 
least two prior TKIs under these conditions but only in the US and Canada. This agent is 
not available for most patients globally, where a bigger unmet medical need is present. 
Thus, there remains an unmet need for patients with CML who have failed at least two 
prior TKIs despite the existence of multiple agents.
Primary Objective
and Key 
Secondary 
Objective
Primary Objective: To compare the Major Molecular Response (MMR) rate at 24 
weeks of asciminib versus bosutinib
Key Secondary Objective: To compare MMR rate at 96 weeks of asciminib versus 
bosutinib
Secondary 
Objectives
●
To compare additional efficacy parameters of asciminib versus bosutinib:
●
cytogenetic response rate (Complete, Partial, Major, Minor, Minimal, no 
response) at and by all scheduled data collection time points, including 24, 48 and 96 
weeks
●
MMR rate at all scheduled data collection time points (except 24 and 96 weeks 
which are already covered by primary and key secondary endpoints)
●
MMR rate by all scheduled data collection time points, including 24, 48 and 96 
weeks
●
Time to MMR
●
Duration of MMR
●
Time to CCyR
●
Duration of CCyR
●
Time to treatment failure


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●
Progression free survival
●
Overall survival
●
To compare the safety and tolerability profile of asciminib versus bosutinib by type, 
frequency and severity of adverse events, changes in laboratory values that fall outside 
the pre-determined ranges and clinically notable ECG and other safety data (vital signs, 
physical examination)
●
To characterize the PK of asciminib in the CML-CP population (Trough plasma 
concentrations, PK parameters in full PK group: Cmax, Tmax, AUC0-12h, CL/F)
●    To assess the safety of asciminib when administered as treatment after bosutinib 
failure according to the 2013 ELN Guidelines
Study design
This study is a randomized, phase 3, open-label, active-controlled multi-center study. 
Patients will be randomized to the novel BCR-ABL1 TKI asciminib and bosutinib in a 2:1 
ratio. The randomization is to be stratified to ensure the study population is balanced 
between the arms with respect to the patient’s cytogenetic response status at baseline 
(Major Cytogenetic response (complete or partial) vs. No major cytogenetic response 
(minor, minimal or none)).
The study design incorporates a 2:1 randomization, allocating more patients to the 
asciminib arm in order to learn more about the safety profile of the experimental therapy,
whereas the safety of bosutinib therapy is well documented. Treatment duration for each 
patient in the present study is for up to 96 weeks after the last randomized patient 
receives the first dose, or up to 48 weeks after the last patient has switched from 
bosutinib to asciminib whichever is longer unless patients have discontinued treatment 
earlier, which should be adequate to address both the primary objective of the study, i.e. 
determination of the MMR rate at 24 weeks, as well as secondary efficacy and safety 
objectives. Patients on bosutinib will be able to switch to asciminib treatment up to 96 
weeks after the last patient has been randomized.
If patients in the bosutinib arm have documented treatment failure according to the 2013
ELN Guidelines (Baccarani et al 2013), they will have the option to receive asciminib.
Each patient who switches to asciminib after bosutinib failure can remain on asciminib 
treatment for up to 48 weeks after the last bosutinib failure patient has switched to 
asciminib during the treatment period unless patients have discontinued treatment 
earlier.
Population
Two-hundred and twenty-two (222) patients with CML-CP who had prior treatment with 
two or more ATP binding site TKIs will be randomized on a 2:1 basis to receive either 
asciminib or bosutinib. Patients with known history of T315I and/or V299L mutations at 
study entry will be excluded from the trial since bosutinib, the comparator, is not 
approved for these patients.
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Male or female patients with a diagnosis of CML-CP ≥ 18 years of age
2. Patients must meet all of the following laboratory values at the screening visit:
●
< 15% blasts in peripheral blood and bone marrow
●
< 30% blasts plus promyelocytes in peripheral blood and 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
3a. Patients intolerant to the most recent TKI therapy, BCR-ABL1 ratio > 0.1% IS 
according to central laboratory at the screening examination
4. Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, 
nilotinib, dasatinib, radotinib or ponatinib)
5. Failure (adapted from the 2013 ELN Guidelines; Baccarani et al 2013) or intolerance 
to the most recent TKI therapy at the time of screening 


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●
Failure is defined for CML-CP patients (CP at the time of initiation of last 
therapy) as follows. Patients must meet at least 1 of the following criteria.
●
Three months after the initiation of therapy: No CHR or > 95% Ph+ 
metaphases
●
Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS 
and/or > 65% Ph+ metaphases
●
Twelve months after initiation of therapy: BCR-ABL1 ratio > 10% IS 
and/or > 35% Ph+ metaphases
●
At any time after the initiation of therapy, loss of CHR, CCyR or PCyR
●
At any time after the initiation of therapy, the development of new 
BCR-ABL1 mutations which potentially cause resistance to study treatment 
●
At any time after the initiation of therapy, confirmed loss of MMR in 2 
consecutive tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS
●
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
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
7. Adequate end organ function as defined by (as per central laboratory tests):
●
Total bilirubin ≤ 1.5 x ULN) except for patients with Gilbert’s syndrome who may 
only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
●
Aspartate transaminase (AST) ≤ 3.0 x ULN
●
Alanine transaminase (ALT) ≤ 3.0 x ULN
●
Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN -  ≤ 1.5 x ULN, value must 
be considered not clinically significant and not associated with risk factors for acute 
pancreatitis
●
Alkaline phosphatase ≤ 2.5 x ULN
●
Creatinine clearance ≥ 50mL/min as calculated using Cockcroft-Gault formula
8. 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.
9. Written informed consent obtained prior to any screening procedures.
10a. 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
11. Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of 
screening which are amenable to standardized RQ-PCR quantification.
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Known presence of the T315I or V299L mutation at any time prior to study entry
2. Known second chronic phase of CML after previous progression to AP/BC


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3. Previous treatment with a hematopoietic stem-cell transplantation
4. Patient planning to undergo allogeneic hematopoietic stem cell transplantation
5. 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 TdP” 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
6. 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)
7. History of acute pancreatitis within 1 year of study entry or past medical history of 
chronic pancreatitis
9. History of acute or chronic liver disease
10. Known presence of significant congenital or acquired bleeding disorder unrelated to 
cancer
11. 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
12. Known history of Human Immunodeficiency Virus (HIV), chronic Hepatitis B (HBV), 
or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) 
and Hepatitis B core antibody (HBcAb / anti HBc) will be performed at screening
13. 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)
14a.
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
●
Moderate or strong inducers of CYP3A
●
Moderate or strong inhibitors of CYP3A 
15. Previous treatment with or known/ suspected hypersensitivity to asciminib or any of 
its excipients.
16. Previous treatment with or known/ suspected hypersensitivity to bosutinib or any of 
its excipients.
17. Participation in a prior investigational study within 30 days prior to randomization or 
within 5 half-lives of the investigational product, whichever is longer
18. Pregnant or nursing (lactating) women
19a.
Women of child-bearing potential, defined as all women physiologically capable 
of becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 3 days after last dose of asciminib and one month after last dose 
of bosutinib. 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


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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.
Conditions to be 
fulfilled for 
asciminib switch
1. Failure to bosutinib treatment up to 96 weeks after the last patient received the first 
dose (adapted from the 2013 ELN Guidelines; Baccarani et al 2013). Patients must 
meet at least 1 of the following criteria. Failure is defined as follows:

Three months after the initiation of therapy or thereafter: No CHR or > 95% Ph+ 
metaphases.

Six months after the initiation of therapy or thereafter: BCR-ABL1 ratio > 10% 
IS and/or > 65% Ph+ metaphases.

Twelve months after initiation of therapy or thereafter: BCR-ABL1 ratio > 10% 
IS and/or > 35% Ph+ metaphases.

At any time after the initiation of therapy, loss of CHR, CCyR or PCyR.

At any time after the initiation of therapy, detection of new BCR-ABL1
mutations which potentially cause resistance to study treatment (asciminib or 
bosutinib).

At any time after the initiation of therapy, confirmed loss of MMR in 2 
consecutive tests.

At any time after the initiation of therapy, new clonal chromosome abnormalities 
in Ph+ cells: CCA/Ph+.
Conditions preventing patients to switch to asciminib:

Any Grade 3 or 4 toxicity which has not resolved to Grade 2 or lower within 28
days and before starting asciminib treatment.

Asymptomatic (Grade 2) pancreatitis if not resolved within 28 days 

Disease progression while on bosutinib treatment. The following events are 
considered disease progression:

Accelerated phase (AP) as defined by any of the following:

≥15% blasts in the peripheral blood or bone marrow aspirate, but < 
30% blasts in both the peripheral blood and bone marrow aspirate.

≥30% blasts plus promyelocytes in peripheral blood or bone marrow 
aspirate.

≥20% basophils in the peripheral blood.

Thrombocytopenia (< 100 x 109/L) that is unrelated to therapy.

Blast crisis (BC) as defined by any of the following:

≥30% blasts in peripheral blood or bone marrow aspirate


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
Appearance of extramedullary involvement other than 
hepatosplenomegaly proven by biopsy (i.e., chloroma).

QTcF at time of switch > 480 msec or inability to determine QTc interval
Investigational 
and reference 
therapy
Asciminib 40 mg BID
Bosutinib 500 mg QD
Efficacy 
assessments
Molecular response (RQ-PCR, mutational analysis)
Cytogenetic response (Bone Marrow Aspirate)
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
Other 
assessments
●
PK sampling (full/sparse)
●
Bone Marrow Biopsy
●
Patient Report Outcomes (MDASI-CML, PGIC, WPAI, EQ--5D-5L, resource 
utilization)
Data analysis
The primary efficacy variable of the study is the Major Molecular Response (MMR) rate 
at 24 weeks. A patient will be counted as having achieved MMR at 24 weeks if he meets 
the MMR criteria (BCR-ABL1 ratio ≤0.1%) at 24 weeks.
The MMR rate at 24 weeks will be calculated based on the FAS and according to the 
Intention To Treat (ITT) principle. MMR rate and its 95% confidence interval based on 
the Pearson-Clopper method will be presented by treatment group. Confidence interval 
for the difference in MMR rate between treatment groups will be provided using the Wald 
method.
The Mantel-Haenszel estimate of the common risk difference and the corresponding 
95% confidence interval will also be provided.
The key secondary endpoint is MMR rate at 96 weeks.
Formal statistical testing of the key secondary endpoint will be performed only if the 
primary endpoint is significant by means of a gatekeeping procedure to control the 
overall alpha level. 
Key words
Phase III, open-label, randomized trial, asciminib, bosutinib, CML-CP, prior treatment 
with 2 or more TKIs


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Amendment 03-US.01 (05-Aug-2020)
Amendment rationale 
As of 25-Jun-2020, 319 patients were screened, 233 patients were randomized in the study.
Patient recruitment has been completed on 22-Oct-2019. The study is currently ongoing.
The primary purpose of the amendment is:
Based on FDA request, requirement for male contraception has been reintroduced in the study.
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.
The requirements for male contraception have been reintroduced in the following sections:

Section 7.2.2.5.3 Pregnancy and assessments of fertility.

Section 8.4 Pregnancies.

Section 11.3 Informed consent procedures.
The enrollment has been completed, thus the eligibility criterion has not been updated.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authority.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 3 (14-Dec-2018)
Amendment rationale 
As of 21-Nov-2018, 137 patients were screened and 86 patients were randomized in the study, 
the study is currently ongoing.
The primary purpose of the amendment is:
Modification of the inclusion criterion of BCR-ABL1 transcript threshold required at study 
entry from a BCR-ABL1 ratio ≥ 1% IS to BCR-ABL1 ratio > 0.1% IS (i.e. not in MMR) for 
patients with intolerance to most recent TKI treatment. The threshold presented in this inclusion 
criteria affects only patients who are intolerant to prior treatment, since patients failing prior 
treatment must fulfill the criteria defined by ELN guidelines (Baccarani et al 2013). Although 
the number of treatment options is increasing, especially for patients with imatinib intolerance, 
alternatives for patients with resistance and/or intolerance to at least two previous TKIs are 
limited (NCCN 2018, ELN 2013). The reason of reducing the BCR-ABL1 ratio is that in routine 
clinical practice, physicians do not wait to observe increased BCR-ABL1 levels to switch 
treatment in patients with intolerance, which may increase the risk of disease progression, 
especially in patients with only limited further treatment options. This is in line with current 
CML treatment guidelines where the switch to an alternative therapy in intolerant patients is 
not linked to a BCR-ABL1 threshold (NCCN 2018, Baccarani et al 2013 and Hochhaus et al 
2017). 
Therefore, the threshold of ≥1% BCR-ABL1 in the current trial is reduced to BCR-ABL1 ratio >
0.1% IS for patients with intolerance to most recent TKI treatment. No more than 66 patients 
(approximately 30% of the overall trial population) that are intolerant to their most recent TKI 
therapy with BCR-ABL1 < 1% will be recruited in order to ensure that the CML third line 
patient population is adequately represented. As the primary endpoint is the rate of MMR at 24 
weeks a baseline molecular response level > 0.1 % BCR-ABL1 is needed.
Patients experiencing documented treatment failure on bosutinib treatment will be allowed to 
switch to asciminib. Patients failing bosutinib treatment will have failed at least their third TKI 
treatment, with limited remaining treatment options. With this amendment patients who have 
failed bosutinib will be offered the possibility to continue in the study by receiving asciminib, 
if investigators consider that this treatment option is in the best interest of the patient. As of 15-
Oct-2018, 4 patients could have potentially benefited from this option. Treatment failure during 
study treatment is assessed by measureable and pre-specified milestones defined by ELN 
criteria (Baccarani et al 2013), which are also used to define treatment failure as entry criteria 
for the study. Only documented treatment failure in the bosutinib arm will be considered for a 
treatment switch. For the purpose of the primary and secondary endpoint analyses, any patient 
meeting the ELN failure criteria while receiving study treatment, (either before or by the time 
of conducting the analysis and irrespective of treatment arm), will be considered as non-
responders for the specific time point and for any subsequent time point. The switch to 
asciminib in case of bosutinib treatment failure is not expected to introduce bias as those 
patients will be regarded as non-responders irrespective of treatment switch and the disease 
burden will certainly not improve without further treatment. There is no option to switch 
patients failing on the asciminib treatment arm, as those patients can be offered approved 


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therapies outside of the context of the study. The efficacy data collected after the switch from 
patients switching to asciminib following bosutinib failure will be analyzed separately as 
exploratory endpoints and will not be included for primary and secondary study endpoints. In 
addition, safety data from patients receiving asciminib after bosutinib failure will be collected 
to further characterize asciminib’s safety profile.
Potassium increase of up to 6.0 mmol/L is acceptable at study entry if associated with creatinine 
clearance within normal limits. Grade 2 increase of potassium is acceptable in case of normal 
creatinine clearance as this is not considered to be a risk factor for QTc prolongation. Total 
calcium (corrected for serum albumin) increase of up to 12.5 mg/dl or 3.1 mmol/L (Grade 2) is 
acceptable at study entry if associated with creatinine clearance within normal limits as this is 
not considered to be a risk factor for QTc prolongation.
A change to creatinine clearance instead of GFR is being made in relation to the magnesium 
inclusion requirement as GFR in this study is expressed by creatinine clearance.
Exclusion criteria #19 is being modified under this amendment in order to define the duration 
of the use of highly effective methods of contraception after the last dose of bosutinib under 
this study (one month after last dose of bosutinib). This is being done in order to align with the 
latest Bosulif® USPI. 
Exclusion criteria #21 has also been removed under this amendment. In embryofetal 
development studies with asciminib, fetal malformations (cardiac malformations) and increased 
visceral and skeletal variants were observed in rats and increased incidence of resorptions 
indicative of embryo-fetal mortality and a low incidence of cardiac malformations indicative of 
dysmorphogenesis were observed in rabbits. Asciminib is not genotoxic. As published in the 
literature, small molecules can distribute to seminal fluid and the seminal accumulation 
suggested is semen/plasma ratios up to 11.3 (Klemmt and Scialli 2005). According to the FDA 
guidance, in general, there is increased concern for reproductive or developmental toxicity in 
humans for relative exposure ratios (animal: human) that are < 10 and decreased concern for 
exposure ratios > 25 (FDA Guidance for Industry 2011). The calculations for the asciminib 
safety margin were done based on Cmax (plasma) seen in patients at a dose of 200 mg BID 
(Cmax 6843 ng/ml).  Safety margin calculation based on the embryo-fetal development study 
in rats was 768 and safety margin calculation based on the embryo-fetal development study in 
rabbits was 894. In conclusion, for asciminib, as outlined above, the safety margins are well 
above 25 and therefore no embryo- and fetotoxicity effects can be anticipated via seminal fluid.
Removal of male contraception is in line with the Bosutinib USPI and SmPC.
In addition, patients can be re-screened up to three times for the study, instead of once.  The 
patient population being investigated in this study is heavily pre-treated and patients might not 
have other treatment options outside the trial. There can be many intolerance-related temporary 
conditions resulting in ineligibility for the trial.
Recruitment period extension has been reflected in the VES table. Study length has changed 
with introduction of switch option for patients failing bosutinib treatment.
Patients enrolling in this trial will present a high disease burden after failure of previous 
therapies. Myelosuppression during TKI targeted treatment is a very common effect observed 
due to the suppression of the leukemic clone; this effect is also extended to hematopoiesis of 


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stem cells and progenitors (Steegmann et al 2016). For this reason, the recovery period for 
cytopenias has been extended from 28 to 42 days in order to allow for sufficient time to recover 
from suppression and to re-populate the bone marrow.
The biomarker sampling profile has been revised to remove the gene expression profile in 
leukemic stem cells in both blood and bone marrow due to technical limitations.  In addition, 
there is currently no validated assay available.
A clarification has been made to how the tests for blood urea and Blood Urea Nitrogen (BUN)
are noted. The text "blood urea, Blood Urea Nitrogen (BUN)" has been revised to “blood urea 
or Blood Urea Nitrogen (BUN)” in order to note that either test is permitted.
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.

Change of the purpose of the study by decreasing the requirement of BCR-ABL1 ratio ≥
1% IS to BCR-ABL1 ratio > 0.1% IS at the time of screening for patients with 
intolerance:

Protocol summary.

Section 2.1 Study rationale and purpose.

Section 4.1 Description of study.

Section 5.2 Inclusion criteria.

Section 10.5.2 Other secondary efficacy objectives.

Change of the study design by introducing the switch to asciminib option for patients 
experiencing treatment failure on bosutinib treatment:

Protocol summary.

Section 2.2 Rationale for the study design.

Section 4.1 Description of study.

Figure 4-1 Schematic of Study Design.

Addition of Section 4.1.1 Study treatment switch from bosutinib to asciminib

Section 4.3 Definition of end of study.

Section 6.1.5 Treatment duration

Section 6.7.3.2 Study drug accountability.

Section 7 Visit schedule and assessments:

Addition of Table 7-2 Visit evaluation schedule (study treatment switch phase).

Addition of Section 7.1.2.2 Conditions to be fulfilled for asciminib switch.

Section 7.1.5 Visit windows.

Section 7.1.6 Discontinuation of study treatment.

Section 7.2.1.1 Molecular response.

Section 7.2.1.2 Bone marrow analysis and cytogenetics

Section 7.2.2.1 Physical examination.


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
Section 7.2.2.2 Vital signs.

Section 7.2.2.3 Height and weight.

Section 7.2.2.4 Performance status.

Section 7.2.2.5 Laboratory evaluations.

Section 7.2.2.6 Cardiac assessments.

Section 7.2.3 Pharmacokinetics.

Section 7.2.4 Biomarkers.

Section 10.1.6 Other analysis sets.

Section 10.5.3.1 Analysis set and grouping for the analysis

Addition of new exploratory measure for patients that switch from bosutinib to asciminib:

Table 3-1 Objectives and related endpoints.

Section 10.1.6 Other analysis sets.

Section 10.6 Exploratory objectives:

Section 10.6.1 Exploratory efficacy objectives.

Section 10.6.1.1 Data analysis of exploratory efficacy objectives.

Reference for concomitant medications with a “known risk of TdP” has been updated to 
wwwcrediblemeds.org/

Protocol summary

Section 5.3 Exclusion criteria

Section 6.3.2 Dose adjustments for QTcF prolongation

Section 6.4.3 Prohibited concomitant therapy


Section 5.2 Inclusion criteria and protocol summary: updated inclusion criteria to reflect 
the changes below:

Inclusion Criteria #3: As referenced above, the requirement of BCR-ABL1 ratio ≥ 1% 
IS has been decreased to BCR-ABL1 ratio > 0.1% IS at the time of screening for 
patients intolerant to previous TKI.

Inclusion Criteria #10: Potassium increase of up to 6.0 mmol/L is accepted at study 
entry if associated with creatine clearance within normal limits.  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.  GFR replaced by Creatinine clearance 
(calculated using Cockcroft-Gault formula) in order to maintain consistency 
throughout the protocol as creatinine clearance is already calculated based on 
inclusion criteria #7.

Inclusion Criteria #11: As study eligibility is assessed during screening with BCR-
ABL1 PCR quantification via international scale this requirement was added as 


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clarification. Measurement according to international scale is only possible for typical 
BCR-ABL1 transcripts.

Section 5.3 Exclusion Criteria and Protocol summary: updated exclusion criteria to reflect 
the following changes:

Exclusion Criteria #14: Removal of P-gp as a moderate or strong inhibitor of CYP3A
as P-gp inhibitors are no longer prohibited per updated USPI, and SmPC

Exclusion Criteria #19: Duration of the use of highly effective methods of 
contraception after the last dose of bosutinib has been defined to align with the latest 
bosutinib USPI.

Exclusion Criteria #21 Removal of this criteria in order to align with updated pre-
clinical data.

Section 6.3.1 Dose modification and dose delay: The recovery period for cytopenias has 
been extended from 28 to 42 days in order to allow for sufficient time to recover from 
suppression and to re-populate the bone marrow.

Table 7-1 Visit evaluation schedule: updates due to inadvertent omissions in previous 
protocols and to reflect extension of study treatment period

ECOG Performance status: X has been replaced by “If needed” under Week 6, Week 
10 and Week 14.

Vital signs: added “If needed” under Week 6, Week 10 and Week 14.

Visit name: “W108, W120, W132, W144, W156” has been changed to “Every 12 
weeks up to end of study treatment” to align with new extended recruitment timelines.

Section 7.1.2 Change of patient re-screening allowance from once to up to three times.

Section 7.1.2.2 Addition of new section with screening eligibility criteria for patients 
switching from bosutinib to asciminib.

Section 7.1.4 Change of treatment duration for patients including those patients that 
switch to asciminib after failure on bosutinib. Patients can remain on asciminib treatment 
for up to 96 weeks after the last patient received the first dose in the study or up to 48
weeks after the last patient has switched to asciminib whichever is longer.

Section 7.1.6 Discontinuation of study treatment: updated to specify that the safety follow-
up visit can be conducted by telephone and replacement of “after randomization” by “after 
initiation of therapy” in the event that constitutes a treatment failure.

Section 7.2.2.5.3 Pregnancy and assessments of fertility: Change in requirement for 
reporting pregnancies under this study.  Pregnancies diagnosed in female partners of male 
participants are no longer required to be reported to CMO&PS.  Contraception use by 
sexually active males while on study treatment is no longer required.

Table 7-5 Central clinical laboratory parameters collection plan: Clarification on blood 
urea and Blood Urea Nitrogen (BUN). The text "blood urea, Blood Urea Nitrogen (BUN)" 
has been revised to “blood urea or Blood Urea Nitrogen (BUN)”.

Section 8.4 Pregnancies: removal of male contraception requirement due to new 
information of asciminib embryo and fetotoxicity.

Section 10.4.3 Handling of missing values/censoring/discontinuations: imputation rules 
updated to take in account unscheduled visits close to visit Week 24.


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
Section 10.5.1.1. Analysis for key secondary endpoints: imputation rules updated to take 
in account unscheduled visits close to visit Week 96.

Section 14 Appendices: updates to reflect that P-gp inhibitors are no longer prohibited

Section 14.2 Appendix List of concomitant medications for patients on bosutinib:

Removal of P-gp inhibitors from Table 14-3 Prohibited concomitant medications 
for bosutinib arm.

Addition of new medications to Category Torsade de pointe (TdP) TdP/QT risk: 
Known.

Addition of new category, TdP/QT risk: Possible.

Addition of new category, TdP/QT risk: Conditional.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 2 (13-Jul-2018)
Amendment rationale 
As of 29-Jun-2018, this study has been submitted in 25 and approved in 24 countries. Eighty 
five (85) sites were initiated, 67 patients were screened and 38 patients were randomized in the 
study.
The primary purposes of the amendment are:
The frequency of bone marrow aspirate (BMA) to perform cytogenetic analysis has been 
decreased in accordance with treatment guidelines (European Leukemia Network (ELN) 
Guidelines (Baccarani et al 2013), National Comprehensive Cancer Network (NCCN) (Clinical 
Practice Guidelines in Oncology-Chronic Myeloid Leukemia v4.2018). Initially BMAs were 
foreseen at screening, every 24 weeks thereafter and at end of treatment. With the protocol 
amendment BMA is no longer needed for patients that have achieved MMR during study, 
however BMA assessment is requested at the time of end of treatment for biomarker analysis. 
Toxicity studies performed in rats, dogs and cynomolgus monkeys identified the pancreas as 
potential target tissues. Therefore the assessment for laboratory parameters that are associated 
with pancreatitis were part of the inclusion criteria (amylase, lipase). Serum lipase is the 
preferred test due to its improved sensitivity, and a threshold concentration of 2-3 x ULN is 
recommended for the diagnosis of pancreatitis. There are a number of other conditions that can 
elevate lipase, including TKI pretreatment, thus the screening threshold for lipase is increased 
from ≤ULN to ≤ 1.5 x ULN (CTCAE v4.03 grade 1), as patients with history of acute 
pancreatitis within 1 year of study and history of chronic pancreatitis are excluded. Amylase is 
not a specific marker for pancreatitis, as up to 60% of total serum amylase originates from non-
pancreatic sources. Its short half-life reduces its value as a diagnostic test in the early clinical 
course. Lipase has replaced amylase as the biochemical test of choice for acute pancreatitis due 
to its higher specificity (Basnayake 2015), therefore the requirement of amylase ≤ ULN at 
screening has been removed.
Assessments for visits at weeks 6, 10 and 14 will be limited to the monitoring of the bone 
marrow function to allow for adjustments of study treatment. Assessments will comprise a 
complete blood count to detect neutropenia and thrombocytopenia which are among the most 
frequent adverse reactions [Asciminib Investigator’s Brochure, Bosutinib label]. The physical 
examination must be done at site only in case of previous or newly occurring adverse events.
The concomitant medication section has been updated to reflect the most recent clinical updates 
on asciminib as well to align with the Bosutinib label.
In addition some minor inconsistencies (discrepancies between sections, typos) have been 
corrected.
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.

ABL001 has been replaced by International Nonproprietary Name (INN) asciminib 
throughout the protocol amendment.




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
Section 6.3.1 Dose modification and dose delay: clarification made on treatment 
discontinuation.

Table 6-2 Criteria for dose reduction/interruption and re-initiation of asciminib and 
bosutinib treatment for adverse drug reactions: 

Gastro intestinal/ Pancreatitis/Grade 2: precisions provided and treatment delay 
changed from 7 to 21 days to give investigators sufficient time for re-assessment.

Removal of “other adverse event” section which was redundant with the section “non-
hematological adverse event reaction except where further specified in individual 
section”.

Mandatory instructions for grade 3 and 4 “Non-hematological adverse event reaction 
except where further specified in individual section” for bosutinib have been aligned 
with those of asciminib: dose hold until resolved to ≤ grade 1, to handle the patients 
identically independent of the treatment assigned.

Section 6.3.2 Dose adjustments for QTcF prolongation: adapting the dose adjustment
concerning QT prolonging agents to the classification known, possible or conditional risk 
for TdP, and adding the external web link to qtdrugs.org.

Section 6.4.2 Permitted concomitant therapy requiring caution and/or action: updated with 
the most clinical data available.

Section 6.4.3 Prohibited concomitant therapy (asciminib):

Section on other anticancer agent added,

Sections on strong CYP3A4/5 inhibitors and P-gp inhibitors: prohibition on P-gp 
inhibitors has been removed and moved under requiring caution and/or action section 
based on CABL001A2102 ADME study,

Section on strong CYP3A4/5, UGT1A/2B inducers updated to provide instructions on 
action to be taken in case these inducers are taken,

Section on NTI substrates of CYP3A4/5, CYP2C8 and CYP2C9 removed based on a 
most updated PBPK modeling predicting a negligible risk for sensitive CYP3A4/5, 
CYP2C8, or CYP2C9 substrates and moved under requiring caution and/or action 
section,

Section on QT prolonging agents updated to change agents known to prolong QT 
interval to agents with “known”, “possible” or “conditional” risk of Torsades de 
Pointes.

Section 6.5.1 Permitted concomitant therapy requiring caution (bosutinib): has been 
updated to reflect the bosutinib label information regarding the use of QT prolonging agents. 

Section 6.5.2 Prohibited concomitant therapy (bosutinib): 

Section on other anticancer agent added,

Concomitant use with CYP3A4/5 inhibitors/inducers: further clarifications on 
necessary actions. 

Table 7-1 Visit evaluation schedule: 

Exploratory BCR-ABL1 mutation analysis (Sanger Sequencing) for patients with 
mutations at Week 1 Day 1: rephrased to indicate that this assessment will be 
performed without any dedicated blood collection.






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
Section 10.5.2 Other secondary efficacy objectives: update of descriptive statistics 
definition and removal of presentation of p value as no formal statistical testing will be 
performed.

Section 10.6.1 Exploratory efficacy objectives and Section 10.6.3 Exploratory biomarker 
objectives: 

Correction of time points for BCR-ABL1 mutation characterization (baseline 
corrected to Week 1 Day 1, adding “upon confirmed loss of MMR, and changed 
“and” to “and/or” End of treatment).

 

Section 10.6.4.1 Resource utilization: correction on duration of resource utilization 
reporting.

Section 10.7 Interim analysis: clarification concerning the analysis of the key secondary 
endpoint at week 96 if statistical significance is not reached for primary endpoint at week 
24.

Section 14 Appendices: the lists of concomitant medications for patients on asciminib and 
bosutinib have been updated based on the internal Pharmacokinetic Sciences 
memorandum on Drug-Drug Interaction (release date: January 2018).

Some minor inconsistencies (discrepancies between sections, typos) have been corrected.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.






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1
Background
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. 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).
Multiple agents, including nilotinib, dasatinib, ponatinib, bosutinib, radotinib (Korea) and 
omacetaxine (USA, Canada) are able to combat 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 


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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.
There remains an unmet need for new compounds in patients with CML who have failed at least 
two prior TKIs. Current practice suggests that a second generation TKI will have been used for 
first line therapy for about one half of patients with CML, meaning that most patients who have 
failed at least two prior TKIs will have failed at least one if not two second generation TKIs: 
dasatinib and/or nilotinib. Potentially, such patients may also have failed bosutinib and/or 
ponatinib (Soverini 2014). Patients having failed at least two TKIs may have limited sensitivity 
to the remaining available agents and, thus, there exists a need for new safe and effective therapy. 
In addition, mutations will have developed in 21 to 33% of patients that prevent the use of 
specific TKIs, increasing the need for a better and alternative compound (Soverini 2014). 
Omacetaxine, a chemotherapeutic agent, is available for patients who have failed at least two 
prior TKIs under these conditions but only in the US and Canada. This agent is not available 
for most patients globally, where a bigger unmet medical need is present. Thus, there remains 
an unmet need for active and safe drugs in patients with CML who have failed at least two prior 
tyrosine kinase inhibitors (TKI), even in the presence of approved drugs, as described below.
1.2
Introduction to investigational treatment
1.2.1
Overview of asciminib (ABL001)
Asciminib is an orally bioavailable specific BCR-ABL1 inhibitor with a novel mechanism of 
action. In contrast to inhibitors such as imatinib, nilotinib, dasatinib and bosutinib that bind 
within the ATP-binding site of the ABL kinase domain, asciminib inhibits ABL tyrosine kinase 
activity by binding to a particular allosteric site on the kinase domain, which has only been 
identified on ABL1, ABL2 and BCR-ABL1. Consequently, asciminib is specific for the latter 
three enzymes.
Asciminib potently and selectively inhibits the proliferation of cell lines that express BCR-
ABL1. By virtue of asciminib not interacting with the ATP-binding site, the drug maintains 
activity against cells expressing clinically observed ATP-binding TKI resistance mutations.
1.2.1.1
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.


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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.
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.


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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 
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 extend 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 
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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. Therefore, strong 
inhibitors of CYP3A4/5 should be avoided and are prohibited in this study. Strong inducers of 
CYP3A4/5 have the potential to reduce asciminib concentrations. Therefore, the use of strong 
inducers of CYP3A4/5 or UGT1A/2B is prohibited in this trial.
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 
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.
1.2.1.2
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 01-Sep-2017, a total of 239 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


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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 major molecular response and reduction in the BCR-
ABL1 % IS. Asciminib has demonstrated anti-tumor activity at doses greater or equal to 10 mg 
BID as well as daily higher 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). 
Of the 62 patients with BCR-ABL1 no greater than 10 % IS at screening and without T315I 
mutation, 1-log reduction of BCRABL1 % IS was achieved in 16 of 62 (25.8%) patients by 6 
months and 19 of 62 (30.6%) patients by 12 months. For asciminib 40 mg BID dose, of the 17 
patients studied, 1-log reduction of BCRABL1 % IS was achieved in 5 of 17 (29.4%) patients 
by 6 months, and 12 months. 
Please refer to 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. All 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 was 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.


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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 %) 
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% 


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(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.
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 
overall exposure decreased by approximately 65% when administered with a high-fat meal.
Therefore, asciminib will be administered in a fasted state.
1.2.2
Overview of bosutinib
Bosutinib (Bosulif®) is indicated for the treatment of adult patients with newly-diagnosed 
chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ 
CML) and for the treatment of patients with chronic, accelerated, or blast phase Ph+ chronic 
myelogenous leukemia (CML) with resistance or intolerance to prior therapy (500 mg QD) 
[Bosulif® USPI] as well as for newly-diagnosed CML-CP (400 mg QD), and in Europe for the 
treatment of adult patients with chronic phase (CP), accelerated phase (AP), and blast phase 
(BP) Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) previously 
treated with one or more tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib and 
dasatinib are not considered appropriate treatment options [EU Summary of Product 
Characteristics (SmPC)]. Bosutinib has been evaluated in patients treated with one or more prior 
TKIs.
For patients treated with bosutinib after prior imatinib only, the MMR rate is approximately 15% 
at 24 weeks overall, and approximately 10% in imatinib-resistant patients and 20% in imatinib-
intolerant patients (Gambacorti-Passerini 2014). The cytogenetic, molecular, and hematological 
response rates did not appear to differ greatly between patients who were imatinib-resistant or 
imatinib-intolerant (Gambacorti-Passerini 2014).
Twenty seven percent of patients treated with bosutinib after at least 2 previous TKIs achieved 
MCyR rate by Week 24 [Bosulif® USPI]. For patients previously treated with imatinib and 
either dasatinib or nilotinib, after a median of 28.5 months follow-up, the cumulative rate of 
Major Molecular Response (MMR) is 15% (Khoury 2012). The cytogenetic, molecular, and 
hematological response rates appeared to be lower in patients who were resistant to dasatinib 
after imatinib treatment as compared to patients who were intolerant to dasatinib after imatinib 
treatment (Khoury 2012). In a small (30 patient) compassionate use trial of patients previously 
treated with imatinib, dasatinib and nilotinib, after a median duration of treatment of 9.3 months, 
the cumulative MMR rate was 14% (García-Gutiérrez 2015). Based on these data, the MMR 
rate at 6 month with bosutinib treatment in patients treated with at least 2 prior TKIs is estimated 
to be approximately 10-15%.
Bosutinib has no activity against the T315I and V299L mutant form of BCR-ABL1. 
Accordingly, the pivotal trial leading to the registration in the 3rd line setting excluded patients 
with a known history of the T315I or V299L mutation [Bosulif® USPI].


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2
Rationale
2.1
Study rationale and purpose
Asciminib is an agent intended to be evaluated for the treatment of patients with CML. In the 
ongoing study [CABL001X2101] study, asciminib was found to produce clinically meaningful 
and durable responses in patients who have had treatment failure after a minimum of 2 prior 
ATP-binding site TKIs, with an acceptable safety and tolerability profile.
The purpose of this pivotal study is to compare the efficacy of asciminib with that of bosutinib 
in the treatment of patients with CML-CP having previously been treated with a minimum of 
two prior ATP-binding site TKIs. Patients with intolerance to most recent TKI therapy must 
have BCR-ABL1 ratio >  0.1% IS at screening and patients experiencing failure to most recent
therapy must meet the definition of treatment failure as per the 2013 ELN guidelines (Baccarani 
et al 2013).
Imatinib, nilotinib and dasatinib are indicated for the treatment of patients with newly diagnosed 
CML. Multiple agents, including nilotinib, dasatinib, ponatinib, bosutinib, radotinib (Korea) 
and omacetaxine (USA, Canada) are approved for patients with CML-CP previously treated 
with prior therapy. Imatinib is a first generation TKI; nilotinib, dasatinib, bosutinib, ponatinib 
and radotinib are considered second generation TKIs and have activity in patients previously 
treated with imatinib. The activity of nilotinib or dasatinib in patients previously treated with a 
second generation TKI is not known. All the currently approved BCR-ABL1 TKIs are 
enzymatic site inhibitors, in distinction to asciminib which is an allosteric TKI. Omacetaxine is 
a cytotoxic chemotherapeutic agent.
2.2
Rationale for the study design
Asciminib is an orally bioavailable specific BCR-ABL1 inhibitor with a novel mechanism of 
action. In contrast to other TKIs that bind within the ATP-binding site of the ABL kinase 
domain, asciminib inhibits ABL tyrosine kinase activity by binding to a particular allosteric site 
on the kinase domain that is utilized by a myristate group to auto-regulate the native ABL1 
kinase. With allosteric inhibition of BCR-ABL1 being a novel mechanism of action, asciminib
produces clinically meaningful and durable responses in patients who have had treatment failure 
after a minimum of 2 prior ATP-binding site TKIs, with an acceptable safety and tolerability 
profile as demonstrated in study [CABL001X2101].
The development of asciminib, presents an opportunity to evaluate the beneficial effects of 
inhibition of BCR-ABL1 in the treatment of patients with CML. The proposed study design is 
expected to adequately allow an assessment of the efficacy, safety and tolerability of asciminib
in a population of patients with continuing medical need i.e., patients who have been treated 
with at least two prior TKIs and are in the need for further therapeutic intervention.
Bosutinib is one of the TKIs with proven clinical benefit in CP-CML patients previously treated 
with one or more tyrosine kinase inhibitor(s) and is currently approved for this indication in 
many countries, including the European Union. The proposed study will evaluate asciminib in 
comparison to bosutinib at the approved doses in the targeted population.






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Additional preliminary PK-efficacy and PK-safety analyses to assess the exposure-response 
relationship for asciminib were conducted (Section 1.2.1.2). 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 
amylase.
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. Of note, the dose of asciminib single agent BID is further being evaluated in patients with 
the T315I mutation. At present the recommended dose of 40 mg BID is for patients without the 
T315I mutation. For this reason, patients with the T315I mutation are excluded from this study.
2.4
Rationale for choice of combination drugs
Not Applicable.
2.5
Rationale for choice of comparators drug bosutinib
The guidance provided by the NCCN and the ELN (Baccarani et al 2013), recommends 
bosutinib as a treatment in CML-CP patients who fail first-line or second-line treatment with 
imatinib or nilotinib or dasatinib. Consistent with these recommendations and clinical practice, 
bosutinib was selected to be an appropriate comparator in a study of 3rd line CML-CP patients 
after failure of at least 2 prior TKIs, and is the comparator that will be used in the present study.
It is to be noted that bosutinib has no activity against the T315I and V299L mutant form of 
BCR-ABL1. Patients who have the T315I or V299L mutations documented in their medical 
record will already be excluded from this study. Bosutinib is known to be active against 
E255K/V, F317L/V/I/C, F359V/C/I, T315A, and Y253H and therefore, these mutations are not 
considered in the exclusion criteria for the current study.
Ponatinib is not selected as the comparator in the present clinical trial, because the comparator 
in this study needs to be an approved agent administered at the approved dose. Currently, the 
ponatinib dose is being evaluated in a randomized trial as a post-approval commitment due to 
the occurrence of vascular risks at the current approved dose of ponatinib. The dose of ponatinib 
that will be approved and will be used in practice at the completion of the present study may 
not be the approved dose at the time of initiation of the present study.
2.6
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 6.3. 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).


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An important potential risk for patients enrolling on the experimental arm of the study with 
asciminib will be that this agent may be ineffective. However, the evidence to date at the doses 
to be administered in a similar population of patients in the study [CABL001X2101] suggests 
that asciminib is an active agent. Further, the adverse event profile of asciminib is similar 
qualitatively to that observed with other TKIs targeting BCR-ABL1 (Section 1.2.1.2). The risk 
of asciminib not being effective has been mitigated in that patients will be observed closely for 
evidence of efficacy, based on assessment of hematologic, cytogenetic and molecular response 
data, which will permit rapid decision making as to discontinuation of therapy if necessary.
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.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To compare the MMR rate at 24 weeks of asciminib versus 
bosutinib 
Major Molecular Response (MMR) rate at 24 weeks
Refer to Section 10.4
Key secondary
To compare additional parameters of the efficacy of asciminib 
versus bosutinib 
MMR rate at 96 weeks
Refer to Section 10.5.1
Other secondary
To compare additional parameters of the efficacy of asciminib 
versus bosutinib
●
Cytogenetic response rate (Complete, Partial, Major, Minor, Minimal, 
no response) at and by all scheduled data collection time points 
including 24, 48 and 96 weeks
●
MMR rate at all scheduled data collection time points (except 24 and 
96 weeks which are already covered by primary and key secondary 
endpoints)
●
MMR rate by all scheduled data collection time points including 24, 
48 and 96 weeks
●
Time to MMR
●
Duration of MMR
●
Time to CCyR
●
Duration of CCyR
●
Time to treatment failure
●
Progression free survival
●
Overall survival
Refer to Section 10.5.2
To compare the safety and tolerability profile of asciminib versus 
bosutinib
Type, frequency and severity of adverse events,
changes in laboratory values that fall outside the pre-determined ranges 
and clinically notable ECG and other safety data (vital signs, physical 
examination)
To characterize the PK of asciminib in the CML-CP population
To assess the safety of asciminib when administered as 
treatment after bosutinib failure according to the 2013 ELN 
Guidelines
Trough plasma concentrations,
PK parameters in full PK group: Cmax, Tmax, AUC0-12h, CL/F
Type, frequency and severity of adverse events, changes in laboratory 
values that fall outside the pre-determined ranges and clinically notable 
ECG and other safety data (vital signs, physical examination)
Refer to Section 10.6




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Objective
Endpoint
Analysis

Time to MMR

Duration of MMR

Time to CCyR

Duration of CCyR

Time to treatment failure


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4
Study design
4.1
Description of study design
The study is a phase 3, multi-center, open-label randomized study of oral asciminib versus 
bosutinib in patients with Chronic Myelogenous Leukemia in chronic phase (CML-CP), 
previously treated with 2 or more tyrosine kinase inhibitors.
The trial is designed to compare the efficacy and safety of asciminib with that of bosutinib in 
the treatment of patients with CML-CP having previously been treated with a minimum of two 
prior ATP-binding site TKIs. Patients intolerant to the most recent TKI therapy must have BCR-
ABL1 ratio > 0.1% IS at screening and patients failing their most recent TKI therapy must meet 
the definition of treatment failure as per the 2013 ELN guidelines (Baccarani et al 2013). No 
more than 66 patients (approximately 30% of the overall trial population) that are intolerant to 
their most recent TKI therapy with BCR-ABL1 < 1% will be recruited in order to ensure that 
the CML third line patient population is adequately represented.
The study will also investigate secondary endpoints for efficacy, safety and PK of single-agent 
asciminib compared to bosutinib. Tolerability, PK, PRO and exploratory biomarker activities 
will also be assessed. Safety and efficacy data for patients switching to asciminib will be 
collected and analyzed separately.
Patients meeting all of the inclusion and none of the exclusion criteria will be randomized into 
one of the 2 treatment arms, based on a 2:1 randomization between the asciminib arm and the 
bosutinib arm.
The randomization will be stratified to ensure the study population is balanced between the 
arms with respect to cytogenetic response status (See Section 7.2.1.2) at screening as follows:

Major cytogenetic response (complete or partial)

No major cytogenetic response (minor, minimal or none)
Patients will continue to receive the assigned study treatments (asciminib or bosutinib) until 
the end of study treatment period as defined in Section 4.3. Patients who discontinue their study 
treatment at any time during the study will be followed up for survival and for progression to 
AP/BC for up to 5 years from the date the last randomized patient receives the first dose 
(irrespective of treatment switch for patients failing bosutinib).
Serial PK samples over 12 hours will be collected on Week 2 Day 1 from at least 20 CML-CP 
patients (full PK group) on the asciminib arm, in addition to trough PK samples. These patients 
will be identified sequentially at selected sites that are capable of serial PK sampling over 12 
hours. In the remaining patients in the asciminib arm and in patients that have switched to 
asciminib, sparse post-dose PK samples on Week 1 Day 1 and trough PK samples will be 
collected (sparse PK group).


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Figure 4-1
Schematic of Study Design
4.1.1
Study treatment switch from bosutinib to asciminib
Patients with documented treatment failure (as per the 2013 ELN guidelines; Baccarani et al 
2013) while on bosutinib treatment will have the option to switch to asciminib treatment within
96 weeks after the last patient has been randomized on study. The patients who switch to 
asciminib will be able to receive asciminib up to end of study treatment period. At the end of 
the treatment period for patients who, in the opinion of the investigator still derive clinical 
benefit, asciminib treatment will be made available through alternative options including, but 
not limited to, an expanded access/compassionate use/managed access program or access to 
commercial supplies in applicable countries. Discontinuation of asciminib for patients who
have switched over from bosutinib must follow the guidelines provided in Section 7.1.6.
Eligibility criteria for patients switching to asciminib are described in Section 7.1.
4.2
Timing of interim analyses and design adaptations
Not applicable. There are no formal interim analyses or design adaptations planned for this 
study. See Section 8.6 for documentation of safety DMC.
4.3
Definition of end of study
The patients are treated in the study up to end of study treatment period defined as up to 96 
weeks after the last patient receives the first dose or up to 48 weeks after the last patient has 
switched to asciminib treatment whichever is longer unless patients have discontinued treatment 
earlier. The end of the study, concluding the survival follow-up, will occur 5 years from the 
date when the last patient enrolled into the study receives the first dose of the randomized 
treatment.
The primary analysis (cut-off date) is defined as the date when all randomized patients have 
been on study treatment for 24 weeks (Section 10.4) or discontinued earlier. Subsequent to this 


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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 assigned study treatments (asciminib or bosutinib)
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 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.
Patients will be followed for survival and progression for up to 5 years from the date the last
randomized patient receives the first study dose (irrespective of treatment switch for patients 
failing bosutinib). Information on subsequent treatments will also be collected. An updated 
analysis of OS and PFS will be performed at the end of the follow-up period in the final study 
CSR.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be contacted as soon as possible and instructed to stop taking study 
medication. The end of treatment visit should be scheduled and the same assessments should 
be performed as described in Section 7 for a discontinued or withdrawn patient. 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 patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
Two-hundred and twenty-two (222) patients with CML-CP who had prior treatment with two 
or more ATP binding site TKIs will be randomized in a 2:1 fashion to receive either asciminib 
or bosutinib. No patients with a medical history of the T315I or V299L mutation at study entry 
will be included in the trial. 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 
(Baccarani et al 2013), and is outlined below in the inclusion criteria.
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Male or female patients with a diagnosis of CML-CP ≥ 18 years of age


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2. Patients must meet all of the following laboratory values at the screening visit:

< 15% blasts in peripheral blood and bone marrow

< 30% blasts plus promyelocytes in peripheral blood and 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
3a.  BCR-ABL1 ratio > 0.1% IS according to central laboratory at the screening examination, 
for patients intolerant to the most recent TKI therapy
4. Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, nilotinib, 
dasatinib, radotinib or ponatinib)
5. Failure (adapted from the 2013 ELN Guidelines; Baccarani et al 2013) or intolerance to 
the most recent TKI therapy at the time of screening 

Failure is defined for CML-CP patients (CP at the time of initiation of last therapy) as 
follows. Patients must meet at least 1 of the following criteria.

Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases

Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 
65% Ph+ metaphases

Twelve months after initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 
35% Ph+ metaphases

At any time after the initiation of therapy, loss of CHR, CCyR or PCyR

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 after the initiation of therapy, confirmed loss of MMR in 2 
consecutive tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS

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
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
7. Adequate end organ function as defined by (as per central laboratory tests):

Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert’s syndrome who may 
only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN


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
Aspartate transaminase (AST) ≤ 3.0 x ULN

Alanine transaminase (ALT) ≤ 3.0 x ULN

Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN -  ≤ 1.5 x ULN, value must be 
considered not clinically significant and not associated with risk factors for acute 
pancreatitis

Alkaline phosphatase ≤ 2.5 x ULN

Creatinine clearance ≥ 50 mL/min as calculated using Cockcroft-Gault formula
8. 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.
9. Written informed consent obtained prior to any screening procedures.
10a.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.
11. Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of screening 
which are amenable to standardized RQ-PCR quantification.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Known presence of the T315I or V299L mutation at any time prior to study entry
2. Known second chronic phase of CML after previous progression to AP/BC
3. Previous treatment with a hematopoietic stem-cell transplantation
4. Patient planning to undergo allogeneic hematopoietic stem cell transplantation
5. 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:


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
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
6. 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)
7. History of acute pancreatitis within 1 year of study entry or past medical history of chronic 
pancreatitis
9. History of acute or chronic liver disease
10. Known presence of significant congenital or acquired bleeding disorder unrelated to 
cancer
11. 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
12. Known history of Human Immunodeficiency Virus (HIV), chronic Hepatitis B (HBV), or 
chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) 
and Hepatitis B core antibody (HBcAb / anti HBc) will be performed at screening
13. 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)
14a. 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

Moderate or strong inducers of CYP3A

Moderate or strong inhibitors of CYP3A 
15. Previous treatment with or known/ suspected hypersensitivity to asciminib or any of its
excipients.
16. Previous treatment with or known/ suspected hypersensitivity to bosutinib or any of its
excipients.
17. Participation in a prior investigational study within 30 days prior to randomization or 
within 5 half-lives of the investigational product, whichever is longer
18. Pregnant or nursing (lactating) women
19a. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 3 days after last dose of asciminib and one month after last dose of
bosutinib. Highly effective contraception methods include:


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
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 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.
6
Treatment
6.1
Study treatment
The investigational treatments for this study are asciminib (40 mg BID) and bosutinib (500 mg 
QD). Novartis will supply asciminib to the investigational site as 20 mg and 40 mg tablets.
Bosutinib will be supplied to the investigational site as 100 mg and 500 mg tablets.
6.1.1
Dosing regimen
Asciminib
Asciminib 20 or 40 mg strength tablets will be administered orally twice-daily (BID), without 
food. 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


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
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
Bosutinib
Bosutinib 500 mg or 100 mg tablets will be administered orally once daily (QD) with food. If 
a dose is missed beyond 12 hours, the patient should skip the dose and take the usual dose on 
the following day.
Table 6-1
Dose and treatment schedule
Study 
treatments
Pharmaceutical form 
and route of 
administration
Dose
Frequency and/or
Regimen
Fasting Condition
Asciminib
Tablet for oral use
20 mga
Twice-daily 
Fasting
Asciminib
Tablet for oral use
40 mg 
Twice-daily 
Fasting
Bosutinib
Tablet for oral use
100 mgb
Once-daily
Non-fasting
Bosutinib
Tablet for oral use
500 mg
Once-daily
Non-fasting
a 20 mg tablets will be dispensed to patients in the instance of dose reduction.
b 100 mg tablets will be dispensed to patients in the instance of dose modifications.
On days when serial blood samples are collected for asciminib PK analysis, patients will be 
instructed to bring their drug supply to the site, and take the dose in the clinic, under supervision 
of the site personnel. The exact time for dose administration and meal intake must be recorded 
in the electronic Case Report Form (eCRF).
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
6.1.2
Ancillary treatments
Not applicable.
6.1.3
Rescue medication
Not applicable.
6.1.4
Guidelines for continuation of treatment
Not applicable. See Section 6.3.
6.1.5
Treatment duration
There is no fixed duration of treatment planned per patient. The patients are treated in the study 
up to end of study treatment period defined as up to 96 weeks after the last patient receives the 
first dose or up to 48 weeks after the last patient has switched to asciminib treatment whichever 
is longer unless patients have discontinued treatment earlier.  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.


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6.2
Dose escalation guidelines
Dose escalation beyond the standard doses of 40 mg BID for asciminib is not permitted.
Dose escalation above 500 mg QD for bosutinib is permitted in this study. Bosutinib escalation 
guidelines are as follows:
Consider dose escalation to 600 mg once daily in patients who are currently taking 500 mg 
daily, did not have Grade 3 or higher adverse events and who:

Did not reach complete hematological response (CHR) by week 8

Did not reach complete cytogenetic response (CCyR) by week 12
6.3
Dose modifications
6.3.1
Dose modification and dose delay
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” are 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 on 
the asciminib arm per protocol. 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 either asciminib or bosutinib 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. 


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Table 6-2
Criteria for dose reduction/interruption and re-initiation of asciminib and bosutinib treatment for adverse drug 
reactions
Dose modifications for both asciminib and bosutinib
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 4.03
Asciminib
Bosutinib
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
Recommendation: Maintain dose level
Grade 2 (ANC < 1.5 – 1.0 x 109/L)
Recommendation: Maintain dose level
Recommendation: Maintain dose level
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 
Mandatory: Hold dose until resolved to ≤ Grade 2 and platelets ≤ 
Grade 2 (recheck CBC 2x/week), then:
if resolved in ≤ 14 days, then maintain dose level
If resolved in > 14 days, 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 
Mandatory: Hold dose until resolved to ≤ Grade 2 and platelets ≤ 
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
Mandatory: Hold dose until resolved, then reduce dose 1 dose 
level
Thrombocytopenia
Grade 1 (PLT < LLN – 75 X 109/L)
Recommendation: Maintain dose level
Recommendation: Maintain dose level
Grade 2 (PLT < 75 - 50 x 109/L)
Recommendation: Maintain dose level
Recommendation: Maintain dose level


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Dose modifications for both asciminib and bosutinib
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 4.03
Asciminib
Bosutinib
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
Mandatory: Hold dose until resolved to ≤ Grade 2 and 
neutrophils ≤ 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
Mandatory: Hold dose until resolved to ≤ Grade 2 and 
neutrophils ≤ 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: Hold dose until resolved to ≤ Grade 2, 
then maintain current dose level. 
Recommendation: Hold dose until resolved to ≤ Grade 2, then 
reduce dose 1 additional 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
Recommendation: Maintain dose level
Grade 3
Mandatory: Hold dose until resolved to ≤ Grade 1, then 
reduce dose 1 dose level
Mandatory: Hold dose until resolved to ≤ Grade 1, then reduce 
dose 1 dose level, If clinically appropriate, re-escalation of the 
dose back to baseline dose level (500 mg) should be considered
Grade 4
Mandatory: Permanently discontinue patient from study 
drug treatment.
Mandatory: Hold dose until resolved to ≤ Grade 1, then reduce 
dose 1 dose level; If clinically appropriate, re-escalation of the 
dose back to baseline dose level (500 mg) should be considered
Investigations (Renal)
Serum creatinine
Grade 1 (> ULN - 1.5 x ULN)
Recommendation: Maintain dose level
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
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.
Mandatory: Permanently discontinue patient from study drug 
treatment.
Grade 4 (> 6.0 x ULN)
Mandatory: Permanently discontinue patient from study 
drug treatment.
Mandatory: Permanently discontinue patient from study drug 
treatment.


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Dose modifications for both asciminib and bosutinib
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 4.03
Asciminib
Bosutinib
Investigations (Hepatic)
Isolated total Bilirubin elevation
> ULN – 1.5 x ULN
Recommendation: Maintain dose level
Recommendation: Maintain dose level
> 1.5 - 3.0 x ULN
Recommendation: Hold dose. Monitor LFTsb weekly, or 
more frequently if clinically indicated, until resolved to ≤ 
1.5 x ULN:
if resolved in ≤ 14 days, then maintain dose level
if resolved in > 14 days, then reduce dose 1 dose level
Recommendation: Hold dose. Monitor LFTsb weekly, or more 
frequently if clinically indicated, until resolved to ≤ 1.5 x ULN:
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*
Mandatory: Hold dose. Monitor LFTsb weekly, or more 
frequently if clinically indicated, until resolved to ≤1.5 x 
ULN:
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.
Mandatory: Hold dose. Monitor LFTsb weekly, or more frequently 
if clinically indicated, until resolved to ≤ 1.5 x ULN:
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*
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.
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
> ULN - 3.0 x ULN
Recommendation: Maintain dose level
Recommendation: Maintain dose level
> 3.0 - 5.0 x ULN
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
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


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Dose modifications for both asciminib and bosutinib
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 4.03
Asciminib
Bosutinib
> 5.0 - 10.0 x ULN
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: Then
If resolved in ≤ 14 days, maintain dose level
If resolved in > 14 days, reduce dose 1 dose level
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 ≤ 2.5 x ULN: Then
Recommendation: If resolved in ≤ 28 days, reduce dose 1 
dose level
Recommendation: If resolved in > 28 days, Discontinue patient 
from study drug treatment
> 10.0 - 20.0 x ULN
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 ≤ 
baseline. Then reduce dose 1 dose level.
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 ≤ 2.5 x ULN. Then
Recommendation: If resolved in ≤ 28 days, reduce dose 1 
dose level maintain dose level
Recommendation: If resolved in > 28 days, Discontinue patient 
from study drug treatment.
> 20.0 x ULN
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.
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 ≤ 2.5 x ULN (then
Recommendation: If resolved in ≤ 28 days, reduce dose 1 
dose level maintain dose level
Recommendation: If resolved in > 28 days, Discontinue patient 
from study drug treatment


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Dose modifications for both asciminib and bosutinib
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 4.03
Asciminib
Bosutinib
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 
6.3.3.1 for additional follow-up evaluations as applicable.
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 6.3.3.1 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
Recommendation: Maintain dose level, measure 2x week
Grade 2 (> 1.5 - 2.0 x ULN)
Recommendation: Maintain dose level, measure 2x 
week
Recommendation: Maintain dose level, measure 2x week
Grade 3 (> 2.0 - 5.0 x ULN)
Mandatory: Hold dose until resolved to Grade ≤ 1 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).
Mandatory: Hold dose until resolved to Grade ≤ 1 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)
Mandatory: Permanently discontinue patient from study 
drug treatment. Obtain appropriate imaging (i.e., MRI, CT 
scan or ultrasound).
Mandatory: Permanently discontinue patient from study drug 
treatment. Obtain appropriate imaging (i.e., MRI, CT scan or 
ultrasound).


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Worst toxicity
CTCAE Grade 4.03
Asciminib
Bosutinib
Vascular disorders
Hypertension
CTCAE Grade 3
Mandatory: Hold dose until resolved ≤ Grade 1, then 
reduce dose 1 dose level
Mandatory: Hold dose until resolved ≤ Grade 1, then reduce 
dose 1 dose level
CTCAE Grade 4
Mandatory: Permanently discontinue patient from study 
drug treatment.
Mandatory: Permanently discontinue patient from study drug 
treatment.
Gastro intestinal
Pancreatitis
Grade 2 (radiologic findings for 
pancreatitis as per CTCAE v4.03, 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).
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).
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
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
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
Mandatory: Hold dose until recovery to ≤ grade 1. 
Recommendation: Bosutinib may then be resumed at 1 dose 
level
Grade 4
Mandatory: Permanently discontinue patient from study 
drug treatment
Mandatory: Hold dose until recovery to ≤ grade 1. 
Recommendation: Bosutinib may then be resumed at 1 dose 
level


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Worst toxicity
CTCAE Grade 4.03
Asciminib
Bosutinib
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)
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)
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
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.
Mandatory: Permanently discontinue patient from study drug 
treatment.
General disorders and administration site conditions
Fatigue/ Asthenia
Grade 1 or 2
Recommendation: Maintain dose level
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
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 4.03)
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


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Worst toxicity
CTCAE Grade 4.03
Asciminib
Bosutinib
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 and bosutinib
Dose reduction*
Starting dose level – 0
Dose level – 1
Asciminib BID
40 mg tablet BID (total daily 
dose 80 mg)
20 mg tablet BID (total daily 
dose 40 mg)
*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.
Dose reduction*
Starting dose level – 0
Dose level – 1
Dose level – 2
Bosutinib QD
500 mg (1-500 mg tablet QD)
400 mg (4-100 mg tablets 
QD)
300 mg (3-100 mg 
tablets QD)
* Dose reduction should be based on the worst toxicity demonstrated at the last dose.
Bosutinib dose reduction below total daily 300 mg is not allowed. 100 mg tablets will be dispensed to patients 
in the instance of dose reduction.
6.3.2
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, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug 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 study drug 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 and 
address clinical conditions that could potentially prolong the QT as per the ECG and 
QTc Clinical Safety Standards Guidelines Section 3.3.1. 

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 for the next treatment(s), (e.g. pre-dose and 2 hours post dose 
after one week and two weeks of treatment re-introduction): 


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
If QTcF remains ≤ 500 msec after dose reduction, continue planned ECG monitoring 
during subsequent treatment 

If QTcF > 500 msec recurs after dose reduction, discontinue patient from trial. 
6.3.3
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.
6.3.3.1
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with 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).
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
1. Laboratory tests should include ALT, AST, albumin, creatinine kinase, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.
2 . A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
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4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study.
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
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”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly
documented.
6.3.4
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria, as well as specific dose modification and stopping rules are 
included in this protocol. Recommended guidelines for prophylactic or supportive treatment for 
expected toxicities, including management of study-drug induced adverse events, i.e., 
hyperglycemia, skin toxicity and diarrhea are provided in Table 6-2. Refer to preclinical toxicity 
and or clinical data found in the [Asciminib Investigator’s Brochure] or bosutinib label.
6.4
Concomitant medications for patients on asciminib
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.
6.4.1
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.


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6.4.2
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 1.2.1.1). 
Therefore CYP3A4/5, CYP2C8 and CYP2C9 substrates with narrow therapeutic index (NTI) 
should be used with caution. 
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 14 appears on both the list of prohibited and the list of 
medications to be used with caution, the medication is prohibited.
6.4.3
Prohibited concomitant therapy
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 is not allowed. 
Strong CYP3A4/5 inhibitors
Every effort should be made NOT to concomitantly administer strong CYP3A4/5 inhibitors.
CYP3A4/5 inhibitors may decrease the metabolism of asciminib and resulting in increased 
serum concentrations and increased exposure. If administration of a strong CYP3A4/5 inhibitor 
cannot be avoided during the study and cannot be switched to an alternative therapy that does 
not strongly inhibit CYP3A4/5, asciminib must be interrupted.
A list of cytochrome P450 isoenzymes and CYP3A4/5inhibitors may be found at 
medicine.iupui.edu/CLINPHARM/ddis/clinical-table.
A classification of CYP3A4/5 SmPC can be found in Section 14-Appendices.
Further information can also be found in the following reference (Venkatakrishnan et al 2001).
Strong CYP3A4/5, and UGT1A/2B inducers
Every effort should be made NOT to concomitantly administer strong CYP3A4 inducers during 
the study.
Additionally, the use of strong inducers of UGT1A/2B is prohibited during the study.
If administration of a strong CYP3A4/5 inducer or 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.


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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.
6.4.4
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 6.4.2 and Section 14.1 
Appendix 1).
Bisphosphonates
The use of bisphosphonates regardless of indication is allowed.
Contraceptives
Hormonal contraceptives are allowed as contraception methods. Highly effective contraception 
should be maintained throughout the study and for 3 days after study treatment discontinuation.
Anticoagulation agents
All anticoagulants or anti-aggregation agents may be administered under the discretion of the 
investigator.
Therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative 
anticoagulants should be used with caution and fully avoided whenever possible because of its 
known interaction with many commonly used medications and certain foods. As warfarin has 
a narrow therapeutic range, and asciminib is possibly an inhibitor of CYP2C9, the major 


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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.
6.5
Concomitant medications for patients on bosutinib
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
6.5.1
Permitted concomitant therapy requiring caution
Bosutinib should be used with caution in patients who have or may develop prolongation of QT, 
including those patients who are taking medicinal products that are known to prolong the QTc 
(e.g., anti-arrhythmic medicinal products such as amiodarone, disopyramide, procainamide, 
quinidine and sotalol and other substances that may prolong QTc) (in accordance with EU 
SmPC dated 05/2018).
If a medication listed in Section 14-Appendices appears on both the list of prohibited and the 
list of medications to be used with caution, the medication is prohibited.


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6.5.2
Prohibited concomitant therapy
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 is not allowed. 
Concomitant use with CYP3A inhibitors
Avoid the concomitant use of strong or moderate CYP3A inhibitors as an increase in bosutinib 
plasma concentration is expected. Strong CYP3A inhibitors include boceprevir, clarithromycin, 
conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole.
Moderate CYP3A inhibitors include amprenavir, aprepitant, atazanavir, ciprofloxacin, 
crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit 
products, imatinib and verapamil) [Bosulif® USPI]. If administration of a strong or moderate 
CYP3A4/5 inhibitor cannot be avoided during the study and cannot be switched to an alternative 
therapy, bosutinib must be interrupted.
Concomitant use with CYP3A inducers
Avoid the concomitant use of strong or moderate CYP3A inducers as a large reduction in 
exposure is expected (strong CYP3A inducers include carbamazepine, phenytoin, rifampin and 
St. John's Wort. Moderate CYP3A inducers include bosentan, efavirenz, etravirine, modafinil 
and nafcillin) [Bosulif® USPI]. However, if administration of a strong or moderate CYP3A4/5 
inducer cannot be avoided during the study and cannot be switched to an alternative therapy, 
temporary interruption of bosutinib is NOT required.
pH Altering Medications
Bosutinib displays pH-dependent aqueous solubility, in vitro. In a cross-over trial in 23 healthy 
volunteers, a single oral dose of 400 mg of bosutinib was either administered alone or in 
combination with multiple-oral doses of 60 mg of lansoprazole (PPI) under fasting conditions. 
Lansoprazole decreased bosutinib Cmax and AUC by 46% and 26%, respectively.
Concomitant administration with PPIs is not allowed.
Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in 
bosutinib exposure. Separate antacid or H2 blocker dosing by more than 2 hours [Bosulif®
USPI].
6.6
Patient numbering, treatment assignment or randomization
6.6.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 


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throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available to the investigator through the Oracle Clinical RDC interface.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to be randomized or start treatment for any 
reason, the reason will be entered into the Screening Disposition page. IRT must be notified 
within 2 days that the patient was not randomized.
6.6.2
Treatment assignment or randomization
Patients will be assigned to one of the 2 treatment arms (Section 4.1 and Section 6.1) in a ratio 
of 2:1. Randomization will be stratified by cytogenetic response status at screening.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication randomization list 
will be produced by or under the responsibility of Novartis Drug Supply Management using a 
validated system that automates the random assignment of medication numbers to medication 
packs containing each of the study treatments.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign 
a randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the patient. The randomization number will not be communicated to the caller.
6.6.3
Treatment blinding
Not applicable.
6.7
Study drug 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.


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6.7.1
Study treatment packaging and labeling
Study treatment, asciminib and bosutinib tablets, will be provided as global clinical open-label 
supply and will be packed and labeled under the responsibility of Novartis, Drug Supply 
Management.
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to study treatment and strength).
Responsible site personnel will identify the study treatment package(s) to dispense by the 
medication number(s) assigned by IRT to the patient. Site personnel will add the patient number 
on the label. If the label has 2-parts (base plus tear-off label), immediately before dispensing 
the package to the patient, site personnel will detach the outer part of the label from the package 
and affix it to the patient’s source document.
Table 6-4
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
asciminib (20 mg and 40 mg)
Tablets in bottle
Labeled as ‘ABL001 20 mg/ABL001 40 
mg’(BID)
bosutinib (100 mg or 500 mg)
Tablets in bottle or tablets in 
blister
Labeled as ‘bosutinib 100 mg or bosutinib 
500 mg’(QD)
6.7.2
Drug supply and storage
Study treatments must be received by designated personnel 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, asciminib and bosutinib should be stored according 
to the instructions specified on the drug labels.
6.7.3
Study drug compliance and accountability
6.7.3.1
Study drug 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 
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.
6.7.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study treatment or at 
the time of study treatment discontinuation during the treatment period as well as during the 
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At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and 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.
6.7.3.3
Handling of other study treatment
Not applicable.
6.7.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, or at the site only if permitted by local regulations and authorized by Novartis in a 
prior agreement.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. Patients can be consented for study participation prior to study day -21.
Table 7-2 lists all of the assessments required by patients that switch treatment from bosutinib 
to asciminib after documented treatment failure of bosutinib.
No eCRF will be used as a source document.
(S) is defined as “Source”
(D) is defined as “Data Based”
























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Category
Protocol 
Section 
7
Switch 
Screening 
Phase
Treatment Switch Phase
Visit name
EOT (Bosutinib)
/
S-Screening/
S-Baseline
S-Week 1 Day 1
S-Week 2 Day 1
S-Week 4
S-Week 6
S-Week 8
S-Week 10
S-Week 12
S-Week 14
S-Week 16
S-Week 20
S-Week 24
S-Week 28
S-Week 32
S-Week 36
S-Week 40
S-Week 44
S-Week 48
S-Week 52
Hematology
D
7.2.2.5.1
X
(if not done 
at EOT)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5.2
X
(if not done 
at EOT)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry-
Hemoglobin A1c
D
7.2.2.5.2
X
(if not done 
at EOT)
Week 12 and as clinically indicated
Coagulation
D
7.2.2.5.2
X
(if not done 
at EOT)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum 
Pregnancy test (if 
applicable)
D
7.2.2.5.3
X
(if not done 
at EOT)
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver 
assessments
D
as clinically indicated














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7.1.1
Molecular pre-screening
Not applicable.
7.1.2
Screening
Written informed consent must be obtained before any study specific medical procedures are 
performed. All screening/baseline assessments (with the exception of Bone Marrow Aspirates) 
should occur within 21 days before Week 1 Day 1.
The screening visit window for bone marrow assessments is 56 days prior to Week 1 Day 1.
Should bone marrow assessments have been performed before the main informed consent is 
signed but within 56 days of Week 1 Day 1, no further bone marrow sampling will be required 
at screening. At end of treatment, a bone marrow exploratory aspirate and/or biopsy must be 
collected even if the screening/baseline bone marrow exploratory aspirate and/or biopsy 
samples were not collected. 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)
and the bone marrow aspirate must be available prior to randomization and first dose of study 
treatment.
For details of assessments required during screening please refer to Table 7-1.
Laboratory baseline assessments (including hematology, chemistry, coagulation 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, the patient ID number will remain the same. All required 
screening activities must be performed when the patient is re-screened for participation in the 
study. No further bone marrow sampling will be done at re-screening if a previous assessment 
was done within 56 days of Week 1 Day 1. After 56 days, new bone marrow biopsy and 
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collected at the time of the bone marrow assessment. 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.
7.1.2.1
Eligibility screening
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be managed via IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
7.1.2.2
Conditions to be fulfilled for asciminib switch
The eligibility assessments of patients who are candidates for asciminib switch will start with 
the bosutinib EOT visit. Assessments conducted during the EOT visit will be used to evaluate 
if all conditions for asciminib switch are fulfilled and there are no conditions preventing patients 
from receiving asciminib treatment. Therefore all efforts MUST be made to ensure that all EOT 
assessments are completed per Table 7-1. In the event that all EOT assessments cannot be 
completed during the EOT visit, they must be completed within 42 days (6 weeks) after the 
bosutinib EOT visit. For details of assessments required for patients that switch treatment from 
bosutinib to asciminib, please refer to Table 7-2. The maximum allowed time frame for patients 
failing bosutinib to start treatment with asciminib is 42 days after bosutinib EOT.
In case a patient presents with a grade 3 or 4 adverse event at the time of the EOT visit or 
develops it after the EOT visit, the adverse event must be resolved to grade 2 or lower before 
starting asciminib treatment and within 28 days of the date of occurrence of the adverse event 
as outlined in the criteria listed below. 
However, a patient who has laboratory test (peripheral blood test) results or ECG results that 
do not satisfy the treatment switch conditions may have the tests repeated multiple times during 
the treatment switch screening period. The last test performed before start of asciminib dosing 
must meet the conditions for treatment switch as listed below.
If a patient does not meet the conditions for treatment switch, they should enter the survival 
follow-up phase.
The conditions for treatment switch will be checked via the IRT system. Please refer and comply 
with detailed guidelines in the IRT manual.
Conditions to fulfill to allow the switch to asciminib:
1. Failure to bosutinib treatment up to 96 weeks after the last patient received the first dose 
(adapted from the 2013 ELN Guidelines; Baccarani et al 2013). Patients must meet at least 
1 of the following criteria. Failure is defined as follows:

Three months after the initiation of therapy or thereafter: No CHR or > 95% Ph+ 
metaphases.

Six months after the initiation of therapy or thereafter: BCR-ABL1 ratio > 10% IS 
and/or > 65% Ph+ metaphases.

Twelve months after initiation of therapy or thereafter: BCR-ABL1 ratio > 10% IS 
and/or > 35% Ph+ metaphases.


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
At any time after the initiation of therapy, loss of CHR, CCyR or PCyR.

At any time after the initiation of therapy, detection of new BCR-ABL1 mutations
which potentially cause resistance to study treatment (asciminib or bosutinib).

At any time after the initiation of therapy, confirmed loss of MMR in 2 consecutive 
tests.

At any time after the initiation of therapy, new clonal chromosome abnormalities in 
Ph+ cells: CCA/Ph+.
Conditions preventing patients to switch to asciminib

Any Grade 3 or 4 toxicity which has not resolved to Grade 2 or lower within 28 days 
and before starting asciminib treatment.

Asymptomatic (Grade 2) pancreatitis if not resolved within 28 days 

Disease progression while on bosutinib treatment. The following events are 
considered disease progression:

Accelerated phase (AP) as defined by any of the following:

≥15% blasts in the peripheral blood or bone marrow aspirate, but < 30% blasts 
in both the peripheral blood and bone marrow aspirate.

≥30% blasts plus promyelocytes in peripheral blood or bone marrow aspirate.

≥20% basophils in the peripheral blood.

Thrombocytopenia (< 100 x 109/L) that is unrelated to therapy.

Blast crisis (BC) as defined by any of the following:

≥30% blasts in peripheral blood or bone marrow aspirate

Appearance of extramedullary involvement other than hepatosplenomegaly 
proven by biopsy (i.e. chloroma).

QTcF at time of switch > 480msec or inability to determine QTc interval
7.1.2.3
Information to be collected on screening failures
Patients who sign an informed consent but fail to be randomized for any reason will be 
considered a screen failure. The reason for not being randomized will be entered on the 
Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details). If the patient fails to be randomized, the IRT must be notified within 2 days 
of the screen fail that the patient was not randomized.
7.1.2.4
Patient demographics and 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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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 and the bone 
marrow aspirate must be available prior to randomization and first dose of study treatment to 
evaluate eligibility and to stratify the patient.
7.1.2.5
Local recruitment procedures-Japan
Given the limited safety data available in Japanese patients, specific recruitment and data 
monitoring procedures will be put in place for Japanese patients randomized to asciminib.
Randomization of these patients will be staggered to avoid enrollment of more than one patient 
on the same day. Safety parameters from a minimum of 2 patients treated on the asciminib arm 
will be reviewed for determining the appropriateness of continuing patient enrollment in Japan.
7.1.3
Run-in period
Not applicable.
7.1.4
Treatment period
There is no fixed duration of treatment planned per patient. All patients will be given the 
opportunity to receive study treatment until the end of study treatment period as defined in 
(Section 4.3).
During the treatment phase, the patients will receive either asciminib treatment 40 mg BID or 
bosutinib 500 mg QD according to randomization. The dose can be modified, if required from 
the perspective of tolerance, following the guidance in Section 6.2 and Section 6.3. 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).
7.1.5
Visit windows
Study visits from Week 1 Day 1 to Week 2 Day 1 / S-Week 1 Day 1 to S-Week 2 Day 1  should 
be completed on the designated date [with an allowed “visit window” of +/- 1 day for Week 2 
Day 1 / S-Week 2 Day 1]
Study visits from Week 4 to Week 16 / S-Week 4 to S-Week 16 should be completed every 2 
weeks on the designated date [with an allowed “visit window” of +/- 1 day]


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Study visits from Week 20 to Week 96 / S-Week 20 to S-Week 96 should be completed every 
4 weeks on the designated date [with an allowed “visit window” of +/- 2 days]
Study visits from Week 108 to EOT / S-Week 108 to S-EOT should be completed every 12 
weeks on the designated date [with an allowed “visit window” of +/- 7 days]
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.
7.1.6
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a
patient decides to discontinue from the study treatment, the investigator should make a  
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this
decision and record this information in the patient’s chart and on the appropriate eCRF pages.
They may be considered withdrawn if they state an intention to withdraw, fail to return for visits,
or become lost to follow-up for any other reason.
The investigator should discontinue study treatment for a given patient if, he/she believes that
continuation would be detrimental to the patient’s well-being. Patients who discontinue study 
treatment should undergo an end of treatment visit.
For patients who discontinue treatment in treatment period or switch treatment period for 
reasons other than death, lost to follow-up, or withdrawal of consent, the patient should enter 
the survival follow-up phase. Survival visit assessments (survival, antineoplastic therapies, stem 
cell transplant and progression) should be performed every 12 weeks until documented death, 
lost to follow-up, withdrawal of consent or until the end of the study. This visit can be conducted 
by telephone.
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 14-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 T315I or V299L mutations at any time the patient must be 
discontinued from the study treatment.

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 


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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. 
Patients randomized to bosutinib treatment experiencing treatment failure may switch to 
asciminib treatment. The following events will constitute ‘treatment failure’, and are based 
on the ELN criteria (Baccarani et al 2013) defining failure of a second line treatment:

No CHR or > 95% Ph+ metaphases at three months after initiation of therapy or 
thereafter

BCR-ABL1 ratio > 10% IS and/or > 65% Ph+ metaphases at six months after 
initiation of therapy or thereafter

BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases at 12 months after 
initiation of therapy or thereafter

Loss of CHR, CCyR or PCyR at any time after initiation of therapy 

Detection of new BCR-ABL1 mutations which potentially cause resistance to study 
treatment (asciminib or bosutinib) at any time after initiation of therapy 

Confirmed loss of MMR in 2 consecutive tests (Section 7.2.1.1)

New clonal chromosome abnormalities in Ph+ cells: CCA/Ph+: at any time after 
initiation of therapy 

In the event of disease progression the patient must be discontinued from the study
treatment. The following events are considered disease progression.
1. 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)
2. Accelerated phase (AP) as defined by any of the following:

≥ 15% blasts in the peripheral blood or bone marrow aspirate, but < 30% blasts in 
both the peripheral blood and bone marrow aspirate

≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow aspirate

≥ 20% basophils in the peripheral blood

Thrombocytopenia (<100 x 109/L) that is unrelated to therapy
3. Blast crisis (BC) as defined by any of the following:

≥ 30% blasts in peripheral blood or bone marrow aspirate

Appearance of extramedullary involvement other than hepatosplenomegaly proven by 
biopsy (i.e., chloroma).
7.1.7
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data


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In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may
still be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and Rest of World: All biological samples not yet analyzed at the time of withdrawal 
will no longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements.
7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Molecular response
Molecular response (MR) will be assessed in all patients randomized to each treatment arm as 
well as in patients that switch study treatment from bosutinib to asciminib.
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.
Major molecular response 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 randomization 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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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 or loss of CCyR or progression to AP/BC or CML-
related death. Mutational analysis will be performed at a Novartis designated laboratory by 
Sanger sequencing at Week 1 Day 1, upon confirmed loss of MMR and/or at end of treatment. 
If the result at Week 1 Day 1 is positive for a mutation, analysis will be performed every 12 
weeks.
The blood samples will be taken as described in Table 7-1, Table 7-2 and Table 7-3.
Table 7-3
Blood samples (efficacy primary endpoint)
Sample Type
Volume
Visit
Time point
Blood for BCR-ABL1
quantification by RQ-PCR
20 mL
Screening/Baseline / S-Screening/S-Baseline*
Pre-dose
20 mL
Week 4 / S-Week 4
Pre-dose
20 mL
Week 8 /  S-Week 8
Pre-dose
20 mL
Week 12 /  S-Week 12
Pre-dose
20 mL
Week 16 /  S-Week 16
Pre-dose
20 mL
Week 24 /  S-Week 24
Pre-dose
20 mL
Week 36 /  S-Week 36
Pre-dose
20 mL
Week 48 /  S-Week 48
Pre-dose
20 mL
Week 60 /  S-Week 60
Pre-dose
20 mL
Week 72 /  S-Week 72
Pre-dose
20 mL
Week 84 /  S-Week 84
Pre-dose
20 mL
Week 96 /  S-Week 96
Pre-dose
20 mL
Every 12 weeks thereafter up to end of study 
treatment    
Pre-dose
20 mL
End of Treatment / S-End of Treatment
Anytime
Blood for BCR-ABL1 Mutation
analysis by Sanger 
Sequencing
5 mL
Week 1 Day 1 /S-Week 1 Day 1*
Pre-dose
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/ S-End of Treatment
Anytime
Blood for BCR-ABL1 Mutation
analysis only for patients with
mutations at Week 1 Day 1
No sample collected 
-  testing is 
performed on the 
“Blood for BCR-
ABL1 quantification 
by RQ-PCR” sample
Week 12 and every 12 weeks thereafter up to 
end of study treatment
Anytime
*Assessment does not need to be completed during the visit for patients in the treatment switch if already 
collected during the EOT or the treatment switch screening visit.


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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 [CABL001A2301 Laboratory Manual].
7.2.1.2
Bone marrow analysis and cytogenetics
Cytogenetic response will be assessed locally as the percentage of Ph+ metaphases in the bone 
marrow and is defined as the following (a review of a minimum of 20 metaphases is required):

Complete (CCyR) - 0% Ph+ metaphases

Partial (PCyR) - >0 to 35% Ph+ metaphases

Major (MCyR) - 0 to 35% Ph+ metaphases

Minor (mCyR) - >35 to 65% Ph+ metaphases

Minimal - >65 to 95% Ph+ metaphases

None - >95 to 100% Ph+ metaphases.
Bone marrow aspirate for cytogenetic analyses will be performed at screening/baseline 
(performed up to 56 days prior to Week 1 Day 1), at Week 24/S-Week 24, 48/S-48, 72/S-72, 
96/S-96 as long as patient has not achieved MMR and at end of treatment (S-end of treatment 
as specified in Table 7-1 and Table 7-2. For patients on the bosutinib arm an unscheduled bone 
marrow assessment at week 12 may be performed to evaluate cytogenetic response in 
consideration for potential dose escalation.
Quantification of the percentage of Ph+ chromosome metaphases, number of metaphases, 
number positive for Ph chromosome, additional chromosomal abnormalities as well as data 
from cytologic evaluation (microscopic analysis) of percentage of blasts and promyelocytes 
will be recorded on the Bone Marrow eCRF. These exams will be performed and analyzed 
locally. Fluorescent In-situ hybridization (FISH) analysis will not be accepted.
7.2.1.3
Hematologic response
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
7.2.2
Safety and tolerability assessments
Safety will be monitored by the assessments described below as well as collecting of the adverse 
events at every visit. For details on AE collection and reporting, refer to Section 8. 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.


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7.2.2.1
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 7-1 and Table 7-2:

Screening /S-Screening

Week 1 Day 1 / S-Week 1 Day 1

Every 2 weeks from Week 4 to Week 16 / S-Week 4 to S-Week 16. Week 6, 10 and 14 / 
S-Week 6, 10 and 14 assessments must be performed in case of previous or newly 
occurring adverse events.

Every 4 weeks from Week 16 to Week 96 / S-Week 16 to S-Week 96

Every 12 weeks from Week 96 to EOT / S-Week 96 to S-EOT

End of treatment / S-End of treatment visit or early discontinuation / S-early 
discontinuation visit in case of premature discontinuation.
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).
7.2.2.2
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 7-1 and Table 7-2:

Screening / S-Screening

Week 1 Day 1 / S-Week 1 Day 1

Week 2 Day 1 / S-Week 2 Day 1

Every 2 weeks from Week 4 to Week 16 / S-Week 4 to S-Week 16

Every 4 weeks from Week 16 to Week 96 / S-Week 16 to S-Week 96

Every 12 weeks from Week 96 to EOT/ S-Week 96 to S-EOT

End of treatment / S-End of treatment visit or early discontinuation / S-early 
discontinuation visit in case of premature discontinuation.
7.2.2.3
Height and weight
Height in centimeters (cm) will be measured at screening only.
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured at screening and at subsequent time points as specified in Table 7-1 and Table 7-2:

Screening / S-Screening


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
Week 1 Day 1 / S-Week 1 Day 1

Every 12 weeks from Week 12 to EOT / S-Week 12 to S-EOT

End of treatment visit / S-End of treatment or early discontinuation / S-early 
discontinuation visit in case of premature discontinuation.
7.2.2.4
Performance status
ECOG Performance status scale (Table 7-4) will be used as described in the Table 7-1, Table 
7-2 and Table 7-4:

Screening / S-Screening

Week 1 Day 1 / S-Week 1 Day 1

Every 2 weeks from Week 4 to Week 16 / S-Week 4 to S-Week 16

Every 4 weeks from Week 16 to Week 96 / S-Week 16 to S-Week 96

Every 12 weeks from Week 96 to EOT / S-Week 96 to S-EOT

End of treatment / S-End of treatment visit or early discontinuation / S-early 
discontinuation visit in case of premature discontinuation.
More frequent examinations may be performed at the investigator’s discretion, if medically 
indicated.
Table 7-4
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
7.2.2.5
Laboratory evaluations
Central laboratory will be used for analysis of hematology, biochemistry, coagulation, serum 
pregnancy and hepatitis marker specimens collected (safety monitoring) as specified in Table 
7-1, Table 7-2 and Table 7-5. Details on the collections, shipment of the samples and reporting 
of results by the central laboratory are provided to investigators in the [CABL001A2301 
Laboratory Manual]. The time windows granted for laboratory evaluations are identical with 
the corresponding visit time windows for each visit (see Section 7.1.5).
Local laboratory analysis are allowed if there is a clinical suspicion of abnormal laboratory
values which is supported by a reported adverse event and for hematology assessments at Week 
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Table 7-5
Central 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 2 weeks from week 
4 up to week 16, every 4 weeks up to 
week 96, and every 12 weeks thereafter, 
EOT and as clinically indicated / S-
Screening/S-baseline*, S-Week 1 Day 1, 
S-Week 2 Day 1, every 2 weeks from S-
week 4 up to S-week 16, every 4 weeks 
up to S-week 96, and every 12 weeks 
thereafter, S-EOT and as clinically 
indicated
Chemistry
Hemoglobin A1c
Screening/baseline, Week 12 and as 
clinically indicated / S-Screening/S-
baseline*, S-Week 12 and as clinically 
indicated
Chemistry
Creatinine clearance
Screening/baseline / 
S-Screening/S-baseline*
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 96, and every 12 weeks 
thereafter, EOT, and as clinically 
indicated / S-Screening/S-baseline*, S-
Week 1 Day 1, S-Week 2 Day 1, every 4
weeks from S-week 4 up to S-week 96, 
and every 12 weeks thereafter, S-EOT, 
and as clinically indicated
Coagulation
International Normalized Ratio (INR)
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 96, and every 12 weeks thereafter, 
EOT, unscheduled / S-Screening/S-
baseline*, every 4 weeks up to S-week 
96, and every 12 weeks thereafter, S-
EOT, unscheduled
*Assessment does not need to be completed during the screening visit for patients in the treatment switch if 
already collected during the EOT.
**Not applicable for patients being assessed for treatment switch as part of the treatment switch 
screening/baseline visit.
7.2.2.5.1 Hematology
Hematology labs are to be analyzed at each scheduled visit by a central laboratory (Week 6, 10 
and 14 assessments can be performed at site or at any peripheral local laboratory) as specified 
in Table 7-1 and Table 7-2. 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 7-5).


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7.2.2.5.2 Clinical chemistry
Blood chemistry labs are to be analyzed at each scheduled visits by a central laboratory as 
specified in Table 7-1 and Table 7-2. 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. In addition the coagulation parameter 
INR is analyzed at each scheduled visit.
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 7-5).
7.2.2.5.3 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 7-
1 and Table 7-2 of the Visit evaluation schedules. Serum pregnancy test will be performed by 
a central laboratory.
After Week 96 / S-Week 96, monthly urine pregnancy test must be performed by all women of 
child-bearing potential between the three monthly visits (beginning at Week 100 / S-Week 100).
Urine pregnancy tests may be performed at the investigational site or at home. Test results 
performed at home should be recorded onto a patient diary and brought to each scheduled visit 
for the site to review. If a test result indicates a pregnancy, the patient must contact the 
investigator immediately.
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.
During the whole study, women of childbearing potential should employ the use of highly 
effective contraception. Highly effective contraception methods are defined in Section 5.3.
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.
7.2.2.6
Cardiac assessments
7.2.2.6.1 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 


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between each ECG at the time points specified in Table 7-1, Table 7-2, Table 7-6 and Table 7-
7. ECGs should be taken before blood samples for PK if both assessments are scheduled at the 
same time point. In this case recording of ECGs should be planned according to the true time 
of blood sample for PK rather than to the scheduled time point.
Table 7-6
Central ECG collection (all patients)
Week (or Day)
Number of ECGs (per visit)
Time of ECG
Screening/Baseline Day -21 
to -1 / S-Screening/S-
Baseline Day -42 to -1 (all 
patients)
3
3 serial ECGs at the screening visit
Week 1 Day 1 / S-Week 1 
Day 1 (all patients)
3
3 serial ECGs at 2 h post dose
Week 2 Day 1 / S-Week 2 
Day 1 (asciminib/asciminib 
switch patients)
12
3 serial ECGs pre-dose and at 2, 3, 4 h post-
dose
Week 2 Day 1 / S-Week 2 
Day 1 (bosutinib)
3
3 serial ECGs pre-dose
Week 4 / S-Week 4 (all 
patients)
3
3 serial ECGs pre-dose
Week 12 / S-Week 12 (all 
patients)
3
3 serial ECGs pre-dose
Week 24 / S-Week 24 (all 
patients)
3
3 serial ECGs pre-dose
Week 96 / S-Week 96 (all 
patients)
3
3 serial ECGs 30 min* post-dose
Unscheduled (all patients)
3
3 serial ECGs 
* 30 min +/- 5min allowed
Table 7-7
Central ECG collection plan for patients in full PK asciminib group
Week (or Day)
Number of ECGs (per visit)
Time of ECG
Day -21 to -1
3
3 serial ECGs at the screening visit
Week 1 Day 1
3
3 serial ECGs at 2 h post dose
Week 2 Day 1
24
3 serial ECGs pre-dose and at 1, 2, 3, 4, 6, 8, 
12 h post-dose
Week 4
3
3 serial ECGs pre-dose
Week 12
3
3 serial ECGs pre-dose
Week 24
3
3 serial ECGs pre-dose
Week 96
3
3 serial ECGs 30 min* post-dose
Unscheduled
3
3 serial ECGs 
* 30 min +/- 5min allowed
All ECGs performed will be independently reviewed. Instructions for the collection and 
transmission of these ECGs to the independent central reader (ERT (Electronic Research 
Technology, Inc.)) will be provided in the [CABL001A2301 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 ERT. Readings for QTc prolongation will be based on the 


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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 calling ERT. 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 6.3.2.
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.
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.
7.2.2.6.2 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 7-1 and Table 7-2. As both study treatments in the trial are TKIs 
(asciminib and bosutinib), 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 patient’s Family History.
7.2.2.6.3 Echocardiogram
Echocardiograms will be performed to monitor cardiac safety. Assessments are scheduled at 
screening/baseline, Week 20 and end of treatment visits. The echocardiogram will be performed 
and evaluated locally to assess the left ventricular ejection fraction. Any clinically significant 
findings will be collected and reported in the database (i.e. reported as adverse events). For 
patients that switch from bosutinib to asciminib treatment, an echocardiogram will no longer
be required.
7.2.2.6.4 Pulmonary function test
Pulmonary function test will be performed to monitor cardio-pulmonary safety. Assessments 
are scheduled at screening/baseline, Week 20 and end of treatment visits. 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 points. Any clinically significant findings will be collected and reported in the 


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database (i.e. reported as adverse events). For patients that switch from bosutinib to asciminib
treatment, the pulmonary function testing will no longer be required.
7.2.3
Pharmacokinetics
Blood samples for asciminib pharmacokinetics will be collected on all study subjects allocated 
to the asciminib treatment arm. Blood samples for full PK profiles will be collected from at 
least 20 patients. These patients will be identified sequentially at selected sites that are capable 
of serial PK sampling over 12 hours. Asciminib should be taken for at least 3 consecutive days 
without interruption or dose modification prior to full PK day.
Blood samples for asciminib pharmacokinetics will also be collected on patients switching from 
bosutinib to asciminib (see Table 7-8). 
For the assessment of asciminib pharmacokinetics in plasma, serial blood samples will be 
collected following asciminib administration at several time-points (see Table 7-1, Table 7-2, 
Table 7-8 and Table 7-9 below for further details). Remaining plasma samples may be used for 
identification and/or measurement of metabolites of asciminib.
Refer to the [CABL001A2301 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK samples.
Table 7-8
Pharmacokinetic blood collection log (Sparse PK-group-asciminib
arm/ asciminib treatment switch patients)
Week /
S-Week
Day
Scheduled Time 
Point
Dose 
Reference ID
PK Sample No
Blood Volume 
(mL)
1
1
2 h (± 10 min)
101
101
2
2
1
0 h (Pre-dose)a
102/2001b
102
2
1
2 h (± 10 min)
102
103
2
1
3 h (± 15 min)
102
104
2
1
4 h (± 15 min)
102
105
2
4
Any
0 h (Pre-dose)a
103/3001b
106
2
12
Any
0 h (Pre-dose)a
104/4001b
107
2
24
Any
0 h (Pre-dose)a
105/5001b
108
2
96
Any
0 h (Pre-dose)a
106/6001 b
109
2
Unscheduled
1001+
a Pre-dose PK sample should be taken immediately prior to the next administration of asciminib. PK samples 
on Week 2 Day 1 should be taken before and after the morning dose (i.e. 1st dose of the day). PK samples on 
other weeks may be taken immediately prior to the morning dose (i.e. 1st dose of the day) or the evening dose 
(i.e. 2nd dose of the day).
b The first dose reference ID refers to the first dose administered after PK sampling and the second dose 
reference ID refers to the last dose administered prior to the PK sampling.








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7.2.5
Resource utilization
The measures of healthcare Resource Utilization (RU) to be collected include: hospitalization
(H), emergency room (ER) visit, general practitioner (GP) visits, specialist (Sp) visit and urgent 
care (UC) visit. These measures will be used to derive the economic impact of asciminib and 
bosutinib.
Hospitalization visits will also record the number of days in ward and the type of ward (hospital 
unit) and the discharge status. At each RU collection, the reason for the visit (i.e. related to 
CML, AE related to CML therapy or other reason) will be collected in order to quantify the 
impact of asciminib and bosutinib on healthcare resources.
The RU assessment will be completed at each scheduled clinical trial visit as specified in Table 
7-1; the RU will be completed by the investigator however information with respect to the 
number of GP, UC, Sp or ER visits will be ascertained from the patient.
All attempts to collect as much information from the patient as possible should be made in order 
to minimize selection bias.
7.2.6
Patient reported outcomes
The MDASI CML, PGIC, WPAI along with EQ-5D-5L (EuroQol Group (1990), Brooks (1996),
Herdman et al (2011)) will be used to compare data on the patient’s disease-related symptoms 
and health-related quality of life from baseline to EOT between the treatment arms. The WPAI 
will be used to assess work productivity and activity impairment related to the patient’s CML. 
All measures will assess differences between the treatment arms. All tools require patient’s 
direct completion and will be administered utilizing an electronic device for data collection.
Patients with an evaluable baseline score and at least one evaluable post baseline score during 
the treatment period will be included in the change from baseline analyses. Missing data items 
in a scale will be handled according to the manual for each instrument. No imputation will be 
applied if the total or subscale scores are missing at a visit.
The patient should be given the questionnaire(s) to be completed at the scheduled visit before 
any clinical assessments are conducted as specified in Table 7-1. Completion of all 
questionnaires is mandatory; they cannot be skipped. In the event a patient refuses to complete 
the questionnaire(s), the patient’s refusal should be documented in the study data capture system 
and should not be captured as a protocol deviation. Patient questionnaires should be completed 
in the language most familiar to the patient.
The patient should be given sufficient space and time to complete the questionnaires and the 
administered questionnaire should be reviewed for completeness. If missing responses are noted, 
patients should be encouraged to complete any missing responses. 
Completed questionnaire(s) and any unsolicited comments written by the patient should be 
reviewed and assessed by the investigator for responses which may indicate potential AEs or 
SAEs before any clinical study examinations. This assessment should be documented in study 
source records. If AEs or SAEs are confirmed, study investigators should not encourage the 
patient to change responses reported in the completed questionnaires. Study investigators must 
follow reporting instructions outlined in Section 8 (e.g. reference “Adverse Events” Section) of 
the study protocol.


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MDASI-CML
The M.D. Anderson Symptom Inventory – Chronic Myeloid Leukemia (MDASI-CML) is a 26 
item self-administered questionnaire for adult CML patients. Twenty of the items measure the 
severity of disease-related symptoms and are scored from 0 (Not present) to 10 (As Bad as you 
can imagine) and 6 items that measure symptom interference with daily life scored from 0 (Did 
not interfere) to 10 (Interfered completely). Descriptive statistics will be provided for the 
MDASI-CML symptom score and interference score, and the change in the MDASI-CML 
symptom score and interference score from baseline to all available time points to the end of 
study. Additional analysis may be performed and details will be described in the analysis plan.
EQ-5D-5L
EQ-5D-5L is a two-part standardized instrument for measuring health outcomes in a wide range 
of health conditions and treatments. It consists of a descriptive system and a visual analogue 
scale (EQ VAS). The descriptive system comprises the following 5 dimensions: mobility, self-
care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems and extreme problems (or 
unable to perform the activity). The EQ VAS records the respondent’s self-rated health on a 
vertical, visual analogue scale where the endpoints are labeled ‘Best imaginable health state’ 
and ‘worst imaginable health state’. The health states derived from the descriptive system can 
be summarized into a single index score that provides a simple measure of health for clinical 
and economic appraisal. Descriptive statistics will be provided for EQ-5D-5L health index score 
and for the EQ VAS, at each scheduled assessment time point. There should be only ONE 
response for each dimension. Missing values can be coded as ‘9’. Ambiguous values (e.g. 2 
boxes are ticked for a single dimension) should be treated as missing values. Additional analysis 
may be performed and details will be described in a separate analysis plan.
WPAI
The Work Productivity and Activity Impairment Questionnaire (WPAI) is a four-item 
questionnaire which is intended to measure work and activity impairment associated with CML 
for those who self-identify as currently employed for pay. This questionnaire measures self-
reported productivity loss associated with CML during the past seven days. It consists of 
questions about absence from work due to CML, hours spent at work, the reduction in 
productivity at work attributed to CML, and the reduction in productivity while performing 
regular activities. WPAI outcomes are expressed as impairment percentages, with higher 
numbers indicating greater impairment and less productivity, i.e., worse outcomes, Scoring will 
be done according to WPAI instrument guidance resulting in four scores including: Percent 
work time missed due to problem; percent impairment while working due to problem; Percent 
overall work impairment due to problem; and, percent activity impairment due to problem.
Change from baseline in WPAI at each visit, where measured, will be done for each of the four 
derived scores.
PGIC
The Patient Global Impression of Change is comprised of a single question intended to measure 
a patient’s perspective of improvement or deterioration over time relative to treatment. The 


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PGIC uses a seven-point scale where one (1) equals very much improved and seven (7) equals 
very much worse. A summary of Patient Global Impression of Change (PGIC) at each visit, 
where measured will be provided.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
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.
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.
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. 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)


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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 8.2.1
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 
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.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 


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the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.1.3
Adverse events of special interest
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].
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
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 


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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.
8.3
Emergency unblinding of treatment assignment
Not applicable.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 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 on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcome should be collected for the female partners of any male who received
asciminib treatment in this study. Consent to report information regarding pregnancy outcome
should be obtained from the mother.


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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.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided asciminib 
Investigator’s Brochure or bosutinib label. Additional safety information collected between IB 
updates will be communicated in the form of Investigator Notifications. This information will 
be included in the patient informed consent and should be discussed with the patient during the 
study as needed.
8.6
Data Monitoring Committee
This study will institute a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will be constituted prior to the randomization 
of the first patient. The DMC will be responsible to review safety data at approximately 6
months after the first randomized patient has started study treatment. Subsequent reviews will 
be conducted approximately every 6 months on an as and when needed basis thereafter (i.e. if 
significant safety findings are noted). This includes but does not limit the role of the DMC to 
evaluate these data and to provide recommendations to the sponsor to continue, modify or stop 
the study early. The DMC will be in place at least until the conduct of the primary analysis.
It is expected that the DMC will consist at a minimum of two physicians with appropriate 
disease area qualifications and one statistician. There will be a meeting with the DMC 
describing their roles and responsibilities and discussing potential data format and process 
issues prior to the finalization of DMC charter.
It is envisioned that the DMC may make certain types of recommendations, namely:

No safety concerns, ethical to continue the study as planned

Serious safety concerns precluding further study treatment, regardless of efficacy

Recommendation to continue the study but proposing an amendment to the protocol (e.g., 
incorporate an additional safety assessments)
8.7
Steering Committee
In order to monitor study conduct, a Steering Committee (SC) will be established comprising 
investigators participating in the trial. Additionally two sponsor representatives (a physician 
and a statistician) will be active members of this committee.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. Novartis will make final 
decisions on trial conduct based on SC recommendations. Together with the clinical trial team, 
the SC will review protocol amendments as appropriate, and also develop recommendations for 
publications of study results including authorship rules. The details of the role of the Steering 
Committee will be defined in a Steering Committee charter.


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9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient 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 recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the 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 
and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
Data collected by third parties (biochemistry, PCR assessments, biomarkers, PK) will be sent 
electronically to Novartis.
9.4
Database management and quality control
For studies using eCRFs, 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 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using the Novartis Interactive Response Technology.
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
The data will be analyzed by Novartis and/or designated CRO. It is planned that the data from 
participating centers in this protocol will be combined, so that an adequate number of patients 
will be available for analysis.


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Study data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, safety observations and measurements, and all 
relevant PK and PD measurements.
The cut-off date for the primary analysis is defined as the date when all patients have been on 
study treatment for 24 weeks or discontinued earlier. The cut-off date for the end of study
treatment analysis is defined as 30 days after the end of study treatment period (see Section 4.3)
to ensure that all available treatment phase data from all patients up to the last dose of study 
drug taken in this study, will be analyzed and summarized in the end of study treatment phase 
CSR. Patients will be further followed  for survival and progression for up to 5 years from the 
date the last randomized patient receives the first study dose. An update analysis of OS and PFS 
will be performed at the end of the follow-up period in the final study CSR.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
by randomization. According to the intention to treat principle, patients will be analyzed 
according to the treatment and stratum they have been assigned to during the randomization 
procedure.
10.1.2
Safety set
The Safety Set includes all patients who received at least one dose of study treatment. Patients 
will be analyzed according to the study treatment received, where treatment received is defined 
as the randomized treatment if the patient took at least one dose of that treatment or the first 
treatment received if the randomized treatment was never received.
10.1.3
Per-Protocol set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the CSP. The PPS will be used for sensitivity analyses on the primary 
endpoint only.
Oncology standards for protocol deviations potentially leading to exclusion from the PPS are:

Type of indication different from those required by the CSP

If prior therapy does not match with CSP requirements in terms of number and types of 
previous therapy regimens

Another anti-neoplastic therapy administered after start of study treatment and prior to 
first efficacy assessment

Study treatment received different from treatment assigned by randomization
10.1.4
Dose-determining analysis set
Not applicable.


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10.1.5
Pharmacokinetic analysis set
The Pharmacokinetic analysis set (PAS) includes all patients who provide at least one 
evaluable PK concentration. For a concentration to be evaluable, patients are required to:

Take a dose of asciminib prior to sampling,

Take the same dose of asciminib for at least 3 consecutive days without dose interruption 
or dose modification prior to sampling,

For post-dose samples, do not vomit within 4 hours after the dosing of asciminib (this is 
the current dose); for pre-dose samples do not vomit within 4 hours after the dosing of 
asciminib prior to sampling (this is the previous dose),

Have the pre-dose sample collected before the next dose administration.
10.1.6
Other analysis set
For duration of MMR and time to MMR, the MMR Responder Set that will be used is a subset 
of FAS and includes patients who achieve MMR at any time.
For CCyR rates at and by scheduled time points, the CCyR Analysis Set that will be used is a 
subset of FAS and includes patients who are not in CCyR at baseline.
For duration of CCyR and time to CCyR, the Cytogenetic Responder Set that will be used is a 
subset of FAS and includes patients who do not have CCyR at baseline and achieve CCyR at 
any time on study treatment.
Patients who will receive at least one dose of asciminib after bosutinib failure will form the 
Switch Analysis Set which will be used for safety and exploratory efficacy endpoints defined 
on these patients. 
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS or the Safety Set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, by treatment group.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The Safety set will be used for the analyses below.
Categorical data will be summarized as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
The duration of exposure in days to asciminib and bosutinib, as well as the dose intensity 
(computed as the ratio of actual cumulative dose received and actual duration of exposure) and 


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the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity) 
will be summarized by means of descriptive statistics.
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment group and all dosing data 
will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
10.4
Primary objective
The primary objective of the study is to evaluate the efficacy of asciminib at the recommended 
dose in CML patients in chronic phase, previously treated with 2 or more tyrosine kinase 
inhibitors and to compare this efficacy profile in this population with that achieved by patients
receiving bosutinib.
10.4.1
Variable
The primary efficacy variable of the study is the Major Molecular Response (MMR) rate at 24 
weeks. A patient will be counted as having achieved MMR at 24 weeks if he meets the MMR 
criteria (BCR-ABL1 ratio ≤0.1%) at 24 weeks.
10.4.2
Statistical hypothesis, model, and method of analysis
The MMR rate at 24 weeks will be calculated based on the FAS and according to the Intention-
ToTreat (ITT) principle. MMR rate and its 95% confidence interval based on the Pearson-
Clopper method will be presented by treatment group. The confidence interval for the difference 
in MMR rate between treatment groups will be provided using the Wald method.
The null hypothesis is that there is no difference between the treatment groups with respect to 
MMR rate at 24 weeks. The Cochrane-Mantel-Haenszel chi-square test, stratified by the 
randomization stratification factor, i.e. major cytogenetic response status (PCyR or CCyR vs.
others) at screening, will be used to compare MMR rate between the two treatment groups, at 
the two-sided 5% level of significance. The Mantel-Haenszel estimate of the common risk 
difference and the corresponding 95% confidence interval will also be provided.
10.4.3
Handling of missing values/censoring/discontinuations
Only patients with MMR at 24 week visit are considered responders. In other words, any patient 
who achieves MMR before 24 weeks, but is no longer in MMR at 24 weeks, will be considered 
as a non-responder in this primary analysis. Patients discontinuing the randomized treatment 
(having performed an EOT visit) prior to 24 weeks due to any reason will be considered as non-
responders. One exception to the rule above is if the 24-week PCR evaluation is missing, but 
both a PCR evaluation at 16 weeks and a PCR evaluation at 36 weeks indicate MMR, the 24-
week assessment is imputed as a ‘Response’. If PCR evaluations are performed at unscheduled 
visits closer to the Week 24 visit (before or after), these will be taken into account for the 
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10.4.4
Supportive and Sensitivity analyses
The analysis of the primary endpoint will also be repeated on the PPS if the PPS is different 
from the FAS.
Subgroup analyses and a logistic regression analysis will be employed. Refer to the exploratory 
objectives Section 10.6.1 for further details.
10.5
Secondary objectives
The secondary objectives in this study are as follows:

To compare additional parameters of the efficacy of asciminib versus bosutinib, defined 
as:
Key secondary endpoints

MMR rate at 96 weeks
Other efficacy endpoints

Cytogenetic response (Complete, Partial, Major, Minor, Minimal, no response) rate at all 
scheduled data collection time points including, 24, 48 and 96 weeks.

Cytogenetic response (Complete, Partial, Major, Minor, Minimal, no response) rate by all 
scheduled data collection time points including, 24, 48 and 96 weeks.

MMR rate at all scheduled data collection time points (except 24 and 96 weeks which are 
already covered by primary and key secondary endpoints)

MMR rate by all scheduled data collection time points including 24, 48 and 96 weeks.

Time to MMR

Duration of MMR

Time to CCyR

Duration of CCyR

Time to treatment failure

Progression free survival

Overall survival

To compare the safety and tolerability profile of asciminib versus bosutinib

To characterize the PK of asciminib in the CML-CP population
10.5.1
Key secondary objective(s)
The key secondary endpoint to be evaluated is MMR rate at 96 weeks, which is defined as the 
proportion of patients with MMR at 96 weeks and derived in a similar fashion to MMR rate at 
24 weeks.


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10.5.1.1 Analysis for key secondary objectives
The null hypothesis is that there is no difference between the treatment groups with respect to 
MMR rate at 96 weeks. Formal statistical testing of the key secondary endpoint will be 
performed with = 0.05 (two-sided) only if the primary endpoint (i.e. MMR rate at 24 weeks)
is significant by means of a gatekeeping procedure to control the overall alpha level. Otherwise, 
no statistical testing will be performed, and any analysis will be considered exploratory.
MMR rate at 96 weeks will be evaluated in a similar fashion to the primary analysis of MMR 
rate at 24 weeks. The rate and the associated 95% confidence interval based on the Pearson-
Clopper method will be presented by treatment group. Confidence interval for the difference 
between treatment groups will be provided using the Wald method.
Statistical testing will be performed via CMH chi-square test stratified by the randomization 
strata. The Mantel-Haenszel estimate of the common risk difference and the corresponding 95% 
confidence interval will also be provided.
If the PCR evaluation at 96 weeks is missing, but a PCR evaluation both at 84 weeks and 108 
weeks indicate MMR, the 96 week assessment is imputed as a “response”, assuming that MMR 
is maintained between 84 and 108 weeks. If PCR evaluations are performed at unscheduled 
visits closer to the Week 96 visit (before or after), these will be taken into account for the 
imputation.
10.5.2
Other secondary efficacy objectives
Unless otherwise stated the FAS will be used for the analysis of all other secondary efficacy 
endpoints. The exceptions are using the Molecular Responder Set for duration of MMR and 
time to MMR, the CCyR Analysis Set for CCyR rates, and the Cytogenetic Responder Set for 
duration of CCyR and time to CCyR.
No statistical testing of non-key secondary efficacy endpoints will be performed, and any 
analysis will be considered exploratory.
Molecular Response
MMR rates at scheduled time points (except 24 and 96 weeks which have been specified as 
primary and key secondary endpoints) will be evaluated in a similar fashion to the primary 
analysis of MMR rate at 24 weeks. Patients discontinuing the randomized treatment prior to a 
specific time point due to any reason will be considered as non-responders for that time point.
MMR rates by scheduled time points are defined as the proportion of patients who achieve 
MMR at or before the specified visit, i.e. if a patient achieves an MMR but then loses it before 
or at the visit, he/she will still be classed as achieving MMR by that time point.
For each endpoint the rate and the associated 95% confidence interval based on the Pearson-
Clopper method will be presented by treatment group. Confidence intervals for the differences 
in any response rates between treatment groups will be provided using the Wald method.
Statistical testing will be performed via CMH chi-square tests stratified by the randomization 
strata. The Mantel-Haenszel estimate of the common risk difference and the corresponding 95% 
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Duration of MMR is defined in Section 7.2.1.1 as the time between the date of the first 
documented MMR and the earliest date of loss of MMR, progression to AP/BC, or CML-related 
death for patients in the Molecular Responder Set. The time will be censored at the last 
molecular assessment (PCR) date while on treatment for patients who have not experienced any 
of the above events.
Duration of MMR will be analyzed by K-M method and presented by K-M plots. The estimated 
rates of patients who are still responding at various time points will also be provided using K-
M method.
The cumulative incidence of MMR will be graphically displayed by an increasing step function. 
This curve will increase each time (after randomization) at which a new responder is observed 
and thus will increase up to the best observed response rate (e.g. up to 50% if half of the patients 
in the analysis population are able to achieve response).
Time to MMR is defined in Section 7.2.1.1 and calculated as: date of first MMR - date of 
randomization +1, for patients in the Molecular Responder Set. Descriptive statistics (minimum, 
maximum, median, quartiles, mean, sd) of time to MMR will be provided for the two treatment 
groups separately.
Cytogenetic Response
Patients in FAS will be categorized with counts and percentages provided for cytogenetic 
response (Complete, Partial, Major, Minor, Minimal, No Response) at and by (i.e. best response 
up to a specified time point) scheduled time points. Shift tables will also be employed to 
examine the changes in cytogenetic response category from baseline.
Since there are expected to be only limited numbers who are actually in CCyR at baseline the 
analysis of CCyR rate at and by scheduled time points will only include patients who are not in 
CCyR at baseline, i.e. the CCyR Analysis Set.
CCyR rates at and by scheduled time points etc. and the associated 95% confidence intervals 
based on the Pearson-Clopper method will be presented by treatment group with the analysis of 
these endpoints only including patients who are not in CCyR at baseline.
Confidence intervals for the differences in any response rates between treatment groups will be 
provided using the Wald method.
Statistical testing will be performed via CMH chi-square tests stratified by the randomization 
strata. The Mantel-Haenszel estimate of the common risk difference and the corresponding 95% 
confidence interval will also be provided.
Time to CCyR is defined for patients in the Cytogenetic Responder Set as: date of first CCyR 
- date of randomization +1. Descriptive statistics (minimum, maximum, median, quartiles, 
mean, sd) of time to CCyR will be provided for the two treatment groups separately.
The cumulative incidence of CCyR will also be graphically displayed by an increasing step 
function. This curve will increase each time (after randomization) at which a new responder is 
observed and thus will increase up to the best observed response rate.
Duration of CCyR is defined as the time between date of first documented CCyR and the 
earliest date of loss of CCyR, progression to AP/BC, or CML-related death for patients in the 


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Cytogenetic Responder Set. The time will be censored at the last cytogenetic assessment date 
on treatment for patients for whom none of the above events is reported or last PCR evaluation 
on treatment indicating MMR.
Duration of CCyR response will be analyzed by K-M method and presented by K-M plots. The 
estimated rates of patients who are still responding at various time points will also be provided 
using K-M method.
Treatment failure, disease progression and survival
Time to treatment failure (TTF) is defined as the time from date of randomization to an event 
of treatment failure. The following events will constitute ‘treatment failure’, and are based on 
the ELN criteria (Baccarani et al 2013) defining failure of a second line treatment adapted to 
include discontinuation of randomized treatment as an event:

No CHR or > 95% Ph+ metaphases at three months after randomization or thereafter

BCR-ABL1 ratio > 10% IS and/or > 65% Ph+ metaphases at six months after 
randomization or thereafter

BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases at 12 months after 
randomization or thereafter

Loss of CHR, CCyR or PCyR at any time after randomization

Detection of new BCR-ABL1 mutations which potentially cause resistance to study 
treatment at any time after randomization

Confirmed loss of MMR

New clonal chromosome abnormalities in Ph+ cells: CCA/Ph+: at any time after 
randomization

Discontinuation from randomized treatment for any reason
For patients who have not reached treatment failure, their TTFs will be censored at the time of 
last study assessment (PCR, cytogenetic, hematologic or extramedullary) before the cut-off date.
Progression-Free-Survival (PFS) is defined as the time from the date of randomization to the 
earliest occurrence of documented disease progression to AP/BC or the date of death from any 
cause (including progressions and deaths observed during the survival follow-up period) before 
the cut-off date.
The time will be censored at the date of last study assessment (PCR, cytogenetic, hematologic 
or extramedullary) or last post-treatment follow-up for patients without event.
Overall survival (OS) is defined as the time from the date of randomization to the date of death 
(including the survival follow-up period). Patients who are alive at the time of the analysis data 
cutoff date will be censored at the date of last contact before the cut-off date.
TTF, PFS and OS will be estimated and graphically displayed using the K-M approach on FAS. 
The estimated rates by K-M method at various time points will be provided and the endpoints 
will be compared between the two treatment groups using stratified log-rank test stratified by 
the randomization strata. The hazard ratio and 95% confidence intervals will be computed from 
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10.5.3
Safety objectives
10.5.3.1 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 group.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of subject’s first informed consent to the day before first 
administration of study treatment
2. on-treatment period: from day of first administration of study treatment to 30 days after 
last actual administration of the same study treatment (including start and stop date)
3. post-treatment period: starting at day 31 after last administration of any study treatment
Summary tables for safety data will be presented for the on-treatment period. Comparative 
analysis will be performed only for the on-treatment period. Listings of safety data will include 
pre-treatment, on-treatment, and post-treatment periods, with a flag to indicate data collected 
before or after the on-treatment period.
The same analysis will be done for patients that switch to asciminib after treatment failure on 
bosutinib. However, safety events that initiated on or after start of asciminib during the switch 
treatment phase will be included.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs.
The incidence of treatment-emergent adverse events (new or worsening from baseline) 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, non-serious adverse events and adverse events of special interest (AESI)
during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre-treatment, on-
treatment and post-treatment periods) will be listed and those collected before or after the on-
treatment period will be flagged.
10.5.3.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. 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.


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For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following listings and summaries will be generated separately for hematology, and 
biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v4.03

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline in the on-treatment period.

Shift tables using CTCAE grades to compare respective baseline to the worst on-treatment 
value
For laboratory tests where grades are not defined by CTCAE v4.03,

Shift tables using the low/normal/high/ (low and high) classification to compare respective 
baseline to the worst on-treatment value.
10.5.3.4 Other safety data
ECG
ECGs (12-lead) including PR, QRS, QT, QTcF, and HR intervals will be obtained for each 
subject during the study. ECG data will be read and interpreted centrally.
Categorical analysis of QT/QTc interval data based on the number of patients meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these patients will be produced by treatment group.
Vital signs
Data on vital signs will be tabulated and listed, notable values will be flagged.
10.5.3.5 Supportive analyses for secondary objectives
Not applicable.
10.5.3.6 Tolerability
Tolerability of each study treatment will be assessed by summarizing the number of subjects
with dose interruptions and dose reductions. Reasons for dose interruptions and dose reductions 
will be listed by subject and summarized.
10.5.4
Secondary PK objectives
The PK objective is to characterize the PK of asciminib in CML population.
Using PAS, summary statistics (n, mean, SD, coefficient of variation (CV) for mean, geometric 
mean, CV for geometric mean, median, minimum and maximum) will be presented for plasma 
concentration at each scheduled time point. The geometric mean with mean (SD) and individual 
plasma concentration versus time profiles of asciminib will be displayed graphically.


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Using Safety set, concentration data will be listed. Concentration values below the limit of 
quantification (BLQ) will be set to zero by the Bioanalyst and displayed in listings as zero with 
a flag. BLQ values will be handled as zero in any calculations of summary statistics, but handled 
as missing for the calculation of the geometric means and CVs.
Pharmacokinetic parameters will be determined by non-compartmental method(s) using the 
pharmacokinetic profile of asciminib in patients with full PK sampling. PK parameters listed in 
Table 10-1 will be derived and reported, when feasible.
Population PK modeling may be performed and the results may be reported in a separate 
population PK report. Data from this study may be combined with data from other studies for 
this analysis.
Table 10-1
Non compartmental pharmacokinetic parameters in full PK group
AUC0-12h
The area under the plasma concentration-time curve from time zero to 12 h (mass x time x 
volume-1)a
Cmax
The maximum (peak) observed plasma drug concentration after dose administration (mass x 
volume-1)
Tmax
The time to reach maximum (peak) plasma drug concentration after dose administration (time)
CL/F
The total body clearance of drug from the plasma after oral administration (volume x time-1)
10.6
Exploratory objectives
10.6.1
Exploratory efficacy objectives

To evaluate the influence of factors such as major cytogenetic status at baseline, 
failure/intolerance to prior TKIs, line of therapy, gender, race and age on the effect of 
asciminib with respect to the primary efficacy endpoint.

To characterize mutations in the BCR-ABL1 gene at Week 1 Day 1, upon confirmed loss of 
molecular response and/or at end of treatment and examine their association with molecular 
and cytogenetic response for asciminib vs. bosutinib.

To assess the efficacy of asciminib when administered as treatment after bosutinib failure 
according to the 2013 ELN Guidelines.
10.6.1.1 Data analysis of exploratory efficacy objectives
Subgroup analyses will be performed to evaluate the influence of factors such as baseline major 
cytogenetic response status, baseline/Week 1 Day 1 BCR-ABL1 ATP-binding site mutation 
status (from local historical record and from Sanger Sequencing), failure/intolerance to prior 
TKIs, line of therapy, gender, race and age on the primary efficacy endpoint. In addition, a 
logistic regression analysis will incorporate the key baseline variables into the model to further 
evaluate the impact of these variables on the primary endpoint and to provide a treatment effect 
estimate which is adjusted for imbalances in the treatment groups. An adjusted odds ratio for 
the treatment effect with associated 95% confidence intervals will be presented. Mantel-
Haenszel estimates of the common odds ratio and the corresponding 95% confidence interval 
will also be provided. The effect of asciminib when administered as treatment after bosutinib 
failure will be assessed using the Switch Analysis Set to estimate response rates (cytogenetic 
and molecular response) at all scheduled time points after switch, as well as time-to and duration 






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10.6.4.2 Patient Reported Outcomes
The MDASI CML, PGIC along with EQ-5D-5L will be used to compare data on the patient’s 
disease-related symptoms and health-related quality of life from baseline to EOT between the 
treatment arms. The WPAI will be used to assess work productivity and activity impairment 
related to the patient’s CML. All measures will assess differences between the treatment arms.
Patients with an evaluable baseline score and at least one evaluable post baseline score during 
the treatment period will be included in the change from baseline analyses. Missing data items 
in a scale will be handled according to the manual for each instrument. No imputation will be 
applied if the total or subscale scores are missing at a visit.
10.7
Interim analysis
No formal interim analysis is planned for this trial. As described in Section 10, three or four
formal analyses are planned: the primary at week 24, another at the 96-week end of study 
treatment and a PFS/OS update at year 5.

24-week primary analysis: Formal testing of the primary endpoint with full alpha will be 
performed. Analyses of other efficacy endpoints at and by 24 weeks will also be
performed.

96-week analysis: Formal statistical testing of the key secondary endpoint will be 
performed with = 0.05 (two-sided) only if the primary endpoint (i.e. MMR rate at 24 
weeks) is significant. Otherwise, no statistical testing will be performed, and any analysis
will be considered exploratory. Analyses of other efficacy endpoints (including MMR rate 
at 48 weeks) will also be performed.

End of study treatment analysis (if required) similar to the 96-week analysis without 
formal statistical testing.

5-year PFS/OS update analysis: PFS and OS
In addition DMC safety analyses will be conducted as described in Section 8.6.
10.8
Sample size calculation
To test the null hypothesis that the response rate is equal in the two groups, based on two-sided 
5% level of significance and with 90% power, 222 patients will be needed in total (i.e. 148 
patients in the asciminib arm and 74 patients in the bosutinib arm based on 2:1 randomization 
allocation). This assumes that asciminib leads to a 20% improvement in the MMR rate at 24 
weeks over bosutinib from 15% to 35% which corresponds to an odds ratio of 3.05.
The assumed bosutinib MMR rate of 15% at 24 weeks is based on previous trials evaluating 
bosutinib therapy (Khoury 2012, Gambacorti-Passerini 2014, García-Gutiérrez 2015).
No more than 66 patients (approximately 30% of the overall trial population) that are intolerant 
to their most recent TKI therapy with BCR-ABL1 < 1% will be recruited in order to ensure that 
the CML third line patient population is adequately represented.


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10.9
Power for analysis of key secondary variables
If the primary analysis of MMR rate at 24 weeks is statistically significant, then the key 
secondary endpoint MMR rate at 96 weeks will be tested, with the overall alpha controlled at 
the 5% two-sided level. The testing will use a gatekeeping strategy. Full details of the testing 
strategy are provided in Section 10.5.1.
Table 10-2 below summarizes the treatment effects of the key secondary endpoint which can 
be detected with 80% and 90% power, based on the specified assumptions regarding the 
bosutinib effect. The calculations were made using the software package PASS (2008).
Table 10-2
Detectable effect sizes for key secondary endpoint
Endpoint
Anticipated effect 
with bosutinib
2-sided alpha
Power
Detectable 
effect size§
MMR rate at 96 weeks
30%*
0.05
90%
80%
≥ 23%
≥ 20%
*: Gambacorti-Passerini et al. 2014, Figure 1D.
§: Absolute difference from the anticipated effect with bosutinib.
For MMR rate at 96 weeks, if the anticipated effect with bosutinib is 30%, then the given sample 
size with 2-sided alpha=0.05 would allow to detect an absolute difference of at least 23% (i.e. 
MMR rate at 96 weeks with asciminib is at least 53%) for 90% power and of at least 20% (i.e. 
MMR rate at 96 weeks with asciminib is at least 50%) for 80% power.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. 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 Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.


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11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their eCRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication 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 requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
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.
Additional consent form
Not applicable.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.3.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. clinicaltrials.gov before study start. In 
addition, results of interventional clinical trials in adult patients are posted on 
novartisclinicaltrials.com, a publicly accessible database of clinical study results within 1 year 
of study completion (i.e., LPLV), those for interventional clinical trials involving pediatric 
patients within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (icmje.org) and other specific guidelines of 
the journal or congress to which the publication will be submitted
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 


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present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study electronic case report form (eCRF) is the primary data 
collection instrument for the study. The investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported in the eCRFs and all other required reports. Data 
reported on the eCRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the eCRF 
must be recorded. Any missing data must be explained. For electronic CRFs an audit trail will 
be maintained by the system.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.


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11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
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/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
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/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
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 (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.


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identified by quinacrine, fluorescence and Giemsa staining. Nature; 243:290-93.
[Soverini S, Branford S, Nicolini FE, et al (2014)] Implications of BCR-ABL1 kinase 
domain-mediated resistance in chronic myeloid leukemia. Leuk Res; 38(1):10-20.
[Steegmann JL, Baccarani M, Breccia M, et al (2016)] European LeukemiaNet 
recommendations for the management and avoidance of adverse events of treatment in 
chronic myeloid leukaemia. Leukemia; 30(8):1648-71.
[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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14
Appendices
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 6.4 for patients on 
asciminib and Section 6.5 for patients on bosutinib. 
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.
14.1
Appendix 1 List of concomitant medications for patients on 
asciminib
Table 14-1
Prohibited concomitant medications for asciminib arm
Category
Drug Names
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,
Strong inducers of 
CYP3A
carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, rifabutin, 
rifampicin, St. John’s wort (Hypericum perforatum)1
UGT1A1/2B7 
inducers
UGT1A1: carbamazepine, cigarette smoke, rifampicin, testosterone propiate, 
UGT2B7: Barbiturates
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 


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Category
Drug Names
(orphan drug in us), tizanidine, tolterodine, toremifene, trimipramine, vardenafil, 
vemurafenib, venlafaxine, vorinostat, zotepine
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 preparation-
dependent. 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).
Table 14-2
Concomitant medications to be used with caution in asciminib arm
Category
Drug Names
Narrow Therapeutic 
index substrates of 
CYP2C8
Paclitaxel
Narrow Therapeutic 
index substrates of 
CYP2C9
phenytoin, warfarin (also sensitive)
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,survorexant, talinolol4, telaprevir4, 
telmisartan4, ticagrelor4, tipranavir4, tolvaptan4, valspodar, vandetanib, verapamil4, 
voclosporin, vorapaxar.
3 Evidence of in vivo DDI
4 Dual P-gp and CYP3A4 inhibitor
5 Herbal product


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Appendix 2 List of concomitant medications for patients on
bosutinib
Table 14-3
Prohibited concomitant medications for bosutinib arm
Category
Drug Names
Strong inhibitors of 
CYP3A
boceprevir, clarithromycin, cobicistat, conivaptan, grapefruit juice2, idelalisib, indinavir, 
itraconazole, ketoconazole, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, 
telaprevir, telithromycin, troleandomycin, voriconazole, atazanavir/ritonavir1, 
danoprevir/ritonavir1, darunavir/ritonavir1, elvitegravir/ritonavir1, indinavir/ritonavir1, 
lopinavir/ritonavir1, ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak)1 , 
saquinavir/ritonavir1, tipranavir/ritonavir1
Moderate inhibitors of 
CYP3A
aprepitant, amprenavir, atazanavir, cimetidine, ciprofloxacin, crizotinib, cyclosporine, 
darunavir, diltiazem, dronedarone, erythromycin, faldaprevir, fluconazole, grapefruit 
juice2, imatinib, isavuconazole, netupitant, nilotinib, tofisopam, Schisandra sphenanthera
(nan wu wei zi)3, asafoetida resin (Ferula asafoetida)3, verapamil
Strong inducers of 
CYP3A
carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, rifabutin, 
rifampicin, St. John’s wort (Hypericum perforatum)3
Moderate inducers of 
CYP3A
bosentan, efavirenz, etravirine, modafinil, nafcillin, ritonavir/tipranavir, thioridazine, 
semagacestat4, talviraline4, lopinavir, lersivirine, 
Proton pump 
inhibitors
dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole. 
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 preparation-
dependent. 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
4 Dual P-gp and CYP3A4 inhibitor
Table 14-4
Concomitant medications to be used with caution in bosutinib arm
Category
Drug Names
Torsade de pointe 
(TdP) TdP/QT risk : 
Known
amiodarone, anagrelide, arsenic trioxide, astemizole (off us mkt), azithromycin, bepridil 
(off us mkt), chloroquine, chlorpromazine, cilostazol, cisapride (off us mkt), citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone (not on us mkt), 
donepezil, dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
grepafloxacin  (off market worldwide), halofantrine, haloperidol, ibutilide, levofloxacin, 
levomethadyl (off mkt worldwide), mesoridazine (off mkt worldwide), methadone, 
moxifloxacin, ondansetron, oxaliplatin, papaverine HCl, pentamidine, pimozide, probucol 
(off mkt worldwide), procainamide (oral off us mkt), propofol, quinidine, sevoflurane, 
sotalol, sparfloxacin (off us mkt), sulpiride (not on us mkt), terfenadine (off us mkt),
thioridazine, vandetanib
TdP/QT risk: 
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 


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Category
Drug Names
(orphan drug in us), tizanidine, tolterodine, toremifene, trimipramine, vardenafil, 
vemurafenib, venlafaxine, vorinostat, zotepine
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


Clinical Development 
Asciminib/ABL001 
 
A phase 3, multi-center, open-label, randomized study of 
oral ABL001 (asciminib) versus bosutinib in patients with 
Chronic Myelogenous Leukemia in chronic phase (CML-
CP), previously treated with 2 or more tyrosine kinase 
inhibitors 
Protocol – Summary of changes 
 
 
 
 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
 


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Protocol No. CABL001A2301 
 
Amendment 3 (14-Dec-2018) 
Amendment rationale  
As of 21-Nov-2018, 137 patients were screened and 86 patients were randomized in the study, 
the study is currently ongoing. 
The primary purpose of the amendment is: 
Modification of the inclusion criterion of BCR-ABL1 transcript threshold required at study 
entry from a BCR-ABL1 ratio ≥ 1% IS to BCR-ABL1 ratio > 0.1% IS (i.e. not in MMR) for 
patients with intolerance to most recent TKI treatment. The threshold presented in this inclusion 
criteria affects only patients who are intolerant to prior treatment, since patients failing prior 
treatment must fulfill the criteria defined by ELN guidelines (Baccarani et al 2013). Although 
the number of treatment options is increasing, especially for patients with imatinib intolerance, 
alternatives for patients with resistance and/or intolerance to at least two previous TKIs are 
limited (NCCN 2018, ELN 2013). The reason of reducing the BCR-ABL1 ratio is that in routine 
clinical practice, physicians do not wait to observe increased BCR-ABL1 levels to switch 
treatment in patients with intolerance, which may increase the risk of disease progression, 
especially in patients with only limited further treatment options. This is in line with current 
CML treatment guidelines where the switch to an alternative therapy in intolerant patients is 
not linked to a BCR-ABL1 threshold (NCCN 2018, Baccarani et al 2013 and Hochhaus et al 
2017).  
Therefore, the threshold of ≥ 1% BCR-ABL1 in the current trial is reduced to BCR-ABL1 ratio > 
0.1% IS for patients with intolerance to most recent TKI treatment. No more than 66 patients 
(approximately 30% of the overall trial population) that are intolerant to their most recent TKI 
therapy with BCR-ABL1 < 1% will be recruited in order to ensure that the CML third line 
patient population is adequately represented. As the primary endpoint is the rate of MMR at 24 
weeks a baseline molecular response level > 0.1 % BCR-ABL1 is needed. 
Patients experiencing documented treatment failure on bosutinib treatment will be allowed to 
switch to asciminib. Patients failing bosutinib treatment will have failed at least their third TKI 
treatment, with limited remaining treatment options. With this amendment patients who have 
failed bosutinib will be offered the possibility to continue in the study by receiving asciminib, 
if investigators consider that this treatment option is in the best interest of the patient. As of 15-
Oct-2018, 4 patients could have potentially benefited from this option. Treatment failure during 
study treatment is assessed by measureable and pre-specified milestones defined by ELN 
criteria (Baccarani et al 2013), which are also used to define treatment failure as entry criteria 
for the study. Only documented treatment failure in the bosutinib arm will be considered for a 
treatment switch. For the purpose of the primary and secondary endpoint analyses, any patient 
meeting the ELN failure criteria while receiving study treatment, (either before or by the time 
of conducting the analysis and irrespective of treatment arm), will be considered as non-
responders for the specific time point and for any subsequent time point. The switch to 
asciminib in case of bosutinib treatment failure is not expected to introduce bias as those 
patients will be regarded as non-responders irrespective of treatment switch and the disease 
burden will certainly not improve without further treatment. There is no option to switch 
patients failing on the asciminib treatment arm, as those patients can be offered approved 


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therapies outside of the context of the study. The efficacy data collected after the switch from 
patients switching to asciminib following bosutinib failure will be analyzed separately as 
exploratory endpoints and will not be included for primary and secondary study endpoints. In 
addition, safety data from patients receiving asciminib after bosutinib failure will be collected 
to further characterize asciminib’s safety profile. 
Potassium increase of up to 6.0 mmol/L is acceptable at study entry if associated with creatinine 
clearance within normal limits. Grade 2 increase of potassium is acceptable in case of normal 
creatinine clearance as this is not considered to be a risk factor for QTc prolongation. Total 
calcium (corrected for serum albumin) increase of up to 12.5 mg/dl or 3.1 mmol/L (Grade 2) is 
acceptable at study entry if associated with creatinine clearance within normal limits as this is 
not considered to be a risk factor for QTc prolongation. 
A change to creatinine clearance instead of GFR is being made in relation to the magnesium 
inclusion requirement as GFR in this study is expressed by creatinine clearance. 
Exclusion criteria #19 is being modified under this amendment in order to define the duration 
of the use of highly effective methods of contraception after the last dose of bosutinib under 
this study (one month after last dose of bosutinib). This is being done in order to align with the 
latest Bosulif® USPI.  
Exclusion criteria #21 has also been removed under this amendment. In embryofetal 
development studies with asciminib, fetal malformations (cardiac malformations) and increased 
visceral and skeletal variants were observed in rats and increased incidence of resorptions 
indicative of embryo-fetal mortality and a low incidence of cardiac malformations indicative of 
dysmorphogenesis were observed in rabbits. Asciminib is not genotoxic. As published in the 
literature, small molecules can distribute to seminal fluid and the seminal accumulation 
suggested is semen/plasma ratios up to 11.3 (Klemmt and Scialli 2005). According to the FDA 
guidance, in general, there is increased concern for reproductive or developmental toxicity in 
humans for relative exposure ratios (animal: human) that are < 10 and decreased concern for 
exposure ratios > 25 (FDA Guidance for Industry 2011). The calculations for the asciminib 
safety margin were done based on Cmax (plasma) seen in patients at a dose of 200 mg BID 
(Cmax 6843 ng/ml).  Safety margin calculation based on the embryo-fetal development study 
in rats was 768 and safety margin calculation based on the embryo-fetal development study in 
rabbits was 894. In conclusion, for asciminib, as outlined above, the safety margins are well 
above 25 and therefore no embryo- and fetotoxicity effects can be anticipated via seminal fluid. 
Removal of male contraception is in line with the Bosutinib USPI and SmPC. 
In addition, patients can be re-screened up to three times for the study, instead of once.  The 
patient population being investigated in this study is heavily pre-treated and patients might not 
have other treatment options outside the trial. There can be many intolerance-related temporary 
conditions resulting in ineligibility for the trial.  
Recruitment period extension has been reflected in the VES table. Study length has changed 
with introduction of switch option for patients failing bosutinib treatment. 
Patients enrolling in this trial will present a high disease burden after failure of previous 
therapies. Myelosuppression during TKI targeted treatment is a very common effect observed 
due to the suppression of the leukemic clone; this effect is also extended to hematopoiesis of 


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stem cells and progenitors (Steegmann et al 2016). For this reason, the recovery period for 
cytopenias has been extended from 28 to 42 days in order to allow for sufficient time to recover 
from suppression and to re-populate the bone marrow. 
The biomarker sampling profile has been revised to remove the gene expression profile in 
leukemic stem cells in both blood and bone marrow due to technical limitations.  In addition, 
there is currently no validated assay available. 
A clarification has been made to how the tests for blood urea and Blood Urea Nitrogen (BUN) 
are noted. The text "blood urea, Blood Urea Nitrogen (BUN)" has been revised to “blood urea 
or Blood Urea Nitrogen (BUN)” in order to note that either test is permitted. 
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. 
 Change of the purpose of the study by decreasing the requirement of BCR-ABL1 ratio ≥  
1% IS to BCR-ABL1 ratio > 0.1% IS at the time of screening for patients with 
intolerance: 
 Protocol summary. 
 Section 2.1 Study rationale and purpose. 
 Section 4.1 Description of study. 
 Section 5.2 Inclusion criteria. 
 Section 10.5.2 Other secondary efficacy objectives. 
 Change of the study design by introducing the switch to asciminib option for patients 
experiencing treatment failure on bosutinib treatment: 
 Protocol summary. 
 Section 2.2 Rationale for the study design. 
 Section 4.1 Description of study. 
 Figure 4-1 Schematic of Study Design. 
 Addition of Section 4.1.1 Study treatment switch from bosutinib to asciminib 
 Section 4.3 Definition of end of study. 
 Section 6.1.5 Treatment duration 
 Section 6.7.3.2 Study drug accountability. 
 Section 7 Visit schedule and assessments: 
 Addition of Table 7-2 Visit evaluation schedule (study treatment switch phase). 
 Addition of Section 7.1.2.2 Conditions to be fulfilled for asciminib switch. 
 Section 7.1.5 Visit windows. 
 Section 7.1.6 Discontinuation of study treatment. 
 Section 7.2.1.1 Molecular response. 
 Section 7.2.1.2 Bone marrow analysis and cytogenetics 
 Section 7.2.2.1 Physical examination. 


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 Section 7.2.2.2 Vital signs. 
 Section 7.2.2.3 Height and weight. 
 Section 7.2.2.4 Performance status. 
 Section 7.2.2.5 Laboratory evaluations. 
 Section 7.2.2.6 Cardiac assessments. 
 Section 7.2.3 Pharmacokinetics. 
 Section 7.2.4 Biomarkers. 
 Section 10.1.6 Other analysis sets. 
 Section 10.5.3.1 Analysis set and grouping for the analysis 
 Addition of new exploratory measure for patients that switch from bosutinib to asciminib: 
 Table 3-1 Objectives and related endpoints. 
 Section 10.1.6 Other analysis sets. 
 Section 10.6 Exploratory objectives: 
 Section 10.6.1 Exploratory efficacy objectives. 
 Section 10.6.1.1 Data analysis of exploratory efficacy objectives. 
 Reference for concomitant medications with a “known risk of TdP” has been updated to 
wwwcrediblemeds.org/ 
 Protocol summary 
 Section 5.3 Exclusion criteria 
 Section 6.3.2 Dose adjustments for QTcF prolongation 
 Section 6.4.3 Prohibited concomitant therapy 
 
 
 
 
 
 
 
 
 
 
 Section 5.2 Inclusion criteria and protocol summary: updated inclusion criteria to reflect 
the changes below: 
 Inclusion Criteria #3: As referenced above, the requirement of BCR-ABL1 ratio ≥ 1% 
IS has been decreased to BCR-ABL1 ratio > 0.1% IS at the time of screening for 
patients intolerant to previous TKI. 
 Inclusion Criteria #10: Potassium increase of up to 6.0 mmol/L is accepted at study 
entry if associated with creatine clearance within normal limits.  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.  GFR replaced by Creatinine clearance 
(calculated using Cockcroft-Gault formula) in order to maintain consistency 
throughout the protocol as creatinine clearance is already calculated based on 
inclusion criteria #7. 
 Inclusion Criteria #11: As study eligibility is assessed during screening with BCR-
ABL1 PCR quantification via international scale this requirement was added as 


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clarification. Measurement according to international scale is only possible for typical 
BCR-ABL1 transcripts. 
 Section 5.3 Exclusion Criteria and Protocol summary: updated exclusion criteria to reflect 
the following changes: 
 Exclusion Criteria #14: Removal of P-gp as a moderate or strong inhibitor of CYP3A 
as P-gp inhibitors are no longer prohibited per updated USPI, and SmPC 
 Exclusion Criteria #19: Duration of the use of highly effective methods of 
contraception after the last dose of bosutinib has been defined to align with the latest 
bosutinib USPI. 
 Exclusion Criteria #21 Removal of this criteria in order to align with updated pre-
clinical data. 
 Section 6.3.1 Dose modification and dose delay: The recovery period for cytopenias has 
been extended from 28 to 42 days in order to allow for sufficient time to recover from 
suppression and to re-populate the bone marrow. 
 Table 7-1 Visit evaluation schedule: updates due to inadvertent omissions in previous 
protocols and to reflect extension of study treatment period 
 ECOG Performance status: X has been replaced by “If needed” under Week 6, Week 
10 and Week 14. 
 Vital signs: added “If needed” under Week 6, Week 10 and Week 14. 
 Visit name: “W108, W120, W132, W144, W156” has been changed to “Every 12 
weeks up to end of study treatment” to align with new extended recruitment timelines. 
 Section 7.1.2 Change of patient re-screening allowance from once to up to three times. 
 Section 7.1.2.2 Addition of new section with screening eligibility criteria for patients 
switching from bosutinib to asciminib. 
 Section 7.1.4 Change of treatment duration for patients including those patients that 
switch to asciminib after failure on bosutinib. Patients can remain on asciminib treatment 
for up to 96 weeks after the last patient received the first dose in the study or up to 48 
weeks after the last patient has switched to asciminib whichever is longer. 
 Section 7.1.6 Discontinuation of study treatment: updated to specify that the safety follow-
up visit can be conducted by telephone and replacement of “after randomization” by “after 
initiation of therapy” in the event that constitutes a treatment failure. 
 Section 7.2.2.5.3 Pregnancy and assessments of fertility: Change in requirement for 
reporting pregnancies under this study.  Pregnancies diagnosed in female partners of male 
participants are no longer required to be reported to CMO&PS.  Contraception use by 
sexually active males while on study treatment is no longer required. 
 Table 7-5 Central clinical laboratory parameters collection plan: Clarification on blood 
urea and Blood Urea Nitrogen (BUN). The text "blood urea, Blood Urea Nitrogen (BUN)" 
has been revised to “blood urea or Blood Urea Nitrogen (BUN)”. 
 Section 8.4 Pregnancies: removal of male contraception requirement due to new 
information of asciminib embryo and fetotoxicity. 
 Section 10.4.3 Handling of missing values/censoring/discontinuations: imputation rules 
updated to take in account unscheduled visits close to visit Week 24. 


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Protocol – Summary of changes 
 
Protocol No. CABL001A2301 
 
 Section 10.5.1.1. Analysis for key secondary endpoints: imputation rules updated to take 
in account unscheduled visits close to visit Week 96. 
 Section 14 Appendices: updates to reflect that P-gp inhibitors are no longer prohibited 
 Section 14.2 Appendix List of concomitant medications for patients on bosutinib: 
 Removal of P-gp inhibitors from Table 14-3 Prohibited concomitant medications 
for bosutinib arm. 
 Addition of new medications to Category Torsade de pointe (TdP) TdP/QT risk: 
Known. 
 Addition of new category, TdP/QT risk: Possible. 
 Addition of new category, TdP/QT risk: Conditional. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Protocol – Summary of changes 
 
Protocol No. CABL001A2301 
 
Amendment 2 (13-Jul-2018) 
Amendment rationale  
As of 29-Jun-2018, this study has been submitted in 25 and approved in 24 countries. Eighty 
five (85) sites were initiated, 67 patients were screened and 38 patients were randomized in the 
study. 
The primary purposes of the amendment are: 
The frequency of bone marrow aspirate (BMA) to perform cytogenetic analysis has been 
decreased in accordance with treatment guidelines (European Leukemia Network (ELN) 
Guidelines (Baccarani et al 2013), National Comprehensive Cancer Network (NCCN) (Clinical 
Practice Guidelines in Oncology-Chronic Myeloid Leukemia v4.2018). Initially BMAs were 
foreseen at screening, every 24 weeks thereafter and at end of treatment. With the protocol 
amendment BMA is no longer needed for patients that have achieved MMR during study, 
however BMA assessment is requested at the time of end of treatment for biomarker analysis.  
Toxicity studies performed in rats, dogs and cynomolgus monkeys identified the pancreas as 
potential target tissues. Therefore the assessment for laboratory parameters that are associated 
with pancreatitis were part of the inclusion criteria (amylase, lipase). Serum lipase is the 
preferred test due to its improved sensitivity, and a threshold concentration of 2-3 x ULN is 
recommended for the diagnosis of pancreatitis. There are a number of other conditions that can 
elevate lipase, including TKI pretreatment, thus the screening threshold for lipase is increased 
from ≤ ULN to ≤ 1.5 x ULN (CTCAE v4.03 grade 1), as patients with history of acute 
pancreatitis within 1 year of study and history of chronic pancreatitis are excluded. Amylase is 
not a specific marker for pancreatitis, as up to 60% of total serum amylase originates from non-
pancreatic sources. Its short half-life reduces its value as a diagnostic test in the early clinical 
course. Lipase has replaced amylase as the biochemical test of choice for acute pancreatitis due 
to its higher specificity (Basnayake 2015), therefore the requirement of amylase ≤ ULN at 
screening has been removed. 
Assessments for visits at weeks 6, 10 and 14 will be limited to the monitoring of the bone 
marrow function to allow for adjustments of study treatment. Assessments will comprise a 
complete blood count to detect neutropenia and thrombocytopenia which are among the most 
frequent adverse reactions [Asciminib Investigator’s Brochure, Bosutinib label]. The physical 
examination must be done at site only in case of previous or newly occurring adverse events. 
The concomitant medication section has been updated to reflect the most recent clinical updates 
on asciminib as well to align with the Bosutinib label. 
In addition some minor inconsistencies (discrepancies between sections, typos) have been 
corrected. 
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. 
 ABL001 has been replaced by International Nonproprietary Name (INN) asciminib 
throughout the protocol amendment. 




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 Section 6.3.1 Dose modification and dose delay: clarification made on treatment 
discontinuation. 
 Table 6-2 Criteria for dose reduction/interruption and re-initiation of asciminib and 
bosutinib treatment for adverse drug reactions:  
 Gastro intestinal/ Pancreatitis/Grade 2: precisions provided and treatment delay 
changed from 7 to 21 days to give investigators sufficient time for re-assessment. 
 Removal of “other adverse event” section which was redundant with the section “non-
hematological adverse event reaction except where further specified in individual 
section”. 
 Mandatory instructions for grade 3 and 4 “Non-hematological adverse event reaction 
except where further specified in individual section” for bosutinib have been aligned 
with those of asciminib: dose hold until resolved to ≤ grade 1, to handle the patients 
identically independent of the treatment assigned. 
 Section 6.3.2 Dose adjustments for QTcF prolongation: adapting the dose adjustment 
concerning QT prolonging agents to the classification known, possible or conditional risk 
for TdP, and adding the external web link to qtdrugs.org.  
 Section 6.4.2 Permitted concomitant therapy requiring caution and/or action: updated with 
the most clinical data available. 
 Section 6.4.3 Prohibited concomitant therapy (asciminib): 
 Section on other anticancer agent added, 
 Sections on strong CYP3A4/5 inhibitors and P-gp inhibitors: prohibition on P-gp 
inhibitors has been removed and moved under requiring caution and/or action section 
based on CABL001A2102 ADME study, 
 Section on strong CYP3A4/5, UGT1A/2B inducers updated to provide instructions on 
action to be taken in case these inducers are taken, 
 Section on NTI substrates of CYP3A4/5, CYP2C8 and CYP2C9 removed based on a 
most updated PBPK modeling predicting a negligible risk for sensitive CYP3A4/5, 
CYP2C8, or CYP2C9 substrates and moved under requiring caution and/or action 
section, 
 Section on QT prolonging agents updated to change agents known to prolong QT 
interval to agents with “known”, “possible” or “conditional” risk of Torsades de 
Pointes. 
 Section 6.5.1 Permitted concomitant therapy requiring caution (bosutinib): has been 
updated to reflect the bosutinib label information regarding the use of QT prolonging agents.  
 Section 6.5.2 Prohibited concomitant therapy (bosutinib):  
 Section on other anticancer agent added, 
 Concomitant use with CYP3A4/5 inhibitors/inducers: further clarifications on 
necessary actions.  
 Table 7-1 Visit evaluation schedule:  
 Exploratory BCR-ABL1 mutation analysis (Sanger Sequencing) for patients with 
mutations at Week 1 Day 1: rephrased to indicate that this assessment will be 
performed without any dedicated blood collection. 






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Protocol – Summary of changes 
 
Protocol No. CABL001A2301 
 
 Section 10.5.2 Other secondary efficacy objectives: update of descriptive statistics 
definition and removal of presentation of p value as no formal statistical testing will be 
performed. 
 Section 10.6.1 Exploratory efficacy objectives and Section 10.6.3 Exploratory biomarker 
objectives:  
 Correction of time points for BCR-ABL1 mutation characterization (baseline 
corrected to Week 1 Day 1, adding “upon confirmed loss of MMR, and changed 
“and” to “and/or” End of treatment). 
 
.  
 Section 10.6.4.1 Resource utilization: correction on duration of resource utilization 
reporting.  
 Section 10.7 Interim analysis: clarification concerning the analysis of the key secondary 
endpoint at week 96 if statistical significance is not reached for primary endpoint at week 
24. 
 Section 14 Appendices: the lists of concomitant medications for patients on asciminib and 
bosutinib have been updated based on the internal Pharmacokinetic Sciences 
memorandum on Drug-Drug Interaction (release date: January 2018). 
 Some minor inconsistencies (discrepancies between sections, typos) have been corrected. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 






2. Statistical Analysis Plan 


Clinical Development
ABL001/asciminib
CABL001A2301
A phase 3, multi-center, open-label, randomized study of 
oral ABL001 versus bosutinib in patients with Chronic 
Myelogenous Leukemia in chronic phase (CML-CP), 
previously treated with 2 or more tyrosine kinase inhibitors
Statistical Analysis Plan (SAP)
Author:
Statistician, 
Document type:
SAP Documentation
Document status:
Final
Release date:
25-Aug-2017
Number of pages:
53
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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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)
25-
Aug-
2017
Prior to DB 
lock
for 
primary 
analysis
Creation 
of 
final version
N/A - First version
NA


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods...............................................................................................................9
2.1
Data analysis general information ...........................................................................9
2.1.1
General definitions................................................................................11
2.2
Analysis sets ..........................................................................................................17
2.2.1
Subgroup of interest ..............................................................................19
2.3
Patient disposition, demographics and other baseline characteristics ...................20
2.3.1
Patient disposition.................................................................................21
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................22
2.4.1
Study treatment / compliance................................................................22
2.4.2
Prior, concomitant and post therapies ...................................................24
2.5
Analysis of the primary objective..........................................................................25
2.5.1
Primary endpoint...................................................................................25
2.5.2
Statistical hypothesis, model, and method of analysis..........................25
2.5.3
Handling of missing values/censoring/discontinuations.......................26
2.5.4
Supportive analyses...............................................................................26
2.6
Analysis of the key secondary objective ...............................................................26
2.6.1
Key secondary endpoint........................................................................26
2.6.2
Statistical hypothesis, model, and method of analysis..........................26
2.6.3
Handling of missing values/censoring/discontinuations.......................27
2.7
Analysis of secondary efficacy objective(s) ..........................................................27
2.7.1
Secondary endpoints .............................................................................27
2.7.2
Statistical hypothesis, model, and method of analysis..........................29
2.7.3
Handling of missing values/censoring/discontinuations.......................31
2.8
Safety analyses.......................................................................................................32
2.8.1
Adverse events (AEs)............................................................................32
2.8.2
Deaths....................................................................................................33
2.8.3
Laboratory data .....................................................................................33
2.8.4
Other safety data ...................................................................................34
2.8.5
Additional Analyses..............................................................................36
2.9
Pharmacokinetic endpoints....................................................................................36


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2.10
PD and PK/PD analyses.........................................................................................38
2.11
Patient-reported outcomes .....................................................................................38
2.11.1
MDASI-CML........................................................................................39
2.11.2
EQ-5D-5L .............................................................................................39
2.11.3
WPAI-CML...........................................................................................40
2.11.4
PGIC......................................................................................................40
2.12
Resource utilization ...............................................................................................41
2.13
Biomarkers.............................................................................................................41
2.13.1
Somatic mutation biomarker data handling and analysis......................43
2.14
Other exploratory analyses ....................................................................................44
2.15
Interim analysis......................................................................................................45
3
Sample size calculation .....................................................................................................45
3.1
Primary analysis.....................................................................................................45
3.2
Power for analysis of key secondary variables......................................................46
4
Change to protocol specified analyses ..............................................................................46
5
Appendix ...........................................................................................................................46
5.1
Imputation rules.....................................................................................................46
5.1.1
Study drug .............................................................................................46
5.1.2
AE, ConMeds and safety assessment date imputation..........................47
5.2
AEs coding/grading ...............................................................................................49
5.3
Laboratory parameters derivations ........................................................................49
5.4
Derivation of PCR results and loss of response.....................................................50
5.5
Statistical models...................................................................................................51
5.5.1
Primary analysis ....................................................................................51
5.5.2
Key secondary analysis .........................................................................52
5.5.3
Other analyses .......................................................................................52
6
Reference...........................................................................................................................53


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List of abbreviations
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AP
Accelerated phase
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic classification
AUC
Area under the curve
BC
Blast crisis
bid
bis in diem/twice a day
CCyR
Complete cytogenetic response
CHR
Complete hematologic response
CMH
Cochrane-Mantel-Haenszel
CML
Chronic myelogenous leukemia
CML-CP
Chronic myelogenous leukemia in chronic phase
CRO
Contract research organization
CSP
Clinical study protocol
CSR
Clinical study report
CTCAE
Common terminology criteria for adverse events
CV
Coefficient of variation
DAR
Dosage administration record
DI
Dose intensity
DMC
Data monitoring committee 
DRL
Drug reference  listing
DSUR
Development safety update report
ECG
Electrocardiogram
eCRF
Electronic case report form
EOT
End of treatment
ER
Emergency room
FAS
Full analysis set
GP
General practitioner
H
Hospitalization
HCRU
Health care resource utilization
HLT
High level term
HLGT
High level group term
IRT
Interactive response technology
IS
International scale
LLOQ
Lower limit of quantitation
LPFT
Last patient first treatment
LSC
Leukemic stem cell
LVEF
Left ventricular ejection fraction
MCyR
Major cytogenetic response


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mCyR
Minor cytogenetic response
MedDRA
Medical dictionary for regulatory activities
MMR
Major molecular response
NCI
National Cancer Institute
NGS
Next generation sequencing
NMQ
Novartis MedDRA Query
OS
Overall survival
PAS
Pharmacokinetic analysis set
PCR
Polymerase chain reaction
PCyR
Partial cytogenetic response
PD
Pharmacodynamic
PDI
Planned dose intensity
PFS
Progression-free rurvival
Ph+
Philadelphia chromosome positive
PK
Pharmacokinetics
PPS
Per-protocol set
PRO
Patient-reported outcomes
PSUR
Periodic safety update report
PT
Preferred term
qd
Qua’que di’e / once a day
RDI
Relative dose intensity
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SMQ
Standardized MedDRA query
SOC
System organ class
Sp
Specialist
TBL
Total bilirubin
TKI
Tyrosine kinase inhibitor
TTF
Time to treatment failure
UC
Urgent care
ULN
Upper limit of norm
VAS
Visual analogue scale
W1D1
Week 1 Day 1
WBC
White blood cells
WHO-DD
World Health Organization Drug Dictionary


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses of primary objective,
secondary objectives and selected exploratory objectives for the clinical study reports (CSR) 
of study CABL001A2301, a phase 3, multi-center, open-label, randomized study of oral 
ABL001 versus bosutinib in patients with Chronic Myelogenous Leukemia in chronic phase 
(CML-CP), previously treated with 2 or more tyrosine kinase inhibitors. 
The content of this SAP is based on protocol CABL001A2301 version 01. All decisions 
regarding safety monitoring analysis for the data monitoring committee, 24-week primary
analysis, 96-week end of study treatment analysis, 5-year progression-free survival 
(PFS)/overall 
survival 
(OS)
update 
analysis,
development 
safety 
update 
report 
(DSUR)/periodic safety update report (PSUR), and postings for ClinTrial.gov and EudraCT,
as defined in this SAP document, have been made prior to the first database lock of the study 
data for the primary analysis.
1.1
Study design
This is a randomized,  Phase III , open-label,  active-controlled, multi-center study  comparing  
safety and efficacy of ABL001 to bosutinib in patients with CML-CP, previously treated with 
2 or more tyrosine kinase inhibitors (Figure 1-1). Approximately 220 patients will be 
randomized to one of the following treatment arms in 2:1 ratio:

ABL001

Bosutinib
Randomization will be stratified by the following factor: cytogenetic response status (with or 
without major cytogenetic response).
Figure 1-1
Schematic of Study Design
Patients will be treated for up to 96 weeks after the last patient received the first study dose
(LPFT), if they do not discontinue study treatment earlier. After the study treatment period 
(i.e. LPFT + 96 weeks), 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 


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access/compassionate use/managed access program or access to commercial supplies in 
applicable countries.
Major Molecular Response (MMR) rate at 24 weeks is the primary endpoint in this study. 
MMR rate at 96 weeks is the key secondary 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 treatment analysis will be 
performed after all patients have been followed for at least 96 weeks or have discontinued 
study earlier. The PFS/OS update analysis will be performed about 5 years after the date the 
last patient received the first study dose.
No formal interim efficacy analysis is planned in this study. A data monitoring committee 
(DMC) will monitor unblinded safety data approximately 6 months after the first randomized 
patient has started study treatment. Subsequent reviews will be conducted approximately 
every 6 months on an as and when needed basis thereafter (ie. if significant safety findings are 
noted) until the primary analysis.
1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Primary
To compare the MMR rate at 24 weeks of 
ABL001 versus bosutinib 
Major Molecular Response (MMR) rate at 24 weeks
Key secondary
To compare additional parameters of the 
efficacy of ABL001 versus bosutinib 
MMR rate at 96 weeks
Other secondary
To compare additional parameters of the 
efficacy of ABL001 versus bosutinib

Cytogenetic response rate (Complete, Partial, Major, 
Minor, Minimal, no response) at and by all scheduled data 
collection time points including 24, 48 and 96 weeks

MMR rate at all scheduled data collection time points  
(except 24 and 96 weeks which are already covered by 
primary and key secondary endpoints)

MMR rate by all scheduled data collection time points 
including 24, 48 and 96 weeks

Time to MMR

Duration of MMR

Time to CCyR

Duration of CCyR

Time to treatment failure

Progression free survival

Overall survival
To compare the safety and tolerability 
profile of ABL001 versus bosutinib
Type, frequency and severity of adverse events,
Changes in laboratory values that fall outside the pre-
determined ranges and clinically notable ECG and other safety 
data (vital signs, physical examination)
To characterize the PK of ABL001 in the 
CML-CP population
Trough plasma concentrations,
PK parameters in full PK group: Cmax, Tmax, AUC0-12h, CL/F 


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Objective
Endpoint
Exploratory
To evaluate the influence of factors such as 
cytogenetic response at baseline, 
failure/intolerance to prior TKIs, line of 
therapy, gender, race and age on the effect 
of ABL001 with respect to the primary 
efficacy endpoint 
Major Molecular Response (MMR) rate at 24 weeks
To explore the exposure-response 
relationships of ABL001; evaluate the effect 
of population covariates
Exposure-safety, exposure-efficacy, and exposure-biomarker
analyses
To characterize mutations in the BCR-ABL1 
gene at baseline and at end of treatment 
and examine their association with 
molecular and cytogenetic response for 
ABL001 vs bosutinib
BCR-ABL1 gene mutations at baseline and at end of treatment 
as determined by Sanger Sequencing
To correlate gene expression profiles in 
leukemic stem cell (LSC)-enriched blood 
and bone marrow with response to ABL001 
vs. bosutinib
Gene expression profile at baseline and changes to gene 
expression at end of treatment 
To characterize the effect of ABL001 vs. 
bosutinib treatment on CML LSC and 
normal progenitor cells (e.g. growth and 
differentiation) and their bone marrow 
microenvironment niches
Assess Week 1 Day1 pre-dose and at EOT correlation of 
molecular and cytogenetic response by flow cytometry analysis 
of:  1) LSCs; 2) T-cell maturation; 3) T-cell activation and 
differentiation; 4) myeloid derived suppressor cells in blood and 
bone marrow aspirates.
Bone marrow biopsies characterization for adaptive immune 
response by IHC (Immunohistochemistry) for PD-L1, CD8
To assess clonal evolution during treatment 
with ABL001 vs. bosutinib
Low level BCR-ABL1 mutation profiles assessed by mass 
spectrometry at baseline and at EOT.  
Clonal evolution of several genes implicated in CML assessed 
by Next Generation Sequencing (NGS) methods 
To evaluate soluble factors that correlate 
with response to ABL001 vs. bosutinib 
treatment in terms of tumor immunogenicity 
status
Baseline and changes from baseline of cytokine expression in 
plasma  
To compare the impact of treatment on 
patient reported outcomes (PRO) including 
CML-specific symptoms, patient quality of 
life, and impact on work productivity and 
activity impairment from baseline and EOT 
between  treatment arms in all patients
Change in symptom burden and interference from baseline over 
time according to the MDASI-CML PRO instrument
Change in patient’s impression of CML symptoms according to 
PGIC
Change in health utility from baseline over time according to 
EQ-5D-5L
To compare the impact of treatment on 
health care resource utilization between 
treatment arms in all patients
Health care resource burden over time
2
Statistical methods
2.1
Data analysis general information
The planned analyses will be performed by Novartis and/or a designated CRO. SAS version 
9.4 or later will be used to perform all data analyses and to generate tables, figures and listings.
There is no planned interim efficacy analysis. Prior to the database lock for the primary 
analysis, tables and figures aggregated by treatment arm for safety data review by the data 


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monitoring committee or for other reporting activities will be produced by an independent 
statistician and independent statistical programmers.
For between-treatment comparisons of efficacy endpoints, randomization stratification factor, 
i.e. cytogenetic response status (MCyR vs no MCyR) at screening, will be included in
respective stratified statistical tests.
Data included in the analyses
The analysis data cut-off dates for the planned analyses are:

Primary analysis: After all randomized patients have been on study treatment for 24
weeks or  discontinued earlier, i.e., LPFT + 24 weeks. 

End of study treatment analysis: 30 days after all patients have been on treatment for 
at least 96 weeks or discontinued earlier, i.e., LPFT + 96 weeks + 30 days. (Note: 
After the study treatment period, the assigned study treatment will be made available, 
may be outside of this study, to patients who in the opinion of the investigators are 
still deriving clinical benefit.) 

PFS/OS update analysis: 5 years from the date when the last patient received the first 
study dose.
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. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
by treatment group; a missing category will be included as applicable. Percentages will be
calculated using the number of patients in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum) by 
treatment group. For pharmacokinetics (PK) concentration and parameters descriptive 
statistics also include coefficient of variation (CV)%, geo-mean and geo-CV%.


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2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, will refer to the ABL001 only. Whereas, study treatment will refer to 
ABL001 or control treatment, i.e. bosutinib.
Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a non-zero 
dose of study treatment was administered as per the Dosage Administration Record (DAR)
electronic case report form (eCRF). The date of first administration of study treatment will 
also be referred as start of study treatment.
The date of first administration of study treatment is the same as the date of first 
administration of investigational drug or control drug. 
Date of last administration of study treatment 
The date of last administration of study treatment is defined as the last date when a non-zero 
dose of study treatment was administered as per DAR eCRF. 
The date of last administration of study treatment is the same as the date of last administration 
of investigational drug or control drug.
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:

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, PK, etc.) is the start of
study treatment.
The reference start date for all other, non-safety assessments (e.g. molecular response, 
survival time, disease progression, ECOG performance status, patient reported outcomes
(PRO), etc.) is the date of randomization.
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.
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.


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A week length is defined as 7 days. If duration is reported in weeks, duration in days will be 
divided by 7.
Baseline
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of randomization is taken as “baseline” value or “baseline” assessment. 
In the context of baseline definition, the efficacy evaluations also include PRO and
performance status. 
For safety evaluations, the last available assessment on or before the date of start of study 
treatment 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 theses 
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 three mutually 
exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment
2. on-treatment period: from date of first administration of study treatment to 30 days 
after date of last actual administration of any study treatment (including start and stop 
date). Note: Patients will be treated for up to LPFT + 96 weeks. This will be the last 
actual administration of study treatment for each patient if the patient has not 
discontinued study treatment earlier. After this period, the assigned study treatment 
will be made available, may be outside of this study, to patients who in the opinion of 
the investigators are still deriving clinical benefit.
3. post-treatment period: starting at day 31 after last administration of study treatment.
If dates are incomplete in a way that clear assignment to pre-, on-, or post-treatment period 
cannot be made, then the respective data will be assigned to the on-treatment period.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change 
from baseline summaries). In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 




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Table 2-2
Time windows for cytogenetic response
Assessment
Target day of assessment
Time Interval
Baseline
≤1
≤ Day 1#
Week 12*
78-84
Day 2 to day 122
Week 24
162-168
Day 123 to day 248
Week 48
330-336
Day 249 to day 416
Week 72
498-504
Day 417 to day 584
Week 96
666-672
Day 585 to day 700
# Day 1 = Date of randomization
* Optional for patients in bosutinib arm to allow potential intra-patient dose escalation
Table 2-3
Time windows for ECG assessments
Assessment
Target day of assessment
Time Interval
Baseline
1
≤ Day 1#
Week 2 Day 1
8
Day 2 to day 14
Week 4
22-28
Day 15 to day 52
Week 12
78-84
Day 53 to day 122
Week 24
162-168
Day 123 to day 329
Week 96
666-672
Day 330 to day 700
# Day 1 = Date of first administration of study treatment
Table 2-4
Time windows for LVEF
Assessment
Target day of assessment
Time Interval
Baseline
≤1
≤ Day 1#
Week 20
134-140
Day 2 to day 168
# Day 1 = Date of first administration of study treatment
Table 2-5
Time windows for pharmacokinetic assessments
Assessment
Target day of assessment
Time Interval
Baseline
1
≤ Day 1#
Week 2 Day 1
8
Day 2 to day 14
Week 4
22-28
Day 15 to day 52
Week 12
78-84
Day 53 to day 122
Week 24
162-168
Day 123 to day 329
Week 96
666-672
Day 330 to day 700
# Day 1 = Date of first administration of study treatment


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For PRO data time windows will be defined for descriptive summary by visit and longitudinal 
data analysis. If more than one assessment is available in the same time window, the 
assessment closest to the planned date will be considered. If two assessments are obtained 
with the same time difference compared to the scheduled visit day, the assessment obtained 
prior to visit will be considered.  
Table 2-6
Time windows for PRO: MDASI-CML, EQ-5D-5L, PGIC
Assessment
Target day of assessment
Time Interval
Baseline
≤1
≤ Day 1#
Week 4
22-28
Day 2 to day 38
Week 8
50-56
Day 39 to day 66
Week 12
78-84
Day 67 to day 94
Week 16
106-112
Day 95 to day 136
Week 24
162-168
Day 137 to day 206
Week 36
246-252
Day 207 to day 290
Week 48
330-336
Day 291 to day 500
Week 96
666-672
Day 501 to day 700
# Day 1 = Date of randomization
Table 2-7
Time windows for PRO: WPAI-CML
Assessment
Target day of assessment
Time Interval
Baseline
≤1
≤ Day 1#
Week 4
22-28
Day 2 to day 52
Week 12
78-84
Day 53 to day 122
Week 24
162-168
Day 123 to day 248
Week 48
330-336
Day 249 to day 500
Week 96
666-672
Day 501 to day 700
# Day 1 = Date of randomization


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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 2-8
Last contact date data sources
Source data
Conditions
Date of randomization 
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/PK 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 the 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
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, patients will be analyzed 
according to the treatment and stratum they have been assigned to during the randomization 
procedure.
Per Protocol Set 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the clinical study protocol (CSP). The PPS will be used for sensitivity 
analyses on the primary endpoint only.
The following list of protocol deviations will lead to exclusion of the patient from the PPS:

Type of indication different from those required by the CSP, e.g., not CML-CP, BCR-
ABL ratio <1% International Scale (IS), with T315I or V299L mutation (INCL03, 
INCL04, INCL05, EXCL01)

If prior therapy does not match with CSP requirements in terms of number and types 
of previous therapy regimens (INCL06)

Study treatment received different from treatment assigned by randomization (TRT08)
Safety Set
The Safety Set includes all subjects who received at least one dose of study treatment. 
Subjects will be analyzed according to the study treatment actually received.
The actual treatment received corresponds to:

the randomized treatment if patients took at least one dose of that treatment;

the first treatment received if the randomized treatment was never received.
Pharmacokinetic Analysis Set
The Pharmacokinetic Analysis Set (PAS) includes all patients who provide at least one 
evaluable PK concentration. For a concentration to be evaluable, patients are required to:

Take a dose of ABL001 prior to sampling

Take the same dose of ABL001 for at least 3 consecutive days without dose 
interruption or dose modification prior to sampling

For pre-dose samples, do not vomit within 4 hours after the dosing of ABL001 prior 
to sampling (this is the previous dose); for post-dose samples, do not vomit within 4 
hours after the dosing of ABL001 (this is the current dose)  

Have the pre-dose sample collected before the next dose administration


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Other analysis sets

For duration of MMR and time to MMR, the MMR Responder Set will be used that 
is a subset of FAS and includes patients who achieve MMR at any time on study 
treatment.

For CCyR rates at and by scheduled time points, the CCyR Analysis Set will be used 
that is a subset of FAS and includes patients who are not in CCyR at baseline.

For duration of CCyR and time to CCyR, the Cytogenetic Responder Set will be use 
that is a subset of FAS and includes patients who do not have CCyR at baseline and 
achieve CCyR at any time on study treatment.
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 subject classification rules defined in 
Table 2-9. 
Table 2-9
Subject classification based on protocol deviations and non protocol 
deviation criteria
Analysis set
Protocol deviations leading to 
exclusion
Non 
protocol 
deviation 
leading to exclusion
FAS 
No written inform consent
Not applicable
Safety set
No written inform consent
No dose of study medication 
Per-protocol set
See definition of PPS
Another 
anti-neoplastic 
therapy administered after 
start of study treatment
PK analysis set
No written inform consent
See definition of PAS
MMR Responder Set
Not applicable
See 
definition
of 
MMR 
Responder Set
CCyR Analysis Set
Not applicable
See 
definition
of 
CCyR 
Analysis Set
Cytogenetic Responder Set
Not applicable
See definition of Cytogenetic 
Responder Set
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a 
patient withdraws full consent is recorded in the eCRF. 


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2.2.1
Subgroup of interest
Subgroup analyses will use the same method as for the analysis in the respective overall 
analysis set. 
The objective for carrying out these subgroup analyses is to identify potential issues that
may be limited to a subgroup of patients, or that are more commonly observed in a subgroup 
of patients.
Summary tables and figures will be generated only if at least 15 patients are present in each 
subgroup. 
Efficacy
The primary efficacy endpoint will be summarized by the following subgroups to examine the 
homogeneity of treatment effect provided that the primary efficacy analysis based on the FAS 
is statistically significant: 

Stratification factor (based on randomization data from Interactive Response 
Technology [IRT]): “Major Cytogenetic Response” or “No Major Cytogenetic 
Response”

Sex: Female or male

Race: Asian, Caucasian, or others

Age category (< 65 years, ≥65 years)

Reason for discontinuation of the last prior Tyrosine Kinase Inhibitor (TKI): 
Failure (i.e. disease progression, lack of efficacy) or intolerance (i.e. adverse event, 
lack of tolerability). 
Note: Only one reason for discontinuation is allowed for each prior therapy.

Number of prior TKI therapies: 2 or ≥3

Historical BCR-ABL1 mutation by local lab: With or without mutation

Baseline BCR-ABL1 mutation by Sanger Sequencing at central lab: Wild type or  
mutant
No formal statistical test of hypotheses will be performed for the subgroups, only point 
estimate of the treatment effect and 95%-confidence intervals will be provided (see Section 
2.14 for further analysis details). The objective of the efficacy subgroup analysis is to 
demonstrate homogeneity of treatment effect in the above subgroups.
Safety
Subgroup analyses for selected safety endpoints will be defined when required.
Japan-specific subgroup analyses
Two subgroups will be formed based on geographic region: Japan or other region (this is not 
based on ethinicity). These subgroup analyses will be only used for submission to Japan 
health authority.
Summary tables and figures will be presented for the two subgroups for the following 
outcome measures:


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
Baseline characteristics: Tables of demographics, diagnosis and extent of cancer,
extramedullary involvement, bone marrow analysis, patient disposition, analysis sets

Exposure: Tables of duration of exposure, dose received

Tables of concomitant medications as well as surgical and medical procedures

PK (only in ABL001 arm): Table and figure of ABL001 concentration by time, figure 
of average trough ABL001 concentration from week 2, 4, 12 and 24 vs. BCR-ABL 
ratio IS (%) at 24 weeks

AEs: Tables of all AEs, treatment-related AEs, AEs requiring dose adjustment or 
interruption, AEs requiring additional therapies, serious adverse events (SAEs), 
adverse events of special interest (AESIs)

ECG: Tables of Notable ECG values, change from baseline in ECG parameters values

Lab: Hematology shift table, biochemistry shift table

Efficacy: Tables of molecular response categories at and by each time point, MMR 
rate at and by each time point, time to MMR, duration of MMR, cytogenetic response 
categories at and by each time point, time to CCyR, duration of CCyR, TTF, PFS, OS. 
Figures of cumulative incidence of MMR and of CCyR.
2.3
Patient disposition, demographics and other baseline 
characteristics
The FAS will be used for all baseline and demographic summaries and listings unless 
otherwise specified. Summaries will be reported by treatment arm and for all patients, and 
listings will be reported by treatment arm to assess baseline comparability. No inferential 
statistics will be provided.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment arm. Categorical data (e.g. age groups: 18 - <65, 65 - <85, and ≥ 85 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.
In addition, a summary table by sex, age group (18 - <65, 65 - <85, and ≥ 85 years) and 
treatment group and another summary table by race and treatment group will be generated 
using the safety set for DSUR/PSUR.
Baseline stratification factors
The number (%) of patients in each stratum (“Major Cytogenetic Response” or “No Major 
Cytogenetic Response”) based on data obtained from the IRT system will be summarized 


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overall and by treatment arm for the FAS. Discordances between the stratum recorded in IRT 
at the time of randomization and the actual stratum recorded in the clinical database through 
the data collected on eCRF will be cross-tabulated and listed.
Diagnosis and extent of cancer
All diagnosis and extent of cancer data will be summarized and listed by treatment arm. 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).
Medical history
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on eCRF will be summarized and listed by treatment arm. The summary will be 
presented by primary system organ class (SOC), preferred term (PT) and treatment arm. 
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 listings will be produced for medical history possibly contributing to 
liver dysfunction, and medical history of protocol solicited cardiovascular events.
Other
All data collected at baseline, including child bearing potential as well as informed consent 
for additional research on study data and biological samples, will be listed.
2.3.1
Patient disposition
Enrollment by country and center will be summarized for all screened patients and also
by treatment arm using the FAS. The number (%) of randomized patients included in the FAS 
will be presented overall and by treatment group. The number (%) of screened and not -
randomized 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 treatment group.
The following summaries will be provided (with % based on the total number of FAS 
patients):

Number (%) of patients who were randomized (based on data from IRT system)

Number (%) of patients who were randomized but not treated (based on DAR eCRF 
page not completed for any study treatment component)

Primary reason for not being treated (based on “End of Screening Phase” and 
“Withdrawl of Informed Consent(s)” eCRF pages)

Number (%) of patients who were treated (based on DAR eCRF pages of each study 
treatment completed with non-zero dose administered)


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
Number (%) of patients who are still on-treatment (based on the “End of Treatment 
Disposition” page not completed); 

Number (%) of patients who discontinued the study treatment phase (based on the 
“End of Treatment Disposition” page) 

Primary reason for study treatment phase discontinuation (based on the “End of 
Treatment Disposition” page)

Number (%) of patients who have entered the survival follow-up (based on the “End 
of Treatment Disposition” page);
Protocol deviations
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the Study Specification Document) overall and by 
treatment group for the FAS. All protocol deviations will be listed.
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized  
by treatment group and stratum. Reasons leading to exclusion from analysis sets will be listed 
by treatment group and stratum as well as tabulated overall and by treatment group.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized by treatment arm. Duration of exposure will be categorized into 
time intervals; frequency counts and percentages will be presented for the number (%) of 
subjects in each interval. The number (%) of subjects who have dose reductions or 
interruptions, and the reasons, will be summarized by treatment group. 
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.  
The safety set will be used for all summaries and listings of study treatment. 
Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug or control:
Duration of exposure to study treatment (days) = (date of last administration of  study 
treatment) – (date of first administration of study treatment) + 1. 
The date of last administration of study treatment is defined in Section 2.1.1.


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Summary of duration of exposure of study treatment will include categorical summaries based 
on intervals (<24 weeks, ≥24 weeks, ≥48 weeks, ≥96 weeks) and continuous summaries (i.e. 
mean, standard deviation etc.).
Cumulative dose
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure. 
The planned cumulative dose for a study treatment refers to the total planned dose as per the 
protocol up to the last date of study treatment administration. The calculations for the two 
study treatments are:

ABL001: 40 mg/administration × 2 (administration/day) × duration of exposure (day) 

Bosutinib:  500 mg/day × duration of exposure prior to dose escalation (day) 
+ 600 mg/day × duration of exposure since dose escalation (day),
where the starting day of dose escalation is identified as the first record in the DAR 
eCRF with dose increased and reason “As per protocol”.
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment 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 study treatment.
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 (day).
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 (day).
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg/day)  / PDI (mg/day).  
DI and RDI will be summarized separately for the two study treatments. 
Dose changes, interruptions or permanent discontinuations
The number of subjects who have dose increase (allowed for bosutinib starting week 8, see 
protocol Section 6.2), dose reductions, dose interruptions or permanent discontinuations, and 
the reasons, will be summarized separately for the two study treatments. 
‘Dose Changed’, ‘Dose Interrupted’ and ‘Dose Permanently Discontinued’ fields from the 
DAR eCRF pages will be used to determine the dose changes, dose interruptions, and 
permanent discontinuations, respectively.


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The corresponding fields ‘Reason for Dose Change/Dose Interrupted’ 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 ABL001 arm, there is only one planned dose, i.e. 80 mg/day. For patients in 
bosutinib arm, the initial planned dose is 500 mg/day and could be changed to 600 mg/day in 
week 8 or later.
For the purpose of 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 change where the actual total daily dose is lower than the most recently
planned dose. Therefore any dose change to correct a dosing error will not be considered a 
dose reduction. Only dose change is collected in the eCRF, while number of reductions will 
be derived programmatically based on the change and the direction of the change.
Increase: A dose change where the actual total daily dose is greater than the most recently
planned dose. Therefore any dose change to correct a dosing error will not be considered a 
dose increase. Only dose change is collected in the eCRF, while number of increase will be 
derived programmatically based on the change and the direction of the change.
2.4.2
Prior, concomitant and post therapies
Prior anti-cancer therapy
The number and percentage of patients who received any prior anti-neoplastic medications 
will be summarized by treatment arm for setting (e.g. adjuvant, metastatic, etc.) and also for
the lowest anatomical therapeutic classification (ATC) class and preferred term. Summaries 
will include total number of regimens. A listing will also be produced. 
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 FAS.
Post treatment anti-cancer therapy
Anti-neoplastic therapies since discontinuation of study treatment will be listed and 
summarized by ATC class, preferred term, overall and by treatment group by means of 
frequency counts and percentages using FAS.
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. 
Concomitant therapies
Concomitant therapies are defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapies include medications (other than study drugs) and medical 


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procedures starting on or after the start date of study treatment, or starting prior to the start 
date of study treatment and continuing after the start date of study treatment. 
Concomitant 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:
1. Therapies starting on or after the start of study treatment but no later than 30 days 
after last dose of study treatment and
2. Therapies starting prior to start of study treatment and continuing after the start of 
study treatment.
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 30 days after the last date of study 
treatment will be flagged in the listing. The safety set will be used for all concomitant 
medication tables and listings.
2.5
Analysis of the primary objective
The primary objective of the study is to evaluate the efficacy of ABL001 at the recommended 
dose in CML patients in chronic phase, previously treated with 2 or more tyrosine kinase 
inhibitors and to compare this efficacy profile in this population with that achieved by patients 
receiving bosutinib. 
2.5.1
Primary endpoint
The primary efficacy variable of the study is the Major Molecular Response (MMR) rate at 24 
weeks. A patient will be counted as having achieved MMR at 24 weeks if he/she meets the 
MMR criterion (BCR-ABL ratio ≤0.1%) at 24 weeks. Details of derivation of Polymerase 
Chain Reaction (PCR) results and calculation of BCR-ABL ratio are presented in Section 5.4.
Further categories of molecular response are defined below:

1% < BCR-ABL ratio ≤ 10%

0.1% < BCR-ABL ratio ≤ 1%

0.01% < BCR-ABL ratio ≤ 0.1%

0.0032% < BCR-ABL ratio ≤ 0.01%

BCR-ABL ratio ≤0.0032%
2.5.2
Statistical hypothesis, model, and method of analysis
The MMR rate at 24 weeks will be calculated based on the FAS and according to the Intent 
To Treat (ITT) principle. MMR rate and its 95% confidence interval based on the Pearson-
Clopper method will be presented by treatment group. 
The null hypothesis is that there is no difference between the treatment groups with respect to 
MMR rate at 24 weeks. The Cochrane-Mantel-Haenszel (CMH) chi-square test, stratified by 


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the randomization stratification factor, i.e. cytogenetic response status (MCyR vs no MCyR) 
at screening, will be used to compare MMR rate between the two treatment groups, at the 
two-sided 5% level of significance. The 95% confidence interval for the difference in MMR 
rate between treatment groups will be provided using the Wald method. The Mantel-Haenszel 
estimate of the common risk difference and the corresponding 95% confidence interval will 
also be presented. 
2.5.3
Handling of missing values/censoring/discontinuations
Only patients with MMR at 24 weeks are considered responders. In other words, any patient 
who achieves MMR before 24 weeks, but is no longer in MMR at 24 weeks, will be 
considered as a non-responder in this primary analysis. Patients discontinuing the randomized 
treatment prior to 24 weeks due to any reason will be considered as non-responders.
One exception to the rule above is if the 24-week PCR evaluation is missing, but both a PCR 
evaluation at 16 weeks and a PCR evaluation at 36 weeks indicate MMR, the 24-week 
assessment is imputed as a ‘Response’, assuming that MMR is maintained between 16 and 36 
weeks.
2.5.4
Supportive analyses
The CMH chi-square test of MMR rate at 24 weeks, stratified by the randomization 
stratification factor (MCyR vs no MCyR at screening), will be repeated using the PPS, if the 
PPS is different from the FAS.
Additional exploratory logistic regression and subgroup analyses are described in Section 2.14.
2.6
Analysis of the key secondary objective
The key secondary objective of the study is to compare additional parameters of the efficacy 
of ABL001 versus bosutinib.
2.6.1
Key secondary endpoint
The key secondary endpoint is MMR rate at 96 weeks, which is defined as the proportion of 
patients with MMR at 96 weeks and derived in a similar fashion to MMR rate at 24 weeks. 
2.6.2
Statistical hypothesis, model, and method of analysis
The null hypothesis is that there is no difference between the treatment groups with respect to 
MMR rate at 96 weeks. Following a gatekeeping procedure to control the overall alpha level, 
only if the primary endpoint is significant, formal statistical testing of the key secondary 
endpoint with two-sided 5% level of significance will be performed using the CMH chi-
square test, stratified by the randomization stratification factor, i.e. cytogenetic response status 
(MCyR vs no MCyR) at screening.
MMR rate and its 95% confidence interval based on the Pearson-Clopper method will be 
presented by treatment group. The 95% confidence interval for the difference in MMR rate 
between treatment groups will be provided using the Wald method. The Mantel-Haenszel 


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estimate of the common risk difference and the corresponding 95% confidence interval will 
also be presented.
2.6.3
Handling of missing values/censoring/discontinuations
Only patients with MMR at 96 weeks are considered responders. In other words, any patient 
who achieves MMR before 96 weeks, but is no longer in MMR at 96 weeks, will be 
considered as a non-responder. Patients discontinuing the randomized treatment prior to 96
weeks due to any reason will be considered as non-responders.
2.7
Analysis of secondary efficacy objective(s)
The other secondary efficacy objective is to compare additional parameters (defined below) of 
the efficacy of ABL001 versus bosutinib.
2.7.1
Secondary endpoints
2.7.1.1
Molecular response
MMR rates at all scheduled data collection time points, except for 24 weeks and 96 weeks 
which are already covered by primary and key secondary endpoints. In addition to baseline 
assessment, the time points include week 4, 8, 12, 16, 36, 48, 60, 72, 84, 108, 120, 132, 144, 
156, 168, and end of treatment.
MMR rates by all scheduled data collection time points, i.e., week 4, 8, 12, 16, 24, 36, 48, 
60, 72, 84, 96, 108, 120, 132, 144, 156 and 168, and end of treatment. These are cumulative 
MMR rates by time points and are defined as the proportion of patients who achieve MMR at 
or before specified visits, i.e. if a patient achieves an MMR but then loses it before or at a 
specific visit, he/she will still be classed as achieving MMR by that specific time point.
Time to MMR is defined for patients in the Molecular Responder Set as: date of first MMR -
date of randomization + 1.
Duration of MMR is defined for patients in the Molecular Responder Set as the time 
between the date of the first documented MMR and the end date of MMR, i.e. the earliest date 
of loss of MMR, progression to accelerated phase (AP)/blast crisis (BC), or CML-related 
death. 
Loss of MMR is defined as confirmed loss of a greater than or equal to 3.0 log reduction in 
BCR-ABL transcript levels compared to the standardized baseline value (= confirmed loss of 
a less than or equal to 0.1% BCR-ABL/ABL by international scale) in association with a ≥ 5-
fold rise in BCR-ABL from the lowest value achieved on study treatment confirmed by a 
duplicate analysis of the same sample. This result has to be confirmed by a subsequent sample 
within 4-6 weeks unless it is associated with confirmed loss of complete hematologic 
response (CHR) or loss of CCyR or progression to AP/BC or CML-related death.
For patients for whom none of the events above is reported, the duration will be censored (see 
Section 2.7.3). The duration of MMR is calculated as: end date or censoring date of MMR -
date of first MMR + 1.


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2.7.1.2
Cytogenetic response
At each assessment time point the cytogenetic response status of each patient is classified as 
complete, partial, major, minor, minimal response and none:

Complete response (CCyR): 0% Philadelphia chromosome positive (Ph+) metaphases

Partial response (PCyR): >0 to 35% Ph+ metaphases

Major response (MCyR = CCyR + PCyR): 0 to 35% Ph+ metaphases

Minor response (mCyR): >35 to 65% Ph+ metaphases

Minimal response: >65 to 95% Ph+ metaphases

None: >95 to 100% Ph+ metaphases.
CCyR rates at all scheduled data collection time points, i.e., week 24, 48, 72 and 96, and 
end of treatment. Such rates are defined as the proportion of patients in CCyR at the 
respective time points among patients in the CCyR Analysis Set, which excludes patients who 
are in CCyR at baseline.
CCyR rates by all scheduled data collection time points, i.e., week 24, 48, 72 and 96, and 
end of treatment. Such rates are defined as the proportion of patients who achieve CCyR at or 
before the respective time points among patients in the CCyR Analysis Set.
Time to CCyR is defined for patients in the Cytogenetic Responder Set as: date of first 
documented CCyR - date of randomization + 1.
Duration of CCyR is defined for patients in the Cytogenetic Responder Set as the time 
between date of first documented CCyR and the end date of CCyR, i.e. the earliest date of loss 
of CCyR, progression to AP/BC, or CML-related death. For patients for whom none of the 
events above is reported or the last PCR evaluation on treatment indicating MMR, the 
duration will be censored (see Section 2.7.3). The duration of CCyR is calculated as: end date 
or censoring date of CCyR - date of first CCyR + 1.
2.7.1.3
Other secondary efficacy endpoints
Time to treatment failure (TTF) is defined for patients in FAS as the time from date of 
randomization to an event of treatment failure. The following events will constitute ‘treatment 
failure’, and are based on the ELN criteria [Baccarani et al. 2013] defining failure of a second 
line treatment adapted to include discontinuation of randomized treatment as an event:

No CHR or > 95% Ph+ metaphases at three months after randomization or thereafter 

BCR-ABL ratio > 10% IS and/or > 65% Ph+ metaphases at six months after 
randomization or thereafter 

BCR-ABL ratio > 10% IS and/or > 35% Ph+ metaphases at 12 months after 
randomization or thereafter

Loss of CHR, CCyR or PCyR at any time after randomization

Detection of new BCR-ABL1 mutations at any time after randomization

Confirmed loss of MMR in 2 consecutive tests, of which one must have a BCR-ABL 
ratio ≥ 1% IS 6 months after randomization


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
New clonal chromosome abnormalities in Ph+ cells: CCA/Ph+: at any time after 
randomization

Discontinuation from randomized treatment for any reason
TTF is calculated as: date of treatment failure or censoring date (see Section 2.7.3) - date of 
randomization + 1.
Progression-Free-Survival (PFS) is defined for patients in FAS as the time from the date of 
randomization to the earliest occurrence of documented disease progression to AP/BC or the 
date of death from any cause (including progressions and deaths observed during the survival 
follow-up period). PFS is calculated as: date of disease progression/death or censoring date 
(see Section 2.7.3) - date of randomization + 1.
Overall survival (OS) is defined for patients in FAS as the time from the date of 
randomization to the date of death (including the survival follow-up period). OS is calculated 
as: date of death or censoring date (see Section 2.7.3) - date of randomization + 1.
2.7.2
Statistical hypothesis, model, and method of analysis
No confirmatory statistical testing of non-key secondary efficacy endpoints will be performed, 
however, nominal p-values will be presented for exploratory purposes (as specified in 
protocol Section 10.5.2).
MMR rates at and by time points
The FAS will be used for these endpoints. For each time point the MMR rate and the 
associated 95% confidence interval based on the Pearson-Clopper method will be presented 
by treatment group. The respective null hypothesis of each MMR rate is that there is no 
difference between treatment groups. Statistical testing will be performed via CMH chi-square 
tests stratified by the randomization strata, i.e. MCyR vs no MCyR at screening. A 95% 
confidence interval for the difference in each MMR rate between treatment groups will be 
provided using the Wald method. The Mantel-Haenszel estimate of the common risk 
difference and the corresponding 95% confidence interval will also be provided.
The cumulative incidence of MMR by treatment group will be graphically displayed by an 
increasing step function. Each curve will increase each time (after randomization) at which a 
new responder is observed and thus will increase up to the best observed response rate (e.g. up 
to 50% if half of the patients in the analysis population are able to achieve MMR).
Molecular response at and by time points
Frequency and percentage of all molecular response categories (defined in Section 2.5.1) by 
treatment arm using FAS will be presented for each time point.
For the by-time-points summary, the within-patient best molecular response category up to 
the specific time points is used to calculate the frequency and percentage.
Time to MMR
The MMR Responder Set will be used. Descriptive statistics (minimum, maximum, median, 
quartiles, mean, sd) of time to MMR will be provided for the two treatment groups separately.


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Duration of MMR
The MMR Responder Set will be used. The survival distribution of duration of MMR will be 
estimated using the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% 
confidence intervals [Brookmeyer and Crowley 1982] of the medians, along with the 
proportion of patients who are still in MMR at 24, 48, 72 and 96 weeks and the associated 95% 
confidence intervals, will be presented for each treatment group.
CCyR rates at and by time points
The CCyR Analysis Set will be used for these endpoints. 
For each time point the CCyR rate and the associated 95% confidence interval based on the 
Pearson-Clopper method will be presented by treatment group. The respective null hypothesis
of each CCyR rate is that there is no difference between treatment groups. Statistical testing 
will be performed via CMH chi-square tests stratified by the randomization strata, i.e. MCyR 
vs no MCyR at screening. A 95% confidence interval for the difference in each CCyR rate 
between treatment groups will be provided using the Wald method. The Mantel-Haenszel 
estimate of the common risk difference and the corresponding 95% confidence interval will 
also be provided.
The cumulative incidence of CCyR by treatment group will be graphically displayed by an 
increasing step function. Each curve will increase each time (after randomization) at which a 
new responder is observed and thus will increase up to the best observed response rate (e.g. up 
to 50% if half of the patients in the analysis population are able to achieve CCyR).
Cytogenetic response at and by time points
Frequency and percentage of all cytogenetic response categories (defined in Section 2.7.1.2) 
by treatment arm using FAS will be presented for each time point. A shift table comparing 
baseline and best post-baseline cytogenetic response categories by treatment will also be 
presented. All assessments of cytogenetic response categories will also be listed by treatment 
arm.
For the by-time-points summary, the within-patient best cytogenetic response category up to 
the specific time points is used to calculate the frequency and percentage.
Assessments of bone marrow aspirate at different time points will also be summarized.
Time to CCyR
The Cytogenetic Responder Set will be used. Descriptive statistics (minimum, maximum, 
median, quartiles, mean, sd) of time to CCyR will be provided for the two treatment groups 
separately.
Duration of CCyR
The Cytogenetic Responder Set will be used. The survival distribution of duration of CCyR 
will be estimated using the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% 
confidence intervals [Brookmeyer and Crowley 1982] of the medians, along with the 


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proportion of patients who are still in CCyR at 24, 48, 72 and 96 weeks and the associated 95% 
confidence intervals, will be presented for each treatment group.
TTF, PFS and OS
For each endpoint the respective null hypothesis is that there is no difference between 
treatment groups. Distribution of each endpoint will be compared between two treatments 
using a stratified log-rank test at an overall two-sided 5% level of significance. The 
stratification will be based on the randomization stratification factor, i.e. cytogenetic response 
status (MCyR vs no MCyR) at screening.
For each endpoint the survival distribution will be estimated using the Kaplan-Meier method, 
and Kaplan-Meier curves, medians and 95% confidence intervals [Brookmeyer and Crowley 
1982] of the medians, along with the proportion of patients who have not experienced the 
respective events at 1, 3 and 5 years and the associated 95% confidence intervals, will be 
presented for each treatment group. The hazard ratio will be calculated, along with its 95% 
confidence interval, using a stratified Cox model.
2.7.3
Handling of missing values/censoring/discontinuations
MMR rates at specific time points: Patients discontinuing the randomized treatment prior to 
a specific time point due to any reason will be considered as non-responders for that time 
point.
Molecular response at specific time points: The category “Missing” will be assigned to

Ongoing cases, i.e. patients who have not discontinued study treatment and have not 
been treated sufficiently long for a specific time point

Discontinued due to progressive disease/death prior to a specific time point

Discontinued due to other reasons prior to a specific time point
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.
CCyR rates at specific time points: Patients discontinuing the randomized treatment prior to 
a specific time point due to any reason will be considered as non-responders for that time 
point.
For the primary analysis and the end of study treatment analysis, the cytogentic response of 
patients who have not discontinued study treatment and have not been treated sufficiently 
long for a specific time point will be classified as “Missing”.
Cytogenetic response at specific time points: The category “Missing” will be assigned to

Ongoing cases, i.e. patients who have not discontinued study treatment and have not 
been treated sufficiently long for a specific time point

Discontinued due to progressive disease/death prior to a specific time point

Discontinued due to other reasons prior to a specific time point


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Duration of CCyR: For patients who have not experienced any event (loss of CCyR, 
progression to AP/BC, or CML-related death) the duration will be censored at the last 
cytogenetic assessment date on treatment or the last PCR evaluation on treatment indicating 
MMR. 
TTF: For patients who have not reached treatment failure, their TTFs will be censored at the 
time of last study assessment (PCR, cytogenetic, hematologic or extramedullary) before the 
cut-off date.
PFS: For patients who have not experienced an event (disease progression to AP/BC or death 
from any cause), their PFS times 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
Safety analyses
All safety analyses will be based on the safety set. All listings and tables will be presented by 
treatment group.
2.8.1
Adverse events (AEs)
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 subjects 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 subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject 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.
In AE 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.
The following adverse event summaries will be produced by treatment arm: overview of 
adverse events and deaths, AEs by SOC and PT, summarized 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.


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2.8.1.1
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
An adverse event of special interest (AESI) is a grouping of adverse events that are of 
scientific and medical concern specific to compound ABL001. These groupings are defined 
using MedDRA terms, SMQs (standardized MedDRA queries), HLGTs (high level group 
terms), HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis 
MedDRA queries, NMQ) may also be used. A NMQ is a customized group of search terms 
which defines a medical concept for which there is no official SMQ available or the available 
SMQ does not completely fit the need. It may include a combination of single terms and/or an 
existing SMQ, narrow or broad. 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 on treatment period will be summarized.
Summaries of these AESIs will be provided by treatment arm (specifying grade, SAE, 
relationship, leading to treatment discontinuation, leading to dose adjustment/interruption, 
hospitalization, death, etc.). 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.
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment deaths) will be 
produced by treatment arm, system organ class and preferred term. 
All deaths will be listed, where post treatment deaths will be flagged. A separate listing of 
deaths prior to starting treatment will be provided for all screened subjects.
2.8.3
Laboratory data
Grading of laboratory values will be assigned programmatically as per National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.  
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 v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
On analyzing laboratory data from all sources (central and local laboratories) will be 
combined. The summaries will include all assessments available for the lab parameter 
collected no later than 30 days after the last study treatment administration date.
The following summaries will be produced separately for hematology and biochemistry 
laboratory data (by laboratory parameter and treatment):


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
Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline in the on-treatment period.

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value. 

For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.
The following listings will be produced separately for hematology and biochemistry for the 
laboratory data:

Listings of all laboratory data, with CTCAE grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.

Listing of all CTCAE grade 3 or 4 laboratory toxicities
Liver function parameters
Liver function parameters of interest are total bilirubin (TBL), Alanine aminotransferase
(ALT), Aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The number (%)
of patients with worst post-baseline values as per Novartis Liver Toxicity guidelines will be 
summarized:
The following summaries will be produced:

ALT or AST > 3x upper limit of norm (ULN)

ALT or AST > 5xULN

ALT or AST > 8xULN

ALT or AST > 10xULN

ALT or AST > 20xULN

TBL > 2xULN

TBL > 3xULN

ALT or AST > 3xULN & TBL > 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN  
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
12-lead ECGs including PR, QRS, QT, QTcF and RR intervals will be obtained centrally for 
each subject during the study. ECG data will be read and interpreted centrally. 
The echocardiogram will be performed and evaluated locally to assess the left ventricular 
ejection fraction (LVEF).
Data handling
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Data analysis
The number and percentage of subjects with notable ECG values will be presented by 
treatment arm. Notable values are defined below:

QT, QTcF

New value of > 450 and ≤ 480 ms

New value of > 480 and ≤ 500 ms

New value of > 500 ms

Increase from Baseline of > 30 ms to ≤  60ms

Increase from Baseline of > 60 ms

HR

Increase from baseline >25% and to a value > 100 bpm

Decrease from baseline >25% and to a value < 50 bpm

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 all ECG assessments will be produced by treatment arm and notable values will 
be flagged. A separate listing of only the subjects with notable ECG values will also be 
produced. In each listing the assessments collected during the post-treatment period will be 
flagged.
Change from baseline ECG parameters by timepoint will also be summarized by treatment.
A listing of all LVEF assessments will be produced by treatment arm. In the listing, the 
assessments collected outside of on-treatment period will be flagged. A summary table by 
treatment arm with descriptive statistics for LVEF at different timepoints (baseline, week 20)
and for change from baseline will be presented. A shift table for LVEF categories (≤40%, 41-
49%, ≥50%) at baseline versus worst value on treatment will also be presented.
2.8.4.2
Cardiovascular risk factor assessment
Prior to randomization and at the end of treatment, for each patient information of the 
following risk factors is collected: heavy smoking, low physical activity, unhealthy diet, and 
other. A listing by treatment arm will be presented. 
Family medical history of each patient for ischemic heart disease, cardiac arrhythmia, sudden 
death, high cholesterol, diabetes mellitus, heart defects (congenital heart disease), and heart 
failure is also collected prior to randomization and at the end of treatment. A listing by 
treatment arm will be presented.


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2.8.4.3
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute), systolic and diastolic blood pressure (mmHg).
Data handling
Vital signs collected on treatment will be summarized. Values measured outside of on 
treatment period will be flagged in the listings.
Data analysis
The number and percentage of subjects with notable vital sign values (high/low) in systolic 
blood pressure, diastolic blood pressure, pulse rate, weight and temperature will be presented 
by treatment arm.         
A listing of all vital sign assessments will be produced by treatment arm and notable values 
will be flagged. In the listing, the assessments collected outside of on-treatment period will be 
flagged. 
2.8.4.4
Liver events
There are separate eCRF pages to collect acetaminophen/paracetamol, autoimmune, drug use 
6 months prior to liver event, immunoglobulin, liver function tests, pathology, related imaging, 
viral serology and potential impact of alcohol use, and an overview eCRF page. Data on the 
overview eCRF page will be listed by treatment arm. Assessments collected during the post-
treatment period will be flagged.
2.8.4.5
Pulmonary function tests
Data of pulmonary function tests will be listed by treatment arm. Assessments collected 
during the post-treatment period will be flagged.
2.8.5
Additional Analyses
Not applicable.
2.9
Pharmacokinetic endpoints
PK parameters
The PK parameters that will be determined are shown in Table 2-10. The PK parameters for 
ABL001 are derived based on the non-compartmental methods using Phoenix WinNonlin®
software version 6.4 in patients with full PK sampling in PAS.


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Table 2-10
Non-compartmental PK parameters for ABL001 in full PK group
AUC0-12h
The area under the plasma concentration-time curve from time zero to 12 
hours (ng*hr*mL-1)
AUClast
The AUC from time zero to the last measurable plasma concentration 
sampling time (Tlast) (ng*hr*mL-1)
Cmax
The maximum (peak) observed plasma concentration after
dose 
administration (ng/mL)
Tmax
The time to reach maximum (peak) plasma concentration after dose 
administration (hr)
Tlast
The time to reach the last measurable plasma concentration after dose 
administration (hr)
CL/F
The total apparent body clearance of drug from the plasma after oral 
administration (L*hr-1)
Descriptive statistics (n, arithmetic mean, CV% mean, standard deviation (SD), median, 
geometric mean, CV% geo-mean, minimum and maximum) will be presented by treatment for 
PAS for all PK parameters defined in Table 2-10 except Tmax, where only n, median, 
minimum and maximum will be presented. 
All individual PK parameters will be listed for patients treated with ABL001 and with full PK 
sampling in the safety set.
PK concentrations 
Descriptive statistics (n, m (number of non-zero concentrations), arithmetic mean, CV% mean, 
SD, median, geometric mean, CV% geo-mean, minimum and maximum) for ABL001
concentration will be presented at each scheduled time point for the PAS.
The mean (+/- SD) and geometric mean concentration-time profiles for ABL001 over time 
will be displayed graphically for PAS on the linear and semi-log view.
All individual plasma ABL001 concentration data will be listed for patients treated with 
ABL001 in the Safety Set.
Handling of PK data below LLOQ or missing
All concentration values below the lower limit of quantitation (LLOQ, 1 ng/mL) are set to 
zero by the Bioanalyst, and will be displayed in the listings as zero and flagged. LLOQ values
will be treated as zero in any calculations of summary statistics, and treated as missing for the 
calculation of the geometric means and their CV%. The number of non-zero concentrations 
will also be reported in the summary statistics.
Missing values for any PK data will not be imputed and will be treated as missing.


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2.10
PD and PK/PD analyses
The potential relationship between ABL001 exposure (e.g. trough concentration) and efficacy,
pharmacodynamics (PD) or safety endpoints may be assessed by graphic exploration and/or 
statistical modeling, as appropriate, including effect of population covariates. Additional 
exposure-response analyses for ECG may be conducted. The concentration data may be 
analyzed by a population approach to evaluate the influence of covariates on drug exposure. If 
applicable, the details of the above-mentioned analyses will be described in a separate
analysis plan and reported separately.
The relationship between average trough plasma concentration up to 24 weeks and BCR-ABL 
ratio IS (%) at 24 weeks will be assessed by graphic exploration. 
2.11
Patient-reported outcomes
The FAS will be used for analyzing PRO data unless specified differently. The MDASI CML, 
PGIC along with EQ-5D-5L will be used to assess patient’s disease-related symptoms and 
health-related quality of life from baseline to EOT; and the WPAI-CML will be used to assess 
work productivity and activity impairment related to the patient’s CML. All tools require 
patient’s direct completion and will be administered utilizing electronic device for data 
collection at scheduled time points from screening to end of treatment.
The baseline is defined in Section 2.1.1. Patients with an evaluable baseline score and at least 
one evaluable post-baseline score during the treatment period will be included in the change 
from baseline analyses. Missing data items in a scale will be handled according to the manual 
for each instrument. No imputation will be applied if the total or subscale scores are missing 
at a visit. All measures will assess differences between the treatment arms.
Compliance to the schedule of administration of each PRO questionnaire will be summarized 
by treatment group, for baseline and scheduled post-baseline assessment time points. The 
following categories, as collected on the eCRF, will be used to describe whether the 
questionnaire was completed at a specific time point:
1. yes, fully completed
2. yes, partly completed
3. no
Repeated measures model for continuous scores
To best utilize the repeated assessments of a given PRO score, a repeated measures model for 
longitudinal data will be used to estimate differences between treatment arms. This repeated 
measures model will include terms for treatment, the stratification factor (major cytogenetic 
response status), time, baseline value as main effects, and an interaction term for treatment by 
time. This analysis will be restricted to patients with an evaluable baseline score and at least 
one evaluable post-baseline score. All data collected until end of treatment (including the end 
of treatment assessment) will be included in the analysis. Note that only data collected under 
treatment (i.e. while the patient is treated) will be included. The end of treatment assessment 
will be included if collected within 7 days of the last dose intake.


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Time will be considered as a continuous variable expressed in weeks, i.e. considering that the 
PRO score follow a linear trend.
As a first approach, an unstructured correlation matrix will be used to model the correlation 
within patients. The structure of the correlation matrix will be investigated and simplified 
using likelihood ratio tested if appropriate.
2.11.1
MDASI-CML
The M.D. Anderson Symptom Inventory – Chronic Myeloid Leukemia (MDASI-CML)
questionnaire is planned to be administered during screening, at weeks 4, 8, 12, 16, 24, 36, 48 
and 96 after randomization.
The MDASI-CML is a 26 item self-administered questionnaire for adult CML patients. 
Twenty of the items measure the severity of disease-related symptoms and are scored from 0 
(Not present) to 10 (As bad as you can imagine) and 6 items that measure symptom 
interference with daily life scored from 0 (Did not interfere) to 10 (Interfered completely). 
The severity score will be calculated when a patient scores at least 11 items out of the 20 
severity items using the formula: (sum of scores for the items answered) / (number of items 
answered). If a patient scores fewer than 11 items, the severity score will be missing.
The interference score will be calculated when a patient scores at least 4 items out of the 6 
interference items using the formula: (sum of scores for the items answered) / (number of 
items answered). If a patient scores fewer than 4 items, the interference score will be missing.
For the severity score and interference score, descriptive statistics (n, mean, SD, median, 25th 
and 75th percentiles) by treatment arm will be provided for the actual scores and changes
from baseline scores at each scheduled assessment time point.
Between-treatment differences for the change in severity and interference scores will be 
evaluated using the above-mentioned repeated measures model. 
2.11.2
EQ-5D-5L
EQ-5D-5L is a two-part standardized instrument for measuring health outcomes in a wide 
range of health conditions and treatments. It consists of a descriptive system and a visual 
analogue scale (EQ VAS). The descriptive system comprises the following 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension 
has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme 
problems (or unable to perform the activity). The EQ VAS records the respondent’s self-rated 
health on a vertical, visual analogue scale where the endpoints are labeled ‘Best imaginable 
health state’ and ‘worst imaginable health state’.
The EQ-5D-5L data will be used to calcutae utility values for the economic evaluation of 
ABL001 and bosutinib in a separate analysis.
The EQ-5D-5L questionnaire is planned to be administered during screening, at weeks 4, 8, 
12, 16, 24, 36, 48 and 96 after randomization.


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Descriptive system
The number and percentage of subjects in the five levels of each EQ-5D demension will be 
presented by treatment group at each assessment time point.
EQ VAS
The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale 
from 0, labeled as ‘worst imaginable health state’, to 100, labeled as ‘best imaginable health 
state’.
For the EQ VAS, descriptive statistics (n, mean, SD, median, 25th and 75th percentiles) by 
treatment arm will be provided for actual values and for the change from baseline at each 
assessment time point.
Between-treatment differences for the changes in EQ VAS score will be evaluated using the 
above-mentioned repeated measures model.
2.11.3
WPAI-CML
The Work Productivity and Activity Impairment Questionnaire – Chronic Myeloid Leukemia
(WPAI-CML) questionnaire is planned to be administered during screening, at weeks 4, 12, 
24, 48 and 96 after randomization.
The WPAI-CML is a six-item questionnaire which is intended to measure work and activity 
impairment associated with CML for those who self-identify as currently employed for pay. 
This questionnaire measures self-reported productivity loss associated with CML during the 
past seven days. It consists of questions about absence from work due to CML, hours spent at 
work, the reduction in productivity at work attributed to CML, and the reduction in 
productivity while performing regular activities. WPAI-CML outcomes are expressed as 
impairment percentages, with higher numbers indicating greater impairment and less 
productivity, i.e., worse outcomes. Scoring will be done according to WPAI-CML instrument 
guidance resulting in four scores including: Percent work time missed due to problem; percent 
impairment while working due to problem; Percent overall work impairment due to problem; 
and, percent activity impairment due to problem.
Descriptive statistics (n, mean, SD, median, 25th and 75th percentiles) for each of the four 
derived outcome scores and changes from baseline scores will be presented by treatment arm 
at each scheduled assessment time point with .
Between-treatment differences for the changes in each of the four outcome scores will be 
evaluated using the above-mentioned repeated measures model. 
2.11.4
PGIC
The Patient Global Impression of Change (PGIC) instrument is planned to be administered 
during screening, at weeks 4, 8, 12, 16, 24, 36, 48 and 96 after randomization
The PGIC is comprised of a single question intended to measure a patient’s perspective of 
improvement or deterioration over time relative to treatment. The PGIC uses a seven-point 


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scale where one (1) equals very much improved and seven (7) equals very much worse. 
Missing values will not be imputed.
The number and percentage of subjects in each of the seven categories for PGIC will be 
presented by treatment group at each assessment time point.
2.12
Resource utilization
Data relating to resource utilization (described in trial protocol Section 7.2.5) from the FAS 
will be used for the purpose of economic evaluation, which will be carried out and reported as 
a separate activity outside the CSR. 
The measures of healthcare resource utilization (HCRU) include: hospitalization (H), 
emergency room (ER) visit, general practitioner (GP) visits, specialist (Sp) visit and urgent 
care (UC) visit. HCRU will be assessed as follows: frequency and duration of hospitalization 
from baseline up to end of treatment; frequency of emergency room visits from baseline up to 
end of treatment; frequency of additional outpatient office visits general practitioner, 
specialist, and urgent care visits from baseline up to end of treatment. Hospitalization visits 
will also record the number of days on ward and the type of ward (hospital unit) and the 
discharge status. At each HCRU collected, the reason for the visit, i.e. related to CML, AE 
related to CML therapy or other reason, will be collected, in order to quantify the impact of 
treatment on healthcare resources.
HCRU data by treatment arm will be summarized in the primary analysis CSR and the end of 
study treatment CSR, with descriptive statistics (n, mean, median, SD, min, max) for 
quantitative variables, and count and percentage for qualitative variables.
2.13
Biomarkers
As a project standard, Novartis will analyze only biomarkers collected in the clinical database.
For exploratory markers, since the studies are not adequately powered to assess specific
biomarker-related hypotheses, the goal of these exploratory statistical analyses should be
considered as the generation of new scientific hypotheses. No adjustment for multiple
comparisons is usually planned for exploratory analyses. Furthermore, additional post hoc
exploratory assessments are expected and may be performed.
There may be circumstances when  a decision is made to stop sample collection, or not 
perform or discontinue their analysis due to either practical or strategic reasons. Under
such circumstances, the number of samples may be inadequate to perform a rigorous data
analysis and the available data will only be listed and potentially summarized.
If not otherwise specified, the FAS will be used for all biomarker analyses on patients with 
biomarker data.


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Exploratory biomarker objectives

To characterize mutations in the BCR-ABL1 gene at baseline and at end of treatment 
and examine their association with molecular and cytogenetic response for ABL001 
vs bosutinib

To correlate gene expression profiles in leukemic stem cell (LSC)-enriched blood and 
bone marrow with response to ABL001 vs. bosutinib

To characterize the effect of ABL001 vs. bosutinib treatment on CML LSC and 
normal progenitor cells (e.g. growth and differentiation) and their bone marrow 
microenvironment niches

To assess clonal evolution during treatment with ABL001 vs. bosutinib

To evaluate soluble factors that correlate with response to ABL001 vs. bosutinib 
treatment in terms of tumor immunogenicity status
Only some analyses for the first exploratory biomarker objective about BCR-ABL1 mutation
listed above are described here and the results will be included in the respective CSRs. 
Additional analyses for this and other exploratory biomarker objectives will be described in 
separate analyses plans, with results reported separately.
List of biomarkers evaluated and the collection time points
The biomarkers evaluated in the study are listed in Table 2-11 below.
Table 2-11
Sample biomarker summary table
Biomarker
Time point
Sample
Method
Immune markers PD-L1 
and CD8
Screening and 
end of treatment
Bone marrow biopsy
Immunohisto-
chemistry
CD34+ enriched leukemic 
stem cells
Screening, week 
24 and end of 
treatment
Bone marrow aspirate
RNA analysis
Leukemic stem cells
characterization
Screening, week 
24 and end of 
treatment
Bone marrow aspirate
Flow cytometry
BCR-ABL1 gene mutation
W1D1 pre-dose 
and end of 
treatment. If 
mutation is 
present at 
baseline, then 
also every 12 
weeks after 
baseline
Peripheral blood
Sanger 
Sequencing
CD34+ enriched leukemic 
stem cells
W1D1 pre-dose 
and end of 
treatment
Peripheral blood
RNA analysis
Low level mutations in 
BCR-ABL1 gene
W1D1 pre-dose 
and end of 
Peripheral blood
Mass 
spectrometry 


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Biomarker
Time point
Sample
Method
treatment
and NGS
ABL001 mode of action in 
patients treated with 
ABL001: T-cell maturation, 
activation and 
differentiation along with 
maturing myeloid and 
leukemic stem cell panels
W1D1 pre-dose, 
Week 4, 8, 12, 24, 
36, 48, 60, 72, 84, 
96 and end of 
treatment
Peripheral blood
Flow cytometry
Circulating cytokines in 
plasma
W1D1 pre-dose,
Week 48 and end 
of treatment
Peripheral blood
MSD and ELISA
Genetic variant analysis of 
the UGT1A1 gene
W1D1
Peripheral blood
Sanger 
Sequencing
General data handling and preprocessing
For bone marrow samples the latest assessment during screening period will be used as the 
baseline value, while for blood samples the week 1 day 1 (W1D1) pre-dose assessment will be
used as the baseline value.
When more than one biomarker data value are available for a subject at any time point, the 
mean of the replicate values will be used for all statistical analyses.
2.13.1
Somatic mutation biomarker data handling and analysis
Handling of somatic biomarker data
Overall, somatic mutation status (wild type or mutant) will be derived from the mutational 
status of the interrogated exons for the BCR-ABL1 gene by Sanger Sequencing. These
may be non-exclusive and the presence of mutation across more than one exon will be
reported in separate categories.
Mutation summary statistics
All somatic mutation data will be reported using counts and percentages by the mutation type 
in the form of contingency tables with the rows containing the different mutations assayed, 
and the treatment groups in the columns. All the mutation categories for a gene will also be
aggregated into mutant, wild type or missing/unknown groups and counts/percentages will be
reported by these three categories as well. A summary table will be presented for baseline 
mutations and another summary table for post-baseline new mutations (not present at 
baseline).
All the mutation data will be listed for each subject ordered by treatment group.
Association between biomarkers and clinical outcome
This analysis does not adjust for multiple comparisons and results may have higher false 
positive rates.


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The relationship between baseline BCR-ABL1 gene mutation data (wild type or mutant) and 
outcome data (with or without MMR at and by 24 and 96 weeks using FAS, with or without 
CCyR at and by 24 and 96 weeks using CCyR analysis set) will be explored by reporting
contingency tables and by applying a logistic regression including treatment group, baseline 
BCR-ABL1 gene mutation and their interaction as covariates. Treatment group will be
included in this summary table.
In addition, the same analysis will be performed for

the relationship between post-baseline new BCR-ABL1 mutation (with or without 
new mutation) up to 48 weeks and outcome data (with or without MMR at 48 and 96 
weeks using FAS, with or without CCyR at 48 and 96 weeks using CCyR analysis 
set).

the relationship between post-baseline new BCR-ABL1 mutation (with or without 
new mutation) up to end of treatment and outcome data (with or without MMR at 96 
weeks using FAS, with or without CCyR at 96 weeks using CCyR analysis set).
The odds ratios bewteen treatment groups with 95% confidence intervals will be reported, for 
each biomarker category and overall. If treatment by biomarker interaction is significant (e.g.
when p < 0.1), overall odds ratio for treatment will not be reported.
2.14
Other exploratory analyses
MMR rate at 24 weeks
The FAS will be used for the following exploratory analyses:
1. A logistic regression model adjusted for the stratification factor will be fit to assess 
treatment effect. An adjusted odds ratio for the treatment effect with associated 95% 
confidence intervals will be presented. Mantel-Haenszel estimates of the common 
odds ratio and the corresponding 95% confidence interval will also be provided.
2. Based on the subgroups specified in Section 2.2.1, the following analyses will be 
performed for each subgroup:

Proportion of patients with MMR at 24 weeks and its 95% confidence interval 
based on the Pearson-Clopper method within each treatment group

The difference in MMR rate at 24 weeks between treatment groups and the 
corresponding Wald 95% confidence interval
Efficacy analyses in subgroups will be purely exploratory and are intended to explore 
the consistency of treatment effect. Forest plot (n, risk difference, Wald 95% 
confidence interval) will be produced to graphically depict the treatment effect 
estimates in different subgroups. No inferential statistics (p-values) will be 
produced for the subgroups.
3. A logistic regression model adjusted for the stratification factor and other important 
variables identified by the subgroup analyses above will be fit to assess treatment 
effect. An adjusted odds ratio for the treatment effect with associated 95% confidence 
intervals will be presented.


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Association between historical BCR-ABL1 mutations and clinical outcome
The relationship between historical BCR-ABL1 gene mutation data (with or without mutation)
from local lab and outcome data (with or without MMR at and by 24 and 96 weeks using FAS, 
with or without CCyR at and by 24 and 96 weeks using CCyR analysis set) will be explored
by reporting contingency tables and by applying a logistic regression including treatment 
group, baseline BCR-ABL1 gene mutation and their interaction as covariates. Treatment
group will be included in this summary table.
Influence of early molecular response levels on long term molecular response 
levels
The relationship between MMR status at 24 weeks and MMR status at 48 and 96 weeks will
be explored using FAS by reporting contingency tables and by applying a logistic regression
including treatment group, MMR status at 24 weeks and their interaction as covariates. 
Treatment group will be included in this summary table. The odds ratios between treatment 
groups with 95% confidence intervals will be reported, for each category of MMR status at 24 
weeks and overall. If the interaction of treatment by MMR status at 24 weeks is significant
(e.g. when p < 0.1), overall odds ratio for treatment will not be reported.
2.15
Interim analysis
No formal interim analysis is planned for this trial.
3
Sample size calculation
3.1
Primary analysis
To test the null hypothesis that the MMR rate at 24 weeks is equal in the two treatment arms, 
based on  two-sided 5% level of significance and with 90% power, 222 patients will be 
needed in total (i.e. 148 patients in the ABL001 arm and 74 patients in the bosutinib arm 
based on 2:1 randomization allocation). The calculations were made using the software 
package PASS (2008).
It is assumed that ABL001 leads to a 20% improvement in the MMR rate at 24 weeks over 
bosutinib from 15% to 35% which corresponds to an odds ratio of 3.05. The assumed 
bosutinib MMR rate of 15% at 24 weeks is based on previous trials evaluating bosutinib 
therapy ([Kuoury et al. 2012], [Gambacorti-Passerini et al. 2014], [García-Gutiérrez et al. 
2015]).


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3.2
Power for analysis of key secondary variables
If the primary analysis of MMR rate at 24 weeks is statistically significant, then the key 
secondary endpoint MMR rate at 96 weeks will be tested, with the overall alpha controlled at 
the 5% two-sided level using a gatekeeping strategy.
Table 3-1 below summarizes the treatment effects of the key secondary endpoint which can be 
detected with 80% and 90% power, based on the specified assumptions regarding the 
bosutinib effect. The calculations were made using the software package PASS (2008).
Table 3-1
Detectable effect sizes for key secondary endpoint
Endpoint
Anticipated effect 
with bosutinib
2-sided alpha
Power
Detectable effect 
size§
MMR rate at 96 weeks
30%*
0.05
90%
80%
≥ 23%
≥ 20%
*: [Gambacorti-Passerini et al. 2014], Figure 1D.
§: Absolute difference from the anticipated effect with bosutinib.
For MMR rate at 96 weeks, if the anticipated effect with bosutinib is 30%, then the given 
sample size with 2-sided alpha=0.05 would allow to detect an absolute difference of at least 
23% (i.e. MMR rate at 96 weeks with ABL001 is at least 53%) for 90% power and of at least 
20% (i.e. MMR rate at 96 weeks with ABL001 is at least 50%) for 80% power.
4
Change to protocol specified analyses
No change from protocol specified analysis was 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 
treatment 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


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
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 treatment 
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 treatment start date then 
o
If stop date contains a full date and stop date is earlier than study 
treatment start date then set start date = 01JanYYYY
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than study 
treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment 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, withdrawl 
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. 


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5.1.2.1
Other imputations
Incomplete date of initial diagnosis of cancer 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 
01-Jan. 
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 4.03. 
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 4.03. 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 v4.03 at the time of analysis will be 
used. For laboratory tests where grades are not defined by CTCAE v4.03, 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 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). 


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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.
5.4
Derivation of PCR results and loss of response
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.  
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


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MMR
Yes 
≤ 0.1%
≥ 3-log reduction
No
> 0.1%
< 3-log reduction
MR4.5
Yes 
≤ 0.0032%
≥ 4.5-log reduction
No
> 0.0032%
< 4.5-log reduction
Loss of MMR is defined in Section 2.7.1.1.
5.5
Statistical models
5.5.1
Primary analysis
The null hypothesis of equality of MMR rate at 24 weeks in the two treatment arm s will be 
tested against two-sided alternative. The statistical hypotheses are:
H0: RA24wk = RB24wk versus HA: RA24wk ≠ RB24wk, for a two-sided test
where RA24wk is the probability of MMR rate at 24 weeks in ABL001 arm and RB24wk is the 
probability of MMR rate at 24 weeks in bosutinib arm.
The Cochran-Mantel-Haenszel chi-square test X2
CMH (implemented via SAS procedure
FREQ with CMH option in the TABLES statement) will be used to test the difference in
response rates between the treatment arms. The p-value corresponding to the CMH test for 
“general association” will be used which follows a Chi-square distribution with one degree of 
freedom.
The 95% confidence interval for the difference in MMR rate at 24 weeks between treatment 
groups will be provided using the Wald method (implemented via SAS procedure FREQ
with RISKDIFF option in the TABLES statement, under the default METHOD=WALD and 
VAR=SAMPLE). If the 2×2 table is with ABL001 in row 1, bosutinib in row 2, MMR in 
column 1 and No MMR in column 2, then the SAS output will give the estimate of (risk 
for MMR at 24 weeks in ABL001 – risk for MMR at 24 weeks in bosutinib). The 
corresponding Mantel-Haenszel estimate of common risk difference and 95% confidence 
interval will also be presented (with RISKDIFF(COMMON) option in the TABLES
statement, taking the Mantel-Haenszel estimate from the SAS output table).
If the sampling assumptions for chi-square test is not met (i.e. the expected frequencies
should exceed 5 for all of table cells), the exact Cochran-Mantel-Haenszel test will be used 
(implemented via SAS procedure MULTTEST). The test is performed by running a stratified
version of the Cochran-Armitage permutation test [Armitage et al. 1969]. In studies with
stratified randomization, the chi-square approximation is considered appropriate for the 
X2
CMH statistics if the rule of Mantel and Fleiss [Mantel and Fleiss 1980] is satisfied.
Confidence interval for MMR rate within each treatment arm
MMR will be summarized in terms of percentage rates with 95% confidence interval
using exact binomial confidence interval (implemented using SAS procedure FREQ with
EXACT statement for one-way table [Clopper and Pearson 1934]).


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5.5.2
Key secondary analysis
The null hypothesis of equality of MMR rate at 96 weeks in the two treatment arms will be 
tested against two-sided alternative. The statistical hypotheses are:
H0: RA96wk = RB96wk versus HA: RA96wk ≠ RB96wk, for a two-sided test
where RA96wk is the probability of MMR rate at 96 weeks in ABL001 arm and RB96wk is the 
probability of MMR rate at 96 weeks in bosutinib arm.
The same approaches as for the primary endpoint (Section 5.5.1) will be applied here for the 
Cochran-Mantel-Haenszel chi-square test X2
CMH, the 95% Wald confidence interval for the 
difference in MMR rate at 96 weeks between treatment groups, the Mantel-Haenszel
estimate of common risk difference with 95% confidence interval, and the confidence 
interval for MMR rate within each treatment arm.
Multiplicity adjustment
Formal statistical testing of the key secondary endpoint will be performed with = 0.05 (two-
sided) only if the primary endpoint is significant by means of a gatekeeping procedure to 
control the overall alpha level.
5.5.3
Other analyses
Mantel-Haenszel common odds ratio
To obtain Mantel-Haenszel estimates of the common odds ratio and the corresponding 95% 
confidence interval in exploratory analyses,  it requires SAS procedure FREQ with CMH and 
RELRISK options in the TABLES statement. 
Logistic Regression 
Odds ratio will be used as a measure of association between treatment and response in 
exploratory analyses (Section 2.14). The odds ratio will be derived from the logistic
regression model (implemented using SAS procedure LOGISTIC, with treatment specified
as an explanatory variable in the CLASS statement) which allows for including not only
the stratification factor but also for adjustments for other covariates (both categorical and
continuous). The odds ratio will be presented with 95% Wald confidence limits.
In cases where an exact test has been used to compare response rates, the odds ratio should be 
determined using exact logistic regression, and the odds ratio presented with exact 95% 
confidence limits. In these cases, SAS PROC LOGISTIC with EXACTONLY option will be 
used.
Kaplan-Meier estimates
An estimate of the survival function in each treatment group will be constructed using
Kaplan-Meier
(product-limit) method
as implemented
in
PROC
LIFETEST
with


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METHOD=KM
option. The
PROC
LIFETEST
statement
will
use
the
option
CONFTYPE=LOGLOG.
Median survival for each treatment group will be obtained along with 95% confidence 
intervals calculated from PROC LIFETEST output using the method of [Brookmeyer and 
Crowley 1982]. Kaplan-Meier estimates of the survival function with 95% confidence
intervals at specific time points will be summarized. The standard error of the Kaplan-
Meier estimate will be calculated using Greenwood’s formula [Collett 1994].
Hazard ratio
Hazard ratio will be estimated by fitting the Cox proportional hazards model using SAS 
procedure PHREG (with TIES=EXACT option in the MODEL statement). 
A stratified unadjusted Cox model will be, i.e. the MODEL statement will include the
treatment group variable as the only covariate and the STRATA statement will include
stratification variable(s). Hazard ratio with two-sided 95% confidence interval will be based 
on Wald test.
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.


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CABL001A2301


Clinical Development
ABL001/asciminib
CABL001A2301
A phase 3, multi-center, open-label, randomized study of 
oral ABL001 (asciminib) versus bosutinib in patients with 
Chronic Myelogenous Leukemia in chronic phase (CML-
CP), previously treated with 2 or more tyrosine kinase 
inhibitors
Statistical Analysis Plan (SAP) – Amendment 3
Author:
Statistician, 
Document type:
SAP Documentation
Document status:
Final Amendment 3
Release date:
10-August-2020
Number of pages:
73
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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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)
25-
Aug-
2017
Prior 
to 
DB 
lock
for 
primary 
analysis
Creation 
of 
final version
N/A - First version
NA
26-
Mar-
2020
Prior 
to 
DB 
lock 
for 
primary 
analysis
Implementation 
of 
protocol 
amendments 2 
and 3. 
ABL001 has been replaced by 
International Nonproprietary 
Name (INN) asciminib.
Introduction of the switch to 
asciminib option for patients 
experiencing treatment failure 
on bosutinib treatment
Update of the definition of 
end of study treatment
Added a potential End-of-
Study-Treatment analysis 
different from the 96-week 
analysis
Addition/removal of
secondary safety objectives 
and exploratory efficacy 
objectives
Throughout the 
SAP amendment
Section 
 
1.1, 
Figure 
1-1
Sections 2.1, 2.3
Analyses added 
throughout 
the 
document
Section 1.1
Table 1-1
Additional 
analyses, 
clarification
Clarification on which data are 
included in 
the analyses, 
which 
assessments 
are 
considered for safety
and 
efficacy analyses
Addition of the treatment arms 
and definition of the date of 
end 
of 
study 
treatment
Removal of windows defined 
for ECGs, LVEF and PK 
assessments as they are not 
needed.
Section 
2.1
Section 
2.1.1


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As per Health Authorities 
request, 
addition 
of 
the 
breakdown per different time 
points of the number (%) of 
patients who discontinued the 
study treatment phase and of 
the primary reason for study 
treatment 
phase 
discontinuation
PAS: 
Removal 
of 
the 
condition related to vomiting
to consider a concentration 
evaluable as the occurrence 
and time of vomiting is not 
collected in the CRF.
Addition 
of 
a
subgroup 
“Stratum reported in the CRF” 
for the analysis by subgroup of 
the primary endpoint (to take 
into 
account 
the 
mistratification cases)
Removal of the subgroup 
“with or without historical 
BCR-ABL1 mutation by local 
lab” as this is not considered 
clinically relevant
Additional analyses of prior 
TKI 
and 
non 
TKI 
antineoplastic therapies
Implementation 
of 
the 
estimand language for the 
primary and key secondary 
objectives
Addition 
of 
a 
sensitivity 
analysis 
of 
the 
primary 
estimand stratifying by the 
stratum recorded in the CRF to 
take into account that many 
stratification errors occurred
Addition of 
Time-to-event 
analyses for time to MMR and 
time to CCyR
Section 
2.3.1
Section 2.2
Section 
2.2.1
Section
2.4.2
Sections 2.5 and 
2.6
Section 
2.5.5
Section 
2.7.2


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Added how time is censored 
for time to MMR/CCyR, 
clarification on how to handle 
missing BMA assessments 
due to MMR being achieved
Added analyses AEs and 
SAEs 
incidence 
rates 
by 
adjusting for exposure and by 
reporting by time intervals to 
account 
for 
potential 
difference 
in 
exposure 
between the treatment arms
Clarified 
handling 
of 
unscheduled 
ECG 
measurements in the analyses 
Section 
2.7.3
Section 
2.8.1
Section 2.8.4.1
4-
June-
2020
Prior 
to 
DB 
lock 
for 
primary 
analysis
Creation 
of 
amendment 2.0
Clarified 
baseline 
for 
mutations
Clarified EOT is mapped to 
defined time points
Modified age subgroup, added 
Line of therapy subgroup and 
moved Without T315I/V299L 
to 
Supplementary 
analysis
(All 
patients 
with 
T315I/V299L 
mutations 
identified at the Week 1 Day 1 
visit are discontinued from 
study treatment when the 
mutation 
results 
become 
available).
Clarified Mutation subgroup 
doesn’t include T315I/V299L 
mutations.
Modified age categories
Added COVID-19 related PDs 
analysis
Added definitions of time on 
treatment, 
duration 
of 
exposure in patient-years and 
average daily dose
Section 
2.1.1
Section 
2.2.1
Section 2.3
Section 
2.3.1
Section 
2.4.1


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Additional analyses of prior 
TKI therapy
Added 
summary 
of 
concomitant therapies for on-
switched treatment period.
Added COVID-19 sensitivity 
analyses for the primary and 
key secondary endpoints
Added 
a 
supplementary 
analysis 
to 
the 
primary 
endpoint
(Patients 
without 
T315I/V299L mutations at 
Week 1 Day 1 visit)
Added new graph for Ctrough 
values of asciminib
Updated the list of changes to 
the protocol specified analyses
Added imputation rules for 
immature cells
Removed imputation rules for 
corrected calcium as corrected 
calcium is collected
Clarified all available values 
for BUN and UREA will be 
reported under the parameter 
name BUN in listing to avoid 
double reporting of same 
information
Definition of loss of MMR: 
Removed 
reference 
to 
confirmation 
of
loss 
of 
CHR/CCyR
Loss 
of 
CHR: 
clarified 
“Progressive 
splenomegaly 
refractory to therapy” is ≥ 5cm
below left intercostal margin”
Implemented 
change 
to 
definition of treatment failure 
(Protocol amendment 3)
Section 
2.4.2
Sections 
2.5.5, 
2.6.5
Section 
2.5.6
Section 
2.9
Section 
4
Section 
5.3
Section 
5.4.1
Section 
5.4.3
Section 
5.4.4
Section 
5.4.5 


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Clarified 
what 
“Thrombocytopenia (<100 x 
109/L) that is unrelated to 
therapy” is.
Added derivation of response 
rates and categories section
Section 5.5.
7-
Aug-
2020
Prior 
to 
DB 
lock 
for 
primary 
analysis
Creation 
of 
amendment 3.0
after FDA type 
C 
teleconference 
on 28 July 2020
As agreed with FDA, added 
sensitivity analyses of the 
primary and key secondary 
endpoints
without 
the 
imputation rule used in the 
main analyses
in case of 
missing PCR evaluations at 
24/96 weeks. 
Per 
FDA 
request, 
added 
another subgroup of interest: 
BCR-ABL ratio at baseline ≥
1% or <1%.
Added calculation rules for 
duration of interrruption.
Added derivation rule for 
corrected calcium using the 
reported total calcium value 
and albumin.
Aligned the definition of loss 
of CCyR with the definition of 
loss of CHR by adding the 
requirement that loss of CCyR 
(Ph+ bone marrow cells to > 
0%) must have led to treatment 
discontinuation because of 
lack of efficacy.
Section 
2.5.5
Section 
2.2.1
Section 
2.4.1
Section 
5.3
Section 5.4.2


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Table of contents
Table of contents .................................................................................................................7
1
Introduction .......................................................................................................................12
1.1
Study design...........................................................................................................12
1.2
Study objectives and endpoints .............................................................................13
2
Statistical methods.............................................................................................................15
2.1
Data analysis general information .........................................................................15
2.1.1
General definitions................................................................................17
2.2
Analysis sets ..........................................................................................................25
2.2.1
Subgroup of interest ..............................................................................26
2.3
Patient disposition, demographics and other baseline characteristics ...................28
2.3.1
Patient disposition.................................................................................29
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................31
2.4.1
Study treatment / compliance................................................................31
2.4.2
Prior, concomitant and post therapies...................................................33
2.5
Analysis of the primary objective/estimand ..........................................................35
2.5.1
Primary endpoint/estimand ...................................................................36
2.5.2
Statistical hypothesis, model, and method of analysis..........................36
2.5.3
Handling of remaining intercurrent events of primary estimand..........36
2.5.4
Handling of missing values not related to intercurrent event ...............36
2.5.5
Sensitivity analyses ...............................................................................36
2.5.6
Supplementary analyses........................................................................37
2.6
Analysis of the key secondary objective/estimand................................................37
2.6.1
Key secondary endpoint/estimand ........................................................38
2.6.2
Statistical hypothesis, model, and method of analysis..........................39
2.6.3
Handling of remaining intercurrent events of primary estimand..........39
2.6.4
Handling of missing values not related to intercurrent event ...............39
2.6.5
Sensitivity analysis................................................................................39
2.7
Analysis of secondary efficacy objective(s)..........................................................39
2.7.1
Secondary endpoints .............................................................................39
2.7.2
Statistical hypothesis, model, and method of analysis..........................42
2.7.3
Handling of missing values/censoring/discontinuations.......................44
2.8
Safety analyses.......................................................................................................45
2.8.1
Adverse events (AEs)............................................................................45
2.8.2
Deaths....................................................................................................46


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2.8.3
Laboratory data .....................................................................................47
2.8.4
Other safety data ...................................................................................48
2.8.5
Additional Analyses..............................................................................50
2.9
Pharmacokinetic endpoints....................................................................................50
2.10
PD and PK/PD analyses.........................................................................................52
2.11
Patient-reported outcomes .....................................................................................52
2.11.1
MDASI-CML........................................................................................53
2.11.2
EQ-5D-5L .............................................................................................53
2.11.3
WPAI-CML...........................................................................................54
2.11.4
PGIC......................................................................................................54
2.12
Resource utilization ...............................................................................................55
2.13
Biomarkers.............................................................................................................55
2.13.1
Somatic mutation biomarker data handling and analysis......................57
2.14
Other exploratory analyses ....................................................................................58
2.15
Interim analysis......................................................................................................59
3
Sample size calculation .....................................................................................................60
3.1
Primary analysis.....................................................................................................60
3.2
Power for analysis of key secondary variables......................................................60
4
Change to protocol specified analyses ..............................................................................60
5
Appendix ...........................................................................................................................61
5.1
Imputation rules.....................................................................................................61
5.1.1
Study drug.............................................................................................61
5.1.2
AE, ConMeds and safety assessment date imputation..........................61
5.2
AEs coding/grading ...............................................................................................63
5.3
Laboratory parameters derivations ........................................................................63
5.4
Efficacy variables ..................................................................................................65
5.4.1
Molecular response ...............................................................................65
5.4.2
Cytogenetic response ............................................................................66
5.4.3
Hematologic response ...........................................................................67
5.4.4
Treatment Failure..................................................................................68
5.4.5
CML progression to accelerated phase (AP) or blast crisis (BC) .........69
5.4.6
CML-related deaths...............................................................................69
5.4.7
Disease progression...............................................................................69
5.4.8
Overall survival.....................................................................................69
5.5
Derivation of response rates and categories ..........................................................70
5.5.1
Response rate at a specific time point...................................................70


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5.5.2
Response rate by a specific time point (best response).........................70
5.6
Statistical models...................................................................................................70
5.6.1
Primary analysis....................................................................................70
5.6.2
Key secondary analysis.........................................................................71
5.6.3
Other analyses .......................................................................................71
5.6.4
Calculation of exposure-adjusted incidence rate...................................72
6
Reference...........................................................................................................................73


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List of abbreviations
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AP
Accelerated phase
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic classification
AUC
Area under the curve
BC
Blast crisis
bid
bis in diem/twice a day
CCyR
Complete cytogenetic response
CHR
Complete hematologic response
CMH
Cochrane-Mantel-Haenszel
CML
Chronic myelogenous leukemia
CML-CP
Chronic myelogenous leukemia in chronic phase
CRO
Contract research organization
CSP
Clinical study protocol
CSR
Clinical study report
CTCAE
Common terminology criteria for adverse events
CV
Coefficient of variation
DAR
Dosage administration record
DI
Dose intensity
DMC
Data monitoring committee 
DRL
Drug reference  listing
DSUR
Development safety update report
ECG
Electrocardiogram
eCRF
Electronic case report form
EOT
End of treatment in the treatment phase (patient level)
EOsT
End of study treatment (study level)
ER
Emergency room
FAS
Full analysis set
FD
First dose date of study treatment during the treatment phase
FDswitch
First dose date of asciminib during the treatment switch phase
GP
General practitioner
H
Hospitalization
HCRU
Health care resource utilization
HLT
High level term
HLGT
High level group term
IRT
Interactive response technology
IS
International scale
LD
Last dose date of study treatment during the treatment phase
LDswitch
Last dose date of asciminib during the treatment switch phase


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LLOQ
Lower limit of quantitation
LPFT
Last patient first treatment
LSC
Leukemic stem cell
LVEF
Left ventricular ejection fraction
MCyR
Major cytogenetic response
mCyR
Minor cytogenetic response
MedDRA
Medical dictionary for regulatory activities
MMR
Major molecular response
NCI
National Cancer Institute
NGS
Next generation sequencing
NMQ
Novartis MedDRA Query
OS
Overall survival
PAS
Pharmacokinetic analysis set
PCR
Polymerase chain reaction
PCyR
Partial cytogenetic response
PD
Pharmacodynamic
PDI
Planned dose intensity
PFS
Progression-free rurvival
Ph+
Philadelphia chromosome positive
PK
Pharmacokinetics
PPS
Per-protocol set
PRO
Patient-reported outcomes
PSUR
Periodic safety update report
PT
Preferred term
qd
Qua’que di’e / once a day
RDI
Relative dose intensity
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
S-EoT
End of treatment in the treatment switch phase (patient level)
SMQ
Standardized MedDRA query
SOC
System organ class
Sp
Specialist
TBL
Total bilirubin
TKI
Tyrosine kinase inhibitor
TTF
Time to treatment failure
UC
Urgent care
ULN
Upper limit of norm
VAS
Visual analogue scale
W1D1
Week 1 Day 1
WBC
White blood cells
WHO-DD
World Health Organization Drug Dictionary


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses of primary objective,
secondary objectives and selected exploratory objectives for the clinical study reports (CSR) of 
study CABL001A2301, a phase 3, multi-center, open-label, randomized study of oral asciminib
versus bosutinib in patients with Chronic Myelogenous Leukemia in chronic phase (CML-CP), 
previously treated with 2 or more tyrosine kinase inhibitors. 
The content of this SAP is based on protocol CABL001A2301 version 03. All decisions 
regarding safety monitoring analysis for the data monitoring committee, 24-week primary
analysis, 96-week analysis, end of study treatment analysis, 5-year progression-free survival 
(PFS)/overall survival (OS) update analysis, and postings for ClinTrial.gov and EudraCT, as 
defined in this SAP document, have been made prior to the first database lock of the study data
for the primary analysis.
1.1
Study design
This is a randomized,  Phase III , open-label,  active-controlled, multi-center study  comparing  
safety and efficacy of asciminib to bosutinib in patients with CML-CP, previously treated with 
2 or more tyrosine kinase inhibitors (Figure 1-1). Approximately 220 patients will be 
randomized to one of the following treatment arms in 2:1 ratio:

asciminib 40 mg BID

Bosutinib 500 mg QD
Randomization will be stratified by the following factor: cytogenetic response status (with or 
without major cytogenetic response).
Figure 1-1
Schematic of Study Design
Patients with documented treatment failure (as per the 2013 ELN guidelines, Baccarani et al 
2013) while on bosutinib treatment will have the option to switch to asciminib treatment within 


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96 weeks after the last patient has been randomized on study. The patients who switch to 
asciminib will be able to receive asciminib up to the end of study treatment (EOsT) period.
Patients will be treated up to the EOsT defined as up to 96 weeks after the last patient received 
the first study dose (LPFT) or up to 48 weeks after the last patient has switched to asciminib 
treatment whichever is longer, if they do not discontinue study treatment earlier. After the EOsT, 
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.
Major Molecular Response (MMR) rate at 24 weeks is the primary endpoint in this study. MMR 
rate at 96 weeks is the key secondary endpoint.
Four analyses are planned for this study, including the 24-week primary analysis, the 96-week 
analysis, the End-of-Study-Treatment (EOsT) analysis, and Progression-Free survival/Overall 
survival (PFS/OS) update analysis The timing when those analyses are conducted is 
summarized in Section 2.1. 
No formal interim efficacy analysis is planned in this study. A data monitoring committee 
(DMC) will monitor unblinded safety data approximately 6 months after the first randomized 
patient has started study treatment. Subsequent reviews will be conducted approximately every 
6 months and when needed thereafter (ie. if significant safety findings are noted) until the 
primary analysis.
1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Primary
To compare the MMR rate at 24 weeks of
asciminib versus bosutinib 
Major Molecular Response (MMR) rate at 24 weeks
Key secondary
To compare additional parameters of the 
efficacy of asciminib versus bosutinib 
MMR rate at 96 weeks
Other secondary
To compare additional parameters of the 
efficacy of asciminib versus bosutinib

Cytogenetic response rate (Complete, Partial, Major, 
Minor, Minimal, no response) at and by all scheduled 
data collection time points including 24, 48 and 96 weeks

MMR rate at all scheduled data collection time points  
(except 24 and 96 weeks which are already covered by 
primary and key secondary endpoints)

MMR rate by all scheduled data collection time points 
including 24, 48 and 96 weeks

Time to MMR

Duration of MMR

Time to CCyR

Duration of CCyR

Time to treatment failure

Progression free survival


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Objective
Endpoint

Overall survival
To compare the safety and tolerability 
profile of asciminib versus bosutinib
Type, frequency and severity of adverse events,
changes in laboratory values that fall outside the pre-
determined ranges and clinically notable ECG and other 
safety data (vital signs)
To characterize the PK of asciminib in the 
CML-CP population
Trough plasma concentrations,
PK parameters in full PK group: Cmax, Tmax, AUC0-12h, 
CL/F 
To assess the safety of asciminib when 
administered as treatment after bosutinib 
failure according to the 2013 ELN 
Guidelines
Type, frequency and severity of adverse events, changes in 
laboratory values that fall outside the pre-determined ranges 
and clinically notable ECG and other safety data (vital signs)


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Objective
Endpoint
Exploratory
To evaluate the influence of factors such 
as cytogenetic response at baseline, 
failure/intolerance to prior TKIs, line of 
therapy, gender, race and age on the 
effect of asciminib with respect to the 
primary efficacy endpoint 
Major Molecular Response (MMR) rate at 24 weeks
To explore the exposure-response 
relationships of asciminib; evaluate the 
effect of population covariates
Exposure-safety, exposure-PD analyses
To characterize mutations in the BCR-
ABL1 gene at Week 1 Day 1, upon 
confirmed loss of MMR and/or at end of 
treatment and examine their association 
with molecular and cytogenetic response 
for asciminib vs bosutinib
BCR-ABL1 gene mutations at Week 1 Day 1, upom confirmed 
loss of MMR and/or at end of treatment as determined by 
Sanger Sequencing
To understand biology of CML and bone 
marrow microenvironment on leukemic 
stem cells (LSCs) eradication, including 
patients’ immunogenicity
Bone marrow biopsies characterization for adaptive immune 
response by immunohistochemistry (IHC); bone marrow 
aspirates to evaluate the effect of treatments on LSCs burden 
and immune cells subsets changes by flow cytometry
To assess clonal evolution during 
treatment with asciminib vs. bosutinib
Low level BCR-ABL1 mutation profiles assessed by mass 
spectrometry at Week 1 Day 1, upon confirmed loss of MMR
and/or at EOT.  
Clonal evolution of several genes implicated in CML assessed 
by Next Generation Sequencing (NGS) methods 
To evaluate soluble/inflammarory factors 
that correlate with response to asciminib
vs. bosutinib treatment
Baseline and changes from baseline of cytokine expression in 
plasma  
To compare the impact of treatment on 
patient reported outcomes (PRO) 
including CML-specific symptoms, patient 
quality of life, and impact on work 
productivity and activity impairment from 
baseline and EOT between  treatment 
arms in all patients
Change in symptom burden and interference from baseline 
over time according to the MDASI-CML PRO instrument
Change in patient’s impression of CML symptoms according 
to Patient Global Impression of Change (PGIC)
Change in health utility from baseline over time according to 
EQ-5D-5L
Change in work productivity and activity impairment over time 
according to WPAI
To compare the impact of treatment on 
health care resource utilization between 
treatment arms in all patients
Health care resource burden over time
2
Statistical methods
2.1
Data analysis general information
The planned analyses will be performed by Novartis and/or a designated CRO. SAS version 9.4 
or later will be used to perform all data analyses and to generate tables, figures and listings.
There is no planned interim efficacy analysis. Prior to the database lock for the primary analysis, 
tables and figures aggregated by treatment arm for safety data review by the data monitoring 
committee or for other reporting activities will be produced by an independent statistician and 
independent statistical programmers.


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For between-treatment comparisons of efficacy endpoints, randomization stratification factor, 
i.e. cytogenetic response status (MCyR vs no MCyR) at screening, will be included in respective
stratified statistical tests.
Data included in the analyses
The analysis data cut-off dates for the planned analyses are:

Primary analysis: After all randomized patients have been on study treatment for 24
weeks or  discontinued earlier, i.e., LPFT + 24 weeks. 

96-week analysis: After all randomized patients have been on study treatment for 96
weeks or  discontinued earlier, i.e., LPFT + 96 weeks

End of study treatment analysis: 30 days after the EOsT. (Note: After the study 
treatment period, the assigned study treatment will be made available, may be outside 
of this study, to patients who in the opinion of the investigators are still deriving 
clinical benefit.) 

PFS/OS update analysis: 5 years from the date when the last randomized patient 
received the first study dose (irrespective of treatment switch for patients failing 
bosutinib).
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. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
by treatment group; a missing category will be included as applicable. Percentages will be
calculated using the number of patients in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum) by treatment group.
For pharmacokinetics (PK) concentration and parameters descriptive statistics also include 
coefficient of variation (CV)%, geo-mean and geo-CV%.


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2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, will refer to the asciminib only. Whereas, study treatment will refer to
asciminib or control treatment, i.e. bosutinib, received during the treatment phase. Switched 
treatment will refer to asciminib received during treatment switch phase.
Treatment arms

Asciminib (Subjects randomized to asciminib arm at the beginning of the study)

Bosutinib (Subjects randomized to bosutinib arm at the beginning of the study)
Date of end of study treatment (EOsT)
The EOsT date is the date that the study treatment is ended for the entire study. On this date, 
patients are treated for at least 96 weeks if they are not eligible to switch study treatment or are 
treated for at least 48 weeks after they have switched to asciminib treatment, unless patients 
have discontinued study treatment earlier
Date of first administration of randomized study treatment 
The date of first administration of randomized study treatment (FD) is derived as the first date 
when a non-zero dose of study treatment was administered as per the Dosage Administration
Record (DAR) electronic case report form (eCRF). The date of first administration of study 
treatment will also be referred as start of study treatment.
The date of first administration of randomized study treatment is the same as the date of first 
administration of investigational drug or control drug.
Date of first administration of switched treatment 
For subjects switching from bosutinib to asciminib, the date of first administration of switched 
treatment (FDswitch) is derived as the first date when a non-zero dose of asciminib was 
administered as per the DAR eCRF. The date of first administration of switched treatment 
(asciminib) will also be referred as start of switched treatment.
Date of last administration of randomized study treatment 
The date of last administration of randomized study treatment (LD) is defined as the last date 
when a non-zero dose of study treatment was administered as per DAR eCRF. For subjects 
switching from bosutinib to asciminib, this includes the dose of bosutinib administered as 
bridging therapy between their treatment failure and the first dose of asciminib administered.
The date of last administration of randomized study treatment is the same as the date of last 
administration of investigational drug or control drug.


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Date of last administration of switched treatment 
The date of last administration of switched treatment (LDswitch) is defined as the last date when 
a non-zero dose of switched treatment (asciminib) was administered as per DAR eCRF.
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:

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, PK, etc.) is the start of study treatment.
The reference start date for all other, non-safety assessments (e.g. molecular response, survival 
time, disease progression, ECOG performance status, patient reported outcomes (PRO), etc.) is
the date of randomization.
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.
Switch study day
The switch study day, describes the day of the event or assessment date, relative to the start of 
switched treatment.
Switch study day = date of event – start of switched treatment + 1, if event is on or after the
start of switched treatment
Switch study day = date of event – start of switched treatment, if event precedes the start of
switched treatment
The switch study day will be displayed in the data listings if an event starts on or after the start 
of switched treatment.
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 
divided by 7.
Baseline for the treatment period
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of randomization is taken as “baseline” value or “baseline” assessment. In 


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the context of baseline definition, the efficacy evaluations also include PRO and performance 
status. 
For safety evaluations, the last available assessment, including unscheduled assessments before 
the date of start of study treatment 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 theses 
measurements would be calculated for baseline (if not already available in the database).
For mutations, the Week 1 Day 1 assessment is taken as “baseline” assessment.
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.
Baseline for the treatment switch period
For subjects switching from bosutinib to asciminib, the last non-missing assessment, including
unscheduled assessments before the date of first administration of asciminib is taken as
‘‘baseline” assessment for the switched treatment period, and denoted as baseline_switch for 
short.
On-treatment assessment/event and observation periods
For adverse event reporting the overall observation period will be divided into three mutually 
exclusive segments for subjects without treatment switching and into up to five mutually 
exclusive segments for subjects switching treatment: 
For subjects without treatment switching:
1. pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment (FD)
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last actual administration of study treatment (including start and stop date) (LD). 
Note: Patients will be treated up to the end of study treatment period (EOsT). This will 
be the last actual administration of study treatment for each patient if the patient has not 
discontinued study treatment earlier. On this date, all patients without treatment 
switching will have been treated for at least 96 weeks unless patients have discontinued 
study treatment earlier. After this period, the assigned study treatment will be made 
available, may be outside of this study, to patients who in the opinion of the investigators 
are still deriving clinical benefit.
3. post-treatment period: starting at day 31 after last administration of study treatment.
For subjects with treatment switching from bosutinib to asciminib:


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1. pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment (FD)
2. on-treatment period: from date of first administration of study treatment to either the 
day before the first administration of asciminib (FDswitch) or  30 days after the date of 
last actual administration of bosutinib (LD), whichever comes first. 
3. post-treatment period: from day 31 after last administration of bosutinib to the day 
before  the first administration of asciminib (FDswitch). If the end date is before the start 
date, this period is not applicable.
4. on-switched treatment period: from date of first administration of asciminib (FDswitch) 
to 30 days after date of last actual administration of asciminib (LD switch).
NOTE: Subjects are treated in the study up to end of study treatment period (EOsT). 
On this date, all subjects with treatment switching will have been treated for at least 48 
weeks after switching unless they have discontinued the switched treatment earlier.
5. Post-switched treatment period: from day 31 after last actual administration of
asciminib (LD switch). 
If dates are incomplete in a way that clear assignment to pre-, on-, post-, on-switched-, post-
switched-treatment period cannot be made, then the respective data will be assigned to the on-
treatment period.
Safety summaries (tables, figures) on the Safety set (respectively on the Switch Analysis Set) 
include only data from the on-treatment (resp. on-switched treatment) period with the exception 
of baseline data which will also be summarized where appropriate (e.g. change from baseline 
summaries). In particular, summary tables for adverse events (AEs) will summarize only on-
treatment (resp. on-switched treatment) events, with a start date during the on-treatment (resp. 
on-switched treatment) period (treatment-emergent AEs) (resp. switched-treatment-emergent 
AEs). In addition, a separate summary for death including on-treatment and post-treatment 
deaths will be provided.
However, all safety data (including those from the pre-treatment, post-treatment and post-
switched treatment period) will be listed and flagged as appropriate.
Efficacy summaries on the FAS (apart from OS and PFS) include data from baseline up to either 
the last assessment on or before the EoT visit or before or on treatment failure, whichever is the 
earliest.
Efficacy summaries on the Switch Analysis Set include data from baseline_switch up to the last 
assessment on or before the S-EoT visit or before or on treatment failure during the switched
treatment period, whichever is the earliest.
The efficacy assessments collected post-treatment failure, post-EoT or post S-EoT visit are not 
included in any efficacy analyses (except for OS and PFS analyses). However, they will be 
listed and flagged as appropriate.


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Windows for multiple assessments 
Data such as molecular response, cytogenetic response collected over time (including 
unscheduled visits) will be summarized by scheduled time point. As patients do not always 
adhere to the visit schedule, visits will be remapped according to visit windows defined in 
Tables 2-1 to Table 2-4 of this document to enable by-visit analysis. Only those protocol-
defined visits will have the visit window defined. Each assessment (including the end of 
treatment assessment), either scheduled or unscheduled, will have a mapped visit assigned, as 
long as study day is available, according to the defined visit window up to the date with data 
included. 
If more than one assessment is assigned to the same time window, the assessment performed 
closest to the target date will be used for by-visit statistical analyses. If 2 assessments within a 
visit window are equidistant from the target date, then the average of the 2 assessments will be 
used. If multiple assessments on the same date, then the the average will be used. Data from all 
assessments (scheduled and unscheduled), including multiple assessments, will be listed.
Table 2-1
Time windows for molecular response
Assessment
Target day of assessment
Time Interval
Baseline
≤1
≤ Day 1#
Week 4
29
Day 2 to day 43
Week 8
57
Day 44 - 71
Week 12
85
Day 72 - 99
Week 16
113
Day 100 to day 141
Week 24
169
Day 142 to day 211
Week k (k=36, 48, …)
kx7 + 1
Day kx7-40 – kx7+43
# Day 1 = Date of randomization
EOT assessments are mapped to the time points as needed.


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Table 2-2
Time windows for cytogenetic response
Assessment
Target day of assessment
Time Interval
Baseline
1
≤ Day 1#
Week 24
169
Day 2 to day 253
Week 48
337
Day 254 to day 421
Week 72
505
Day 422 to day 589
Week 96
673
Day 590 to day 700
# Day 1 = Date of randomization
EOT assessments are mapped to the time points as needed.
For PRO data time windows will be defined for descriptive summary by visit and longitudinal 
data analysis. If more than one assessment is available in the same time window, the assessment 
closest to the planned date will be considered. If two assessments are obtained with the same 
time difference compared to the scheduled visit day, the assessment obtained prior to visit will 
be considered.  
Table 2-3
Time windows for PRO: MDASI-CML, EQ-5D-5L, PGIC
Assessment
Target day of assessment
Time Interval
Baseline
1
≤ Day 1#
Week 4
29
Day 2 - 43
Week 8
57
Day 44 - 71
Week 12
85
Day 72 - 99
Week 16
113
Day 100 - 141
Week 24
169
Day 142 - 211
Week 36
253
Day 212 - 295
Week 48
337
Day 296 - 505
Week 96
673
Day 506 - 700
# Day 1 = Date of randomization
Table 2-4
Time windows for PRO: WPAI-CML
Assessment
Target day of assessment
Time Interval
Baseline
1
≤ Day 1#
Week 4
29
Day 2 - 57
Week 12
85
Day 58 -127
Week 24
169
Day 128- 253
Week 48
337
Day 254 - 505
Week 96
673
Day 506 - 700
# Day 1 = Date of randomization
Here’s the general rule for the target day of assessment and time interval: For Week k visit, 
target day of assessment is defined as k*7+1. For the time interval, “Lower limit” = “upper limit 


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of prior applicable visit” +1. “Upper limit” = “target day of current visit” + integer part of 
(“target day of next applicable visit” – “target day of current visit”)/2. 
Visit window for the switched treatment period will use the same rules as described above but 
with Day 1 being the date of first administration of asciminib. Visit name for the switched 
treatment period will be defined similarly with annotated by beginning with “S-“ (e.g. S-Week 
4) to differentiate from those used for the randomized treatment period.


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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 randomization 
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/PK 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 the 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
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, patients will be analyzed according 
to the treatment and stratum they have been assigned to during the randomization procedure.
Safety Set
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment actually received.
The actual treatment received corresponds to:

the randomized treatment if patients took at least one dose of that treatment;

the first treatment received if the randomized treatment was never received.
Pharmacokinetic Analysis Set
The Pharmacokinetic Analysis Set (PAS) includes all patients who provide at least one 
evaluable PK concentration. For a concentration to be evaluable, patients are required to:

Take a dose of asciminib prior to sampling

Take the same dose of asciminib for at least 3 consecutive days without dose 
interruption or dose modification prior to sampling

Have the pre-dose sample collected before the next dose administration
Other analysis sets

For duration of MMR and time to MMR (descriptive analysis), the MMR Responder 
Set will be used that is a subset of FAS and includes patients who achieve MMR at 
any time on study treatment.

For CCyR rates at and by scheduled time points and time to CCyR (Kaplan-Meier 
analysis), the CCyR Analysis Set will be used that is a subset of FAS and includes 
patients who are not in CCyR at baseline.

For duration of CCyR and time to CCyR (descriptive analysis), the CCyR Responder 
Set will be use that is a subset of FAS and includes patients who do not have CCyR at 
baseline and achieve CCyR at any time on study treatment.

For analyses of patients switched to asciminib, the Switch Analysis Set will be used 
that is a subset of FAS and includes patients who switched from bosutinib to 
asciminib and received at least one dose of asciminib.
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 subject classification rules defined in Table 
2-6. 


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Table 2-6
Subject classification based on protocol deviations and non protocol 
deviation criteria
Analysis set
Protocol deviations leading 
to exclusion
Non 
protocol 
deviation 
leading to exclusion
FAS 
No written inform consent
Not applicable
Safety set
No written inform consent
No dose of study medication 
PK analysis set
No written inform consent
See definition of PAS
MMR Responder Set
Not applicable
See definition
of MMR 
Responder Set
CCyR Analysis Set
Not applicable
See definition
of CCyR 
Analysis Set
CCyR Responder Set
Not applicable
See definition of 
CCyR
Responder Set
Switch Analysis Set
Not applicable
See definition of 
Switch 
Analysis Set
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the eCRF. 
2.2.1
Subgroup of interest
Subgroup analyses will use the same method as for the analysis in the respective overall analysis 
set. 
The objective for carrying out these subgroup analyses is to identify potential issues that
may be limited to a subgroup of patients, or that are more commonly observed in a subgroup 
of patients.
Summary tables and figures will be generated only for subgroups with at least 15 patients. 
Efficacy
The primary efficacy endpoint will be summarized by the following subgroups to examine the 
homogeneity of treatment effect provided that the primary efficacy analysis based on the FAS 
is statistically significant: 

Stratification factor (based on randomization data from Interactive Response 
Technology [IRT]): “Major Cytogenetic Response” or “No Major Cytogenetic 
Response”

Stratum reported in the CRF (derived using the data collected on the Bone Marrow 
Aspirate eCRF at baseline: see Appendix): “Major Cytogenetic Response” or “No 
Major Cytogenetic Response”


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
Sex: Female or male

Race: Asian, Caucasian, or others

Age category (≥18-< 65 years, ≥65 years, ≥75 years,)

Reason for discontinuation of the last prior Tyrosine Kinase Inhibitor (TKI): 
Failure (i.e. lack of efficacy) or intolerance (i.e. adverse event, lack of tolerability). 
Note: Only one reason for discontinuation is allowed for each prior therapy.

Number of prior TKI therapies: 2, 3 or ≥4

Line of therapy of randomized treatment: 3rd, 4th or ≥5th

With or without Week 1 Day 1 BCR-ABL1 mutation (other than T315I or V299L) by 
Sanger Sequencing at central lab: Wild type or  mutant

BCR-ABL ratio at baseline ≥1% or <1%
No formal statistical test of hypotheses will be performed for the subgroups, only point estimate 
of the treatment effect and 95%-confidence intervals will be provided (see Section 2.14 for 
further analysis details). The objective of the efficacy subgroup analysis is to demonstrate 
homogeneity of treatment effect in the above subgroups.
Safety
Subgroup analyses for selected safety endpoints will be defined when required.
Japan-specific subgroup analyses
Two subgroups will be formed based on geographic region: Japan or other region (this is not 
based on ethinicity). These subgroup analyses will be only used for submission to Japan health 
authority.
Summary tables and figures will be presented for the two subgroups for the following outcome 
measures:

Baseline characteristics: Tables of demographics, diagnosis and extent of cancer,
extramedullary involvement, bone marrow analysis, molecular response, prior TKI 
and non-TKI, patient disposition, analysis sets by stratum

Exposure: Tables of duration of exposure, dose received

Tables of concomitant medications as well as surgical and medical procedures

PK (only in asciminib arm): Table and figure of asciminib concentration by time, 
table of asciminib PK parameters (patients with full PK sampling), figure of average 
trough asciminib concentration from week 2, 4, 12 and 24 vs. BCR-ABL ratio IS (%)
at 24 weeks

AEs: Tables of all AEs, treatment-related AEs, AEs requiring dose adjustment or 
interruption, AEs requiring additional therapies, serious adverse events (SAEs), 
adverse events of special interest (AESIs), overview table of AEs and death

ECG: Tables of Notable ECG values, change from baseline in ECG parameters values

Lab: Hematology shift table, biochemistry shift table

Efficacy: Tables of molecular response categories at and by each time point, MMR 
rate at and by each time point, time to MMR, duration of MMR, cytogenetic response 


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categories at and by each time point, time to CCyR, duration of CCyR, TTF, PFS, OS. 
Figures of cumulative incidence of MMR and of CCyR, association between Week 1 
Day 1 BCR-ABL1 gene mutation and clinical outcome.
2.3
Patient disposition, demographics and other baseline 
characteristics
The FAS will be used for all baseline and demographic summaries and listings unless otherwise 
specified. Summaries will be reported by treatment arm and for all patients, and listings will be 
reported by treatment arm to assess baseline comparability. No inferential statistics will be 
provided.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment arm. Categorical data (e.g. age groups: 18 - <65, 65 - <75, and ≥ 75 years and 18 -
<65, ≥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.
For the Switch Analysis Set, the initial baseline and “baseline_switch” value will be 
summarized. Weight, BMI, age and ECOG performance status will be summarized using the 
“baseline_switch” value defined in Section 2.1.2.
In addition, a summary table by sex, age group (18 - <65, 65 - <85, and ≥ 85 years) and treatment 
group and another summary table by race and treatment group will be generated using the safety 
set for DSUR/PSUR.
Baseline stratification factors
The number (%) of patients in each stratum (“Major Cytogenetic Response” or “No Major 
Cytogenetic Response”) based on data obtained from the IRT system will be summarized 
overall and by treatment arm for the FAS. Discordances between the stratum recorded in IRT 
at the time of randomization and the stratum recorded in the clinical database through the data 
collected on eCRF will be cross-tabulated and listed. In case the baseline bone marrow aspirate 
is missing or not evaluable (i.e. < 20 metaphases), the stratum recorded in the clinical database 
will be imputed following the rule described in Appendix 5.1.2.1.
Baseline cytogenetic response and molecular response
Baseline and Baseline_switch will be summarized for cytogenetic response and molecular 
response for the FAS and Switch Analysis Set respectively.
Diagnosis and extent of cancer
All diagnosis and extent of cancer data will be summarized and listed by treatment arm. One
summary table will include time (years) since initial diagnosis (descriptive statistics with N,
mean, median, standard deviation, minimum and maximum) and historical mutation: present 


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(unknown, yes, no), historical CML-associated mutation status (E225K, E255V, E355G, etc.)
(frequency counts and percentages). Another table will include extramedullary involvement: 
any extramedullary involvement (Yes/No) and location of extramedullary involvement (Spleen, 
Liver) (frequency counts and percentages).
For the Switch Analysis Set, the above information will be based on the last observation prior 
to the Baseline_switch.
Medical history
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on eCRF will be summarized and listed by treatment arm. The summary will be 
presented by primary system organ class (SOC), preferred term (PT) and treatment arm. 
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 listings will be produced for medical history possibly contributing to liver 
dysfunction, and medical history of protocol solicited cardiovascular events.
The cardiovascular risk factors, heavy smoking, low physical activity, unhealthy diet, and other, 
are collected prior to randomization and the EoT visit. A listing by treatment arm will be 
presented. 
Family medical history of each patient for ischemic heart disease, cardiac arrhythmia, sudden 
death, high cholesterol, diabetes mellitus, heart defects (congenital heart disease), and heart 
failure is also collected prior to randomization and at the EoT visit. A listing by treatment arm 
will be presented.
Other
All data collected at baseline, including child bearing potential as well as informed consent for 
additional research on study data and biological samples, will be listed.
2.3.1
Patient disposition
Enrollment by country and center will be summarized for all screened patients and also by 
treatment arm using the FAS. The number (%) of randomized patients included in the FAS will 
be presented overall and by treatment group. The number (%) of screened and not-randomized 
patients and the reasons for screening failure will also be displayed. The eligibility criteria will 
be also summarized. 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 treatment group.
The following summaries will be provided (with % based on the total number of FAS patients):

Number (%) of patients who were randomized (based on data from IRT system)

Number (%) of patients who were randomized but not treated (based on DAR eCRF 
page not completed for any study treatment component)

Primary reason for not being treated (based on “End of Treatment Phase Disposition” 
eCRF page)


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
Number (%) of patients who were treated (based on DAR eCRF pages of each study 
treatment completed with non-zero dose administered)

Number (%) of patients who are still on-treatment (based on the “End of Treatment 
Phase Disposition” page not completed); 

Number (%) of patients who discontinued the study treatment phase overall, before 
Week 24,  Week 48 and Week 96 (based on the “End of Treatment Phase 
Disposition” page) 

Primary reason for study treatment phase discontinuation overall, before Week 24,  
Week 48 and Week 96 (based on the “End of Treatment Phase Disposition” page)

Number (%) of patients who have entered the survival follow-up (based on the “End 
of Treatment Phase Disposition” page)

Number (%) of patients in the FAS randomized to the bosutinib arm who switched to 
receive asciminib (based on DAR – ABL0001 eCRF page completed with non-zero 
dose administered during the Treatment switch phase);
The following summaries will be provided with % based on the total number patients in the 
Switch Analysis Set:

Number (%) of patients who switched from bosutinib arm to receive asciminib and are 
still receiving asciminib (based on the “End of Treatment Disposition” eCRF not 
completed during the Treatment switch phase);Number (%) of patients who switched from 
bosutinib arm to receive asciminib and discontinued asciminib (based on the “End of 
Treatment Disposition” eCRF during the Treatment switch phase);

Primary reason for  treatment switch phase discontinuation (based on the “End of 
Treatment Disposition” eCRF during the Treatment switch phase)

Number (%) of patients who have entered the survival follow-up (based on the “End of 
Treatment Disposition” eCRF during the Treatment switch phase)
Protocol deviations
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the Study Specification Document) overall and by treatment 
group for the FAS. All protocol deviations will be listed. In addition, the number (%) of patients 
in the FAS with any COVID-19 related protocol deviation (COVID-19 specific protocol 
deviations as well as non-specific COVID-19 protocol deviations with a COVID-19 
relationship) will be tabulated by deviation category (as specified in the Study Specification 
Document) overall and by treatment group.
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized  by 
treatment group and stratum. Reasons leading to exclusion from analysis sets will be listed by 
treatment group and stratum as well as tabulated overall and by treatment group.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure, actual cumulative dose, average daily dose, dose intensity (DI) and 
relative dose intensity (RDI) will be summarized by treatment arm. Duration of exposure will 
be categorized into time intervals; frequency counts and percentages will be presented for the 
number (%) of subjects in each interval. The number (%) of subjects who have dose reductions 
or interruptions, and the reasons, will be summarized by treatment group. 
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.  
The safety set and Switch Analysis Set will be used for all summaries and listings of randomized 
and switched treatments respectively. 
To summarize exposure data for the randomized treatment period, this will be based on patients 
in the Safety set with the date of last administration of study treatment and the date of first 
administration of study treatment being FD and LD respectively.
To summarize exposure data for the switched treatment period, this will be based on patients in 
the Switch Analysis Set with the date of last administration of  study treatment and the date of 
first administration of study treatment being FDswitch and LDswitch respectively.
Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug or control:
Duration of exposure to study treatment (weeks) = ((date of last administration of  study 
treatment) – (date of first administration of study treatment) + 1) / 7. 
The duration of exposure in patient-years is the total of the duration of exposure in years 
from all the patients in a treatment group. 
The date of last administration of study treatment is defined in Section 2.1.1.
Summary of duration of exposure to study treatment will include categorical summaries based 
on intervals (<24 weeks, ≥24 weeks, ≥48 weeks, ≥96 weeks) and continuous summaries (i.e. 
mean, standard deviation etc.).
Cumulative dose
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure. 
The planned cumulative dose for a study treatment refers to the total planned dose as per the 
protocol up to the last date of study treatment administration. The calculations for the two study 
treatments are:

ABL001: 40 mg/administration × 2 (administration/day) × duration of exposure (day) 


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
Bosutinib:  500 mg/day × duration of exposure prior to dose escalation (day) 
+ 600 mg/day × duration of exposure since dose escalation (day),
where the starting day of dose escalation is identified as the first record in the DAR 
eCRF with dose increased and reason “As per protocol”.
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment 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 study treatment.
Dose intensity and relative dose intensity
Average Daily Dose (ADD) is defined as:
ADD (mg/day) = Actual cumulative dose (mg) / Time on treatment (day).
Time on treatment (weeks) = ((date of last administration of  study treatment) – (date of first 
administration of study treatment) + 1 – number of days with dose interruption*) / 7
*For subjects in the asciminib arm, this includes the half days before and after the period with 
0 dose if the treatment was interrupted after the morning dose and/or resumed in the evening (1 
day record with QD dose administered before or after a record with 0 dose).
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 (day).
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 (day).
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg/day)  / PDI (mg/day).  
ADD, DI and RDI will be summarized separately for the two study treatments. 
Dose changes, interruptions or permanent discontinuations
The number of subjects who have dose increase (allowed for bosutinib starting week 8, see 
protocol Section 6.2), dose reductions, dose interruptions or permanent discontinuations, and 
the reasons, as well as the duration of dose interruption due to any reason will be summarized 
separately for the two study treatments. For any subjects, duration of dose interruption will be 
calculated by adding all individual episodes of dose interruption for that patient. For subjects in 
the asciminb arm, this includes the half days before and after the period with 0 dose if the 
treatment was interrupted after the morning dose and/or resumed in the evening (1 day record 
with QD dose administered before or after a record with 0 dose). 
‘Dose Changed’, ‘Dose Interrupted’ and ‘Dose Permanently Discontinued’ fields from the DAR 
eCRF pages will be used to determine the dose changes, dose interruptions, and permanent 
discontinuations, respectively.


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The corresponding fields ‘Reason for Dose Change/Dose Interrupted’ 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 asciminib arm, there is only one planned dose, i.e. 80 mg/day. For patients in 
bosutinib arm, the initial planned dose is 500 mg/day and could be changed to 600 mg/day in 
week 8 or later.
For the purpose of 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 change where the actual total daily dose is lower than the most recently
planned dose. Therefore any dose change to correct a dosing error will not be considered a dose 
reduction. Only dose change is collected in the eCRF, while number of reductions will be 
derived programmatically based on the change and the direction of the change.
Increase: A dose change where the actual total daily dose is greater than the most recently
planned dose. Therefore any dose change to correct a dosing error will not be considered a dose 
increase. Only dose change is collected in the eCRF, while number of increase will be derived 
programmatically based on the change and the direction of the change.
2.4.2
Prior, concomitant and post therapies
Prior anti-cancer therapy
The number and percentage of patients who received any prior anti-neoplastic medications will 
be summarized by treatment arm for the lowest anatomical therapeutic classification (ATC)
class and preferred term. A listing will also be produced. 
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 FAS.
The following information will be summarized for the FAS and Switch Analysis Set:

Prior TKI by medication (e.g. imatinib, dasatinib, nilotinib, ponatinib, bosutinib, etc.) 

Number of prior TKI (e.g. 2, 3, 4, etc.) 

Number of lines of prior TKI therapy (2, 3, 4, 5+)
A new line of therapy is considered each time a change in TKI occured. Multiple entries 
for the same TKI will be counted as separate lines of therapy if a different TKI is 
received between the different entries.

Time on each line of prior TKI therapy (in years)

Time on last prior TKI (in years)

Reason to discontinue the most recent TKI therapy at the time of screening


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
Prior non-TKI therapies (Yes, No). 
A Sankey-like plot showing the sequence of prior TKIs will be provided.
Note: In case the last TKI given prior to enrollment in the study was a bridging therapy (i.e. 
reason for discontinuation includes a wording related to bridging), it will not be considered in 
the analysis of prior TKIs. In particular, it will not be considered as the last or most recent TKI 
therapy at the time of screening and will not count as an additional line of therapy.
For the Switch Analysis Set, bosutinib received during the randomized treatment period and 
other TKIs received since discontinuation of bosutinib and before first administration of 
asciminib (FDswitch) should be considered as prior TKIs.
Post treatment anti-cancer therapy
Anti-neoplastic therapies since discontinuation of study treatment will be listed and summarized 
by the lowest anatomical therapeutic classification (ATC) class, preferred term, overall and by 
treatment group by means of frequency counts and percentages using FAS.
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. 
Concomitant therapies
Concomitant therapies are defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapies include medications (other than study drugs) and medical 
procedures starting on or after the start date of study treatment, or starting prior to the start date 
of study treatment and continuing after the start date of study treatment. 
Concomitant 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. 
The summaries for the on-treatment period using the Safety Set will include:

Therapies starting on or after the start of randomized study treatment but no later than 
the end of the on-treatment period and

Therapies starting prior to start of randomized study treatment and continuing after 
the start of randomized study treatment.
These summaries for the on-switched treatment period using the Switch Analysis Set will 
include:

Medications starting on or after the start of switched treatment but no later than the 
end of the on-switched treatment period and

Medications starting prior to start of switched treatment and continuing after the start 
of switched treatment.


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All concomitant therapies will be listed using the Safety Set. Any concomitant therapies
starting and ending prior to the start of randomized study treatment or starting beyond end of 
the on-treatment period if not switched, or starting beyond end of on-switched treatment
period if switched will be flagged in the listing. 
The prohibited concomitant medications will be summarized by lowest ATC class and preferred 
term up to the end of on-treatment and on-switched treatment periods, respectively.
2.5
Analysis of the primary objective/estimand
In this section, the targeted treatment effect corresponding to the primary objective as well as 
the primary objective is clarified using the estimand language.
The primary clinical question of interest is: Is the efficacy of asciminib (40 mg bid) superior to 
bosutinib (500 mg qd) in CML patients in chronic phase, previously treated with 2 or more 
tyrosine kinase inhibitors, with regards to achieving MMR at 24 weeks while on study treatment
and without meeting any treatment failure criteria (defined in section 5.4.4) prior to 24 weeks, 
regardless of dose modification,  dose interruption, or deviation in any intake of concomitant 
medications.
The primary estimand is described by the following attributes:
Population: CML patients in chronic phase, previously treated with 2 or more tyrosine kinase 
inhibitors. Further details about the population are provided in Section 5 of the protocol.
Endpoint: Major Molecular Response (MMR) achieved at 24 weeks while on study treatment
without meeting any treatment failure criteria (defined in section 5.4.4) prior to 24 weeks. A 
patient will be counted as having achieved MMR at 24 weeks if he/she meets the MMR criterion
(BCR-ABL ratio ≤0.1%) at 24 weeks while on study treatment unless the patient met any 
treatment failure criteria (defined in section 5.4.4) prior to 24 weeks.
Intercurrent events: 

Treatment discontinuation (i.e. having performed an EOT visit) prior to 24 weeks due to 
any reason (e.g. intolerance, treatment failure, death, etc.): non response

Meeting any treatment failure criteria (defined in section 5.4.4) prior to 24 weeks: non 
response

Dose modification,  dose interruption, or deviation in any intake of concomitant 
medications: ignore (treatment policy strategy)
Treatment of interest: the randomized treatment (the investigational treatment asciminib or the 
control treatment bosutinib) received for at least 24 weeks with or without dose modification, 
dose interruption or deviation in any intake of concomitant medications. Further details about 
the investigational treatment and control treatment are provided in Section 6 of the protocol.
Handling of remaining intercurrent events : no other IE foreseen
The summary measure: difference in MMR rate and its 95% confidence interval at week 24 
between the two treatment arms.


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2.5.1
Primary endpoint/estimand
The primary endpoint is Major Molecular Response (MMR) achieved at 24 weeks while on 
study treatment without meeting any treatment failure criteria (defined in section 5.4.4) prior to 
24 weeks. A patient will be counted as having achieved MMR at 24 weeks if he/she meets the 
MMR criterion (BCR-ABL ratio ≤0.1%) at 24 weeks while on study treatment unless the 
patient met any treatment failure criteria (defined in section 5.4.4) prior to 24 weeks.
MMR will be considered as a binary variable with patients achieving MMR grouped as 
‘responders’ and patients not achieving MMR grouped as ‘non responders’. Only patients with 
MMR at 24 weeks are considered responders. In other words, any patient who achieves MMR 
before 24 weeks, but is no longer in MMR at 24 weeks, will be considered as a non-responder 
in this primary analysis.
Patients discontinuing treatment (i.e. having performed an EOT visit) prior to 24 weeks due to 
any reason (e.g. intolerance, treatment failure, death, etc.) and patients meeting any treatment 
failure criteria (defined in section 5.4.4) prior to 24 weeks will be considered as not having 
achieved MMR at 24 weeks.
Details of derivation of Polymerase Chain Reaction (PCR) results and calculation of BCR-ABL 
ratio are presented in Section 5.4.
2.5.2
Statistical hypothesis, model, and method of analysis
The MMR rate at 24 weeks will be calculated based on the FAS and according to the Intent To 
Treat (ITT) principle. MMR rate and its 95% confidence interval based on the Pearson-Clopper 
method will be presented by treatment group. The 95% confidence interval for the unstratified 
difference in MMR rate between treatment groups will be provided using the Wald method.
The null hypothesis is that there is no difference between the treatment groups with respect to 
MMR rate at 24 weeks. The Cochrane-Mantel-Haenszel (CMH) chi-square test, stratified by 
the randomization stratification factor, i.e. cytogenetic response status (MCyR vs no MCyR) at 
screening, will be used to compare MMR rate between the two treatment groups, at the two-
sided 5% level of significance. The Mantel-Haenszel estimate of the common risk difference 
and the corresponding 95% confidence interval will be presented. 
2.5.3
Handling of remaining intercurrent events of primary estimand
No remaining intercurrent events.
2.5.4
Handling of missing values not related to intercurrent event
Patients with missing PCR evaluations at 24 weeks will be considered as non-responders. 
However, if the 24-week PCR evaluation is missing, but both a PCR evaluation at 16 weeks 
and a PCR evaluation at 36 weeks indicate MMR, the 24-week assessment is imputed as a 
‘Response’, assuming that MMR is maintained between 16 and 36 weeks.
2.5.5
Sensitivity analyses
The following sensitivity analyses will be performed:


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
The CMH chi-square test of MMR rate at 24 weeks will be repeated stratifying by the 
stratum recorded in the CRF (MCyR vs no MCyR at baseline).

Due to the COVID-19 (Coronavirus) pandemic, there is a risk that planned hospital visits 
are cancelled, potentially resulting in missing PCR evaluations. In order to assess the 
impact of COVID-19 (including potential missing data) on the primary endpoint, the 
CMH chi-square test of MMR rate at 24 weeks will be repeated on the FAS excluding the 
patients with planned 24-week visit (start of study treatment + 161 days ) after the start 
date of COVID-19 epidemic. As per Novartis guidance, the start date, in a given country 
or region, is being defined as the approximate time point at which, according to the WHO 
situation reports and the Johns Hopkins database, the number of confirmed COVID-19 
infections started to increase significantly (around 100 confirmed cases) and/or 
governments started to take measures (such as stay-at-home orders) to contain the
epidemic, whichever occurred first (China: January 1, 2020; South Korea: February 20, 
2020; Japan: February 21, 2020; Italy: February 23, 2020 and Rest of the World: March 1, 
2020).

The CMH chi-square test of MMR rate at 24 weeks will be repeated without the 
imputation rule used in the main analysis in case of missing PCR evaluations at 24 weeks.
2.5.6
Supplementary analyses
Additional supplemental logistic regression and subgroup analyses are described in Section 
2.14.
Assess whether the efficacy of asciminib (40 mg bid) is superior to bosutinib (500 mg qd) in 
CML patients in chronic phase, without T315I or V299L mutation detected at Week 1 Day 1 
visit and previously treated with 2 or more tyrosine kinase inhibitors, with regards to achieving 
MMR at 24 weeks while on study treatment and without meeting any treatment failure criteria 
(defined in section 5.4.4) prior to 24 weeks, regardless of dose modification,  dose interruption, 
or deviation in any intake of concomitant medications.
The corresponding estimand attributes are the same as the ones of the primary estimand except 
that the population excludes patients detected with T315I or V299L at Week 1 Day 1 visit (As 
per protocol, these patients were discontinued from study treatment when the mutation results 
became available). 
The CMH chi-square test of MMR rate at 24 weeks will be repeated on the FAS excluding 
patients detected with T315I or V299L at Week 1 Day 1 visit.
2.6
Analysis of the key secondary objective/estimand
The key secondary clinical question of interest is: Is the efficacy of asciminib (40 mg bid) 
superior to bosutinib (500 mg qd) in CML patients in chronic phase, previously treated with 2 
or more tyrosine kinase inhibitors, with regards to achieving MMR at 96 weeks while on study 
treatment and without meeting any treatment failure criteria (defined in section 5.4.4) prior to 
96 weeks, regardless of dose modification,  dose interruption, or deviation in any intake of 
concomitant medications.
The key secondary estimand is described by the following attributes:


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Population: CML patients in chronic phase, previously treated with 2 or more tyrosine kinase 
inhibitors. Further details about the population are provided in Section 5 of the protocol.
Endpoint: Major Molecular Response (MMR) achieved at 96 weeks while being treated without 
meeting any treatment failure criteria (defined in section 5.4.4) prior to 96 weeks. A patient will 
be counted as having achieved MMR at 96 weeks if he/she meets the MMR criterion (BCR-
ABL ratio ≤0.1%) at 96 weeks while on study treatment unless the patient met any treatment 
failure criteria (defined in section 5.4.4) prior to 96 weeks. 
Intercurrent events: 

Treatment discontinuation (i.e. having performed an EOT visit) prior to 96 weeks due to 
any reason (e.g. intolerance, treatment failure, death, etc.): non response

Meeting any treatment failure criteria (defined in section 5.4.4) prior to 96 weeks: non 
response

Dose modification,  dose interruption, or deviation in any intake of concomitant 
medications: ignore (treatment policy strategy)
Treatment of interest: the randomized treatment (the investigational treatment asciminib or the 
control treatment bosutinib) received for at least 96 weeks with or without dose modification, 
dose interruption or deviation in any intake of concomitant medications. Further details about 
the investigational treatment and control treatment are provided in Section 6 of the protocol.
Handling of remaining intercurrent events : no other IE foreseen
The summary measure: difference in MMR rate and its 95% confidence interval at week 96 
between the two treatment arms
The analysis of the key secondary objective will be performed at the time of the 96-week 
analysis.
2.6.1
Key secondary endpoint/estimand
The key secondary endpoint is MMR achieved at 96 weeks while on study treatment without 
meeting any treatment failure criteria (defined in section 5.4.4) prior to 96 weeks. A patient will 
be counted as having achieved MMR at 96 weeks if he/she meets the MMR criterion (BCR-
ABL ratio ≤0.1%) at 96 weeks while on study treatment unless the patient met any treatment 
failure criteria (defined in section 5.4.4) prior to 96 weeks.
MMR will be considered as a binary variable with patients achieving MMR grouped as 
‘responders’ and patients not achieving MMR grouped as ‘non responders’. Only patients with 
MMR at 96 weeks are considered responders. In other words, any patient who achieves MMR 
before 96 weeks, but is no longer in MMR at 96 weeks, will be considered as a non-responder 
in this key secondary analysis.
Patients discontinuing treatment (i.e. having performed an EOT visit) prior to 96 weeks due to 
any reason (e.g. intolerance, treatment failure, death, etc.) and patients meeting any treatment 
failure criteria (defined in section 5.4.4) prior to 96 weeks will be considered as not having 
achieved MMR at 96 weeks.


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2.6.2
Statistical hypothesis, model, and method of analysis
The null hypothesis is that there is no difference between the treatment groups with respect to 
MMR rate at 96 weeks. Following a gatekeeping procedure to control the overall alpha level, 
only if the primary endpoint is significant, formal statistical testing of the key secondary 
endpoint with two-sided 5% level of significance will be performed using the CMH chi-square 
test, stratified by the randomization stratification factor, i.e. cytogenetic response status (MCyR 
vs no MCyR) at screening.
MMR rate and its 95% confidence interval based on the Pearson-Clopper method will be 
presented by treatment group. The 95% confidence interval for the difference in MMR rate 
between treatment groups will be provided using the Wald method. The Mantel-Haenszel 
estimate of the common risk difference and the corresponding 95% confidence interval will 
also be presented.
2.6.3
Handling of remaining intercurrent events of primary estimand
No remaining intercurrent events.
2.6.4
Handling of missing values not related to intercurrent event
Patients with missing PCR evaluations at 96 weeks will be considered as non-responders. 
However, if the 96-week PCR evaluation is missing, but both a PCR evaluation at 84 weeks 
and a PCR evaluation at 108 weeks indicate MMR, the 96-week assessment is imputed as a 
‘Response’, assuming that MMR is maintained between 84 and 108 weeks.
2.6.5
Sensitivity analysis

In order to assess the impact of COVID-19 (including potential missing data) on the key 
secondary endpoint, the CMH chi-square test of MMR rate at 96 weeks will be repeated 
on the FAS excluding the patients with planned 96-week visit (start of study treatment + 
665 days) between the start date of the COVID-19 epidemic (China: January 1, 2020; 
South Korea: February 20, 2020; Japan: February 21, 2020; Italy: February 23, 2020 and 
Rest of the World: March 1, 2020) and its end date (to be defined in the future). 

The CMH chi-square test of MMR rate at 96 weeks will be repeated without the 
imputation rule used in the main analysis in case of missing PCR evaluations at 96 weeks.
2.7
Analysis of secondary efficacy objective(s)
The other secondary efficacy objective is to compare additional parameters (defined below) of 
the efficacy of asciminib versus bosutinib.
2.7.1
Secondary endpoints
2.7.1.1
Molecular response
MMR rates at all scheduled data collection time points, i.e., the protocol-planned visits 
except for 24 weeks and 96 weeks which are already covered by primary and key secondary 
endpoints. Such rates are defined as the proportion of patients with MMR at the respective time 
points.


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MMR rates by all scheduled data collection time points, i.e., the protocol-planned visits.
These are cumulative MMR rates by time points and are defined as the proportion of patients 
who achieve MMR at or before specified visits, i.e. if a patient achieves an MMR but then loses 
it before or at a specific visit, he/she will still be classed as achieving MMR by that specific 
time point.
Molecular response category at specific time points, i.e., the protocol-planned visits. 
Categories of molecular response are defined in Appendix. 
Molecular response category by specific time points, i.e., the protocol-planned visits. This is 
defined as the best (lowest) molecular response category up to the specific time points.
Time to MMR (in weeks) is defined as: (date of first documented MMR - date of randomization 
+ 1)/7.
Duration of MMR is defined for patients in the MMR Responder Set as the time between the 
date of the first documented MMR and the end date of MMR, i.e. the earliest date of confirmed 
loss of MMR, progression to accelerated phase (AP)/blast crisis (BC), or CML-related death. 
Loss of MMR and progression to accelerated phase (AP)/blast crisis (BC) are defined in 
Appendix.
For patients for whom none of the events above is reported, the duration will be censored (see 
Section 2.7.3). The duration of MMR (in weeks) is calculated as: (end date or censoring date of 
MMR - date of first MMR + 1)/7.
2.7.1.2
Cytogenetic response
At each assessment time point the cytogenetic response status of each patient is classified as 
complete, partial, major, minor, minimal response and none (a review of a minimum of 20 
metaphases is required):

Complete response (CCyR): 0% Philadelphia chromosome positive (Ph+) metaphases

Partial response (PCyR): >0 to 35% Ph+ metaphases

Major response (MCyR = CCyR + PCyR): 0 to 35% Ph+ metaphases

Minor response (mCyR): >35 to 65% Ph+ metaphases

Minimal response: >65 to 95% Ph+ metaphases

None: >95 to 100% Ph+ metaphases.
As per protocol, bone marrow aspirate for cytogenetic analyses will be performed as long as 
subjects have not achieved MMR. Therefore, in case no bone marrow aspirate was performed 
but the subject is in MMR at a specific time-point, the subject is considered to have achieved
CCyR at that time-point. The date of CCyR is imputed by the date of MMR at the same 
scheduled time-point.
CCyR rates at all scheduled data collection time points, i.e., the protocol-planned visits. 
Such rates are defined as the proportion of patients in CCyR at the respective time points among 
patients in the CCyR Analysis Set, which excludes patients who are in CCyR at baseline.


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CCyR rates by all scheduled data collection time points, i.e., the protocol-planned visits.
Such rates are defined as the proportion of patients who achieve CCyR at or before the 
respective time points among patients in the CCyR Analysis Set.
Cytogenetic response category at specific time points, i.e., the protocol-planned visits. At 
each assessment time point the cytogenetic response status of each patient is classified as 
complete, partial, major, minor, minimal response and none (a review of a minimum of 20 
metaphase is required) as defined in Appendix.
Cytogenetic response category by specific time points, i.e., the protocol-planned visits. This 
is defined as the best (lowest) cytogenetic response category up to the specific time points.
Time to CCyR (in weeks) is defined for patients as: (date of first documented CCyR - date of 
randomization + 1)/7.
Duration of CCyR is defined for patients in the CCyR Responder Set as the time between date 
of first documented CCyR and the end date of CCyR, i.e. the earliest date of loss of CCyR, 
progression to AP/BC, or CML-related death. Loss of CCyR and progression to AP/BC are 
defined in Appendix. For patients for whom none of the events above is reported, the duration
will be censored (see Section 2.7.3). The duration of CCyR (in weeks) is calculated as: (end
date or censoring date of CCyR - date of first CCyR + 1)/7.
2.7.1.3
Other secondary efficacy endpoints
Time to treatment failure (TTF) is defined for patients in FAS as the time from date of 
randomization to an event of treatment failure. The events that constitute ‘treatment failure’ are 
described in the Appendix. They are based on the ELN criteria [Baccarani et al. 2013] defining 
failure of a second line treatment adapted to include discontinuation of randomized treatment 
as an event.
TTF (in months) is calculated as: (date of treatment failure or censoring date (see Section 2.7.3) 
- date of randomization + 1)/30.4375.
Progression-Free-Survival (PFS) is defined for patients in FAS as the time from the date of 
randomization to the earliest occurrence of documented disease progression to AP/BC or the 
date of death from any cause (including progressions and deaths observed during the survival 
follow-up period). 
PFS (in months) is calculated as: (date of disease progression/death or censoring date (see 
Section 2.7.3) - date of randomization + 1)/30.4375.
Overall survival (OS) is defined for patients in FAS as the time from the date of randomization 
to the date of death (including the survival follow-up period).
OS (in months) is calculated as: (date of death or censoring date (see Section 2.7.3) - date of 
randomization + 1)/30.4375, regardless whether the patient switched from bosutinib to 
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2.7.2
Statistical hypothesis, model, and method of analysis
No confirmatory statistical testing of non-key secondary efficacy endpoints will be performed, 
however, nominal p-values will be presented for exploratory purposes (as specified in protocol 
Section 10.5.2).
MMR rates at and by time points
The FAS will be used for these endpoints. For each time point the MMR rate and the associated 
95% confidence interval based on the Pearson-Clopper method will be presented by treatment 
group. The descriptive p-value obtained via CMH chi-square tests stratified by the 
randomization strata, i.e. MCyR vs no MCyR at screening, will be presented. A 95% confidence 
interval for the difference in each MMR rate between treatment groups will be provided using 
the Wald method. The Mantel-Haenszel estimate of the common risk difference and the 
corresponding 95% confidence interval will also be provided.
The cumulative incidence of MMR by treatment group will be graphically displayed by an 
increasing step function. Each curve will increase each time (after randomization) at which a 
new responder is observed and thus will increase up to the best observed response rate (e.g. up 
to 50% if half of the patients in the analysis population are able to achieve MMR).
Molecular response at and by time points
Frequency and percentage of all molecular response categories (defined in Appendix) by 
treatment arm using FAS will be presented for each time point.
For the by-time-points summary, the within-patient best molecular response category up to the 
specific time points is used to calculate the frequency and percentage.
Time to MMR
The MMR Responder Set will be used. Descriptive statistics (minimum, maximum, median, 
quartiles, mean, sd) of time to MMR will be provided for the two treatment groups separately.
The FAS will be also used to perform similar Time-to-Event analyses as described below for 
duration of MMR.
Duration of MMR
The MMR Responder Set will be used. The survival distribution of duration of MMR will be 
estimated using the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% 
confidence intervals [Brookmeyer and Crowley 1982] of the medians, along with the proportion 
of patients who are still in MMR at 24, 48, 72 and 96 weeks and the associated 95% confidence 
intervals, will be presented for each treatment group.
CCyR rates at and by time points
The CCyR Analysis Set will be used for these endpoints. 
For each time point the CCyR rate and the associated 95% confidence interval based on the 
Pearson-Clopper method will be presented by treatment group. The descriptive p-value 
obtained via CMH chi-square tests stratified by the randomization strata, i.e. MCyR vs no 


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MCyR at screening, will be presented. A 95% confidence interval for the difference in each
CCyR rate between treatment groups will be provided using the Wald method. The Mantel-
Haenszel estimate of the common risk difference and the corresponding 95% confidence 
interval will also be provided.
The cumulative incidence of CCyR by treatment group will be graphically displayed by an 
increasing step function. Each curve will increase each time (after randomization) at which a 
new responder is observed and thus will increase up to the best observed response rate (e.g. up 
to 50% if half of the patients in the analysis population are able to achieve CCyR).
Cytogenetic response at and by time points
Frequency and percentage of all cytogenetic response categories (defined in Section 2.7.1.2) by 
treatment arm using FAS will be presented for each time point. A shift table comparing baseline 
and best post-baseline cytogenetic response categories by treatment will also be presented. All 
assessments of cytogenetic response categories will also be listed by treatment arm.
For the by-time-points summary, the within-patient best cytogenetic response category up to 
the specific time points is used to calculate the frequency and percentage.
Assessments of bone marrow aspirate at different time points will also be summarized.
Time to CCyR
The CCyR Responder Set will be used. Descriptive statistics (minimum, maximum, median, 
quartiles, mean, sd) of time to CCyR will be provided for the two treatment groups separately.
The CCyR analysis set will be also used to perform similar Time-to-Event analyses as described 
below for duration of CCyR. 
Duration of CCyR
The CCyR Responder Set will be used. The survival distribution of duration of CCyR will be 
estimated using the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% 
confidence intervals [Brookmeyer and Crowley 1982] of the medians, along with the proportion 
of patients who are still in CCyR at 24, 48, 72 and 96 weeks and the associated 95% confidence 
intervals, will be presented for each treatment group.
TTF, PFS and OS
For each endpoint the survival distribution will be estimated using the Kaplan-Meier method, 
and Kaplan-Meier curves, medians and 95% confidence intervals [Brookmeyer and Crowley 
1982] of the medians, along with the proportion of patients who have not experienced the 
respective events at 1, 3 and 5 years and the associated 95% confidence intervals, will be 
presented for each treatment group. The hazard ratio between the two treatments will be 
calculated, along with its 95% confidence interval, using a stratified Cox model. The descriptive 
p-value obtained using a stratified log-rank test will be also presented. The stratification will be 
based on the randomization stratification factor, i.e. cytogenetic response status (MCyR vs no 
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2.7.3
Handling of missing values/censoring/discontinuations
MMR rates at specific time points: Patients discontinuing the randomized treatment prior to 
a specific time point due to any reason or patients without an available assessment at that time 
point will be considered as non-responders for that time point.
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 at specific time points: The category “Missing” will be assigned to

Ongoing cases, i.e. patients without assessment at the specific time point who have 
not discontinued study treatment and have not been treated sufficiently long for a 
specific time point

Discontinued due to progressive disease/death prior to a specific time point

Discontinued due to other reasons prior to a specific 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 in the MMR responder set 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.
CCyR rates at specific time points: Patients discontinuing the randomized treatment prior to 
a specific time point due to any reason will be considered as non-responders for that time point.
CCyR rates by specific time points: This will be handled similarly as MMR, but with CCyR 
instead.
Cytogenetic response at specific time points: This will be handled similarly as molecular 
response category.


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Cytogenetic response category by specific time points: This will be handled similarly as 
molecular response category.
Time to CCyR: For patients in the CCyR analysis set who have not experienced any CCyR, 
the time will be censored in the same manner as Time to MMR.
Duration of CCyR: For patients in the CCyR responder set who have not experienced any 
event (loss of CCyR, progression to AP/BC, or CML-related death) the duration will be 
censored at the last cytogenetic assessment date on treatment or the last PCR evaluation on 
treatment indicating MMR, whichever is the latest. 
TTF: For patients in the FAS who have not reached treatment failure, their TTFs will be 
censored at the time of their last study assessment (PCR, cytogenetic, hematologic or 
extramedullary) before the cut-off date.
PFS: For patients who have not experienced an event (disease progression to AP/BC or death 
from any cause), their PFS times will be censored at the date of last study assessment (PCR, 
cytogenetic, hematologic or extramedullary) before the cut-off date, regardless of subsequent 
intake of treatment(s) after randomization.
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, regardless of subsequent intake 
of treatment(s) after randomization.
2.8
Safety analyses
All safety analyses will be based on the safety set, except that the summary of safety data during 
the switched treatment period will be based on the Switch Analysis Set. All listings and tables 
will be presented by treatment group.
2.8.1
Adverse events (AEs)
AE summaries will include all AEs occurring during the on-treatment period (or the on-
switched 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 the on-treatment period will be flagged in the listings.
AEs will be summarized by number and percentage of subjects 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 subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades or 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.
In AE 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 asciminib arm.
The following adverse event summaries will be produced by treatment arm for the Safety set 
and Switch Analysis Set: overview of adverse events and deaths, AEs by SOC and PT,


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summarized by relationship, seriousness, leading to treatment discontinuation, leading to dose 
interruption/adjustment, requiring additional therapy, and leading to fatal outcome. The study 
treatment-related AEs/SAEs/AEs leading to treatment discontinuation as well as SAE with fatal 
outcome are summarized for the Safety set and Switch Analysis set. 
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.
In order to account for differences in exposure between the treatment arms, incidence rates of 
AEs and SAEs will be presented by adjusting for duration of treatment period in patient-years. 
They will also be reported by time intervals (i.e. period of emergence: the event is assigned to 
the interval when it first started): 0 to 2 months, > 2 months to 6 months, > 6 months to 12 
months, >12 months and more after the start of study treatment. 
2.8.1.1
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
An adverse event of special interest (AESI) is a grouping of adverse events that are of scientific 
and medical concern specific to compound asciminib. These groupings are defined using 
MedDRA terms, SMQs (standardized MedDRA queries), HLGTs (high level group terms), 
HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA 
queries, NMQ) may also be used. A NMQ is a customized group of search terms which defines 
a medical concept for which there is no official SMQ available or the available SMQ does not 
completely fit the need. It may include a combination of single terms and/or an existing SMQ, 
narrow or broad. 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 (or the on-switched treatment period) will be 
summarized.
Summaries of these AESIs will be provided by treatment arm (specifying grade, SAE, 
relationship, leading to treatment discontinuation, leading to dose adjustment/interruption, 
death, etc.). 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.
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment deaths) will be 
produced on the Safety set by treatment arm, system organ class and preferred term. 
Similarly, a separate summary for on-switched treatment deaths will be produced on the Switch 
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All deaths will be listed, where deaths occurring during the post-treatment, the on-switched 
treatment or post-switched treatment periods will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened subjects.
2.8.3
Laboratory data
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.  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 v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
On analyzing laboratory data, all sources (central and local laboratories) will be combined. The 
summaries will include all assessments available for the lab parameter collected no later than
30 days after the last study treatment administration date.
The following summaries will be produced on the Safety set separately for hematology and 
biochemistry laboratory data (by laboratory parameter and treatment):

Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline in the on-treatment period.

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value. 

For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.
The same summaries will be produced on the Switch Analysis Set for the on-switched treatment 
period.
The following listings will be produced separately for hematology and biochemistry for the 
laboratory data:

Listings of all laboratory data, with CTCAE grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.

Listing of all CTCAE grade 3 or 4 laboratory toxicities
Liver function parameters
Liver function parameters of interest are total bilirubin (TBL), Alanine aminotransferase
(ALT), Aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The number (%)
of patients with worst post-baseline values as per Novartis DILI Clinical safety guidelines will 
be summarized for the criteria defined by single lab parameter. For combination of various 
parameters, the worst post-baseline values from each single parameter are taken into 
consideration, i.e. it may not come from the concurrent measurement (i.e. same assessment). :
The following summaries will be produced:


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
ALT or AST > 3x upper limit of norm (ULN)

ALT or AST > 5xULN

ALT or AST > 10xULN

ALT or AST > 20xULN

TBL > 2xULN

TBL > 3xULN

ALT or AST > 3xULN & TBL > 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP >= 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN  
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
12-lead ECGs including PR, QRS, QT, QTcF and RR intervals will be obtained centrally for 
each subject during the study. ECG data will be read and interpreted centrally. 
The echocardiogram will be performed and evaluated locally to assess the left ventricular 
ejection fraction (LVEF).
Data handling
The average of the triplicate ECG parameters at each time point will be used in the analyses.
For unscheduled visits, ECGs that are reported on the same day and within 30 minutes apart 
from each other will be assumed to be sequential ECGs and thus will be used to compute the 
mean of the ECG parameters.
Unscheduled ECG measurements will not be used in computing the summary statistics for 
change from Baseline at each post-baseline time point. However, they will be used in the outlier 
analyses (e.g. QTc > 450 ms, > 480 ms, or > 500 ms at any time point, or an increase from 
Baseline in QTc > 30 ms or > 60 ms). End of treatment ECG measurements for discontinued 
patients will be considered as an unscheduled measurement in case it occurs outside a scheduled 
visit.
Data analysis
The number and percentage of subjects with notable ECG values will be presented by treatment 
arm for the Safety set and Switched Analysis Set. Notable values are defined below:

QT, QTcF

New value of > 450 and ≤ 480 ms

New value of > 480 and ≤ 500 ms

New value of > 500 ms

Increase from Baseline of > 30 ms to ≤  60ms

Increase from Baseline of > 60 ms

HR


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
Increase from baseline >25% and to a value > 100 bpm

Decrease from baseline >25% and to a value < 50 bpm

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 all ECG assessments will be produced by treatment arm and notable values will be 
flagged. A separate listing of only the subjects with notable ECG values will also be produced.
In each listing the assessments collected during the post-treatment period will be flagged.
Change from baseline ECG parameters by timepoint will also be summarized by treatment.
A listing of all LVEF assessments will be produced by treatment arm. In the listing, the 
assessments collected outside of on-treatment period will be flagged.
A summary table by treatment arm with descriptive statistics for LVEF at different timepoints
(baseline, week 20) and for change from baseline will be presented. A shift table for LVEF 
categories (≤40%, 41-49%, ≥50%) at baseline versus worst value on treatment will also be 
presented.
2.8.4.2
Cardiovascular risk factor assessment
Prior to randomization and at the end of treatment, for each patient information of the following 
risk factors is collected: heavy smoking, low physical activity, unhealthy diet, and other. A 
listing by treatment arm will be presented. 
Family medical history of each patient for ischemic heart disease, cardiac arrhythmia, sudden 
death, high cholesterol, diabetes mellitus, heart defects (congenital heart disease), and heart 
failure is also collected prior to randomization and at the end of treatment. A listing by treatment 
arm will be presented.
2.8.4.3
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute), systolic and diastolic blood pressure (mmHg).
Data handling
Vital signs collected on treatment will be summarized. Values measured outside of on treatment
period will be flagged in the listings.


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Data analysis
The number and percentage of subjects with notable vital sign values (high/low) in systolic 
blood pressure, diastolic blood pressure, pulse rate, weight and temperature will be presented 
by treatment arm.         
A listing of all vital sign assessments will be produced by treatment arm and notable values will 
be flagged. In the listing, the assessments collected outside of on-treatment period will be 
flagged. 
2.8.4.4
Liver events
There are separate eCRF pages to collect acetaminophen/paracetamol, autoimmune, drug use 6 
months prior to liver event, immunoglobulin, liver function tests, pathology, related imaging, 
viral serology and potential impact of alcohol use, and an overview eCRF page. Data on the 
overview eCRF page will be listed by treatment arm. Assessments collected during the post-
treatment period will be flagged.
2.8.4.5
Pulmonary function tests
Data of pulmonary function tests will be listed by treatment arm. Assessments collected during 
the post-treatment period will be flagged.
2.8.5
Additional Analyses
2.8.5.1
ECOG performance status
ECOG performance status collected on treatment will be summarized. Shift tables will be 
provided comparing baseline with best and worst values during study for each treatment group.
2.9
Pharmacokinetic endpoints
PK parameters
The PK parameters that will be determined are shown in Table 2-7. The PK parameters for
asciminib are derived based on the non-compartmental methods using Phoenix WinNonlin®
software version 6.4 in patients with full PK sampling in PAS.


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Table 2-7
Non-compartmental PK parameters for asciminib in full PK group
AUC0-12h
The area under the plasma concentration-time curve from time zero to 12 
hours (ng*hr*mL-1)
AUClast
The AUC from time zero to the last measurable plasma concentration 
sampling time (Tlast) (ng*hr*mL-1)
Ctrough
Trough plasma concentration (measured concentration at the end of a 
dosing interval at steady state [taken directly before next administration])
Cmax
The maximum (peak) observed plasma concentration after
dose 
administration (ng/mL)
Tmax
The time to reach maximum (peak) plasma concentration after dose 
administration (hr)
Tlast
The time to reach the last measurable plasma concentration after dose 
administration (hr)
CL/F
The total apparent body clearance of drug from the plasma after oral
administration (L*hr-1)
Descriptive statistics (n, arithmetic mean, CV% mean, standard deviation (SD), median, 
geometric mean, CV% geo-mean, minimum and maximum) will be presented by treatment for 
PAS for all PK parameters defined in Table 2-7 except Tmax, where only n, median, minimum 
and maximum will be presented. 
All individual PK parameters will be listed for patients treated with asciminib and with full PK 
sampling in the safety set.
PK concentrations 
Descriptive statistics (n, m (number of non-zero concentrations), arithmetic mean, CV% mean, 
SD, median, geometric mean, CV% geo-mean, minimum and maximum) for asciminib
concentration will be presented at each scheduled time point for the PAS.
The mean (+/- SD) and geometric mean concentration-time profiles for asciminib over time will 
be displayed graphically for PAS on the linear and semi-log view (Week 2 Day 1; for patients 
with full PK sampling only).
The mean (±SD) and median Ctrough values of asciminib over time will be displayed 
graphically for PAS on the linear scale only (Patients with full and sparse PK sampling).
All individual plasma asciminib concentration data will be listed for patients treated with
asciminib in the Safety Set.
Handling of PK data below LLOQ or missing
All concentration values below the lower limit of quantitation (LLOQ, 1 ng/mL) are set to zero 
by the Bioanalyst, and will be displayed in the listings as zero and flagged. LLOQ values will 
be treated as zero in any calculations of summary statistics, and treated as missing for the 


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calculation of the geometric means and their CV%. The number of non-zero concentrations will 
also be reported in the summary statistics.
Missing values for any PK data will not be imputed and will be treated as missing.
2.10
PD and PK/PD analyses
The potential relationship between asciminib exposure (e.g. trough concentration) and efficacy,
pharmacodynamics (PD) or safety endpoints may be assessed by graphic exploration and/or 
statistical modeling, as appropriate, including effect of population covariates. Additional 
exposure-response analyses for ECG may be conducted. The concentration data may be 
analyzed by a population approach to evaluate the influence of covariates on drug exposure. If 
applicable, the details of the above-mentioned analyses will be described in a separate analysis 
plan and reported separately.
The relationship between average trough plasma concentration up to 24 weeks and BCR-ABL 
ratio IS (%) at 24 weeks will be assessed by graphic exploration. 
2.11
Patient-reported outcomes
The FAS will be used for analyzing PRO data unless specified differently. The MDASI CML, 
PGIC along with EQ-5D-5L will be used to assess patient’s disease-related symptoms and 
health-related quality of life from baseline to EOT; and the WPAI-CML will be used to assess 
work productivity and activity impairment related to the patient’s CML. All tools require 
patient’s direct completion and will be administered utilizing electronic device for data 
collection at scheduled time points from screening to end of treatment.
The baseline is defined in Section 2.1.1. Patients with an evaluable baseline score and at least 
one evaluable post-baseline score during the treatment period will be included in the change 
from baseline analyses. Missing data items in a scale will be handled according to the manual 
for each instrument. No imputation will be applied if the total or subscale scores are missing 
at a visit. All measures will assess differences between the treatment arms.
Compliance to the schedule of administration of each PRO questionnaire will be summarized 
by treatment group, for baseline and scheduled post-baseline assessment time points. The 
following categories, as collected on the eCRF, will be used to describe whether the 
questionnaire was completed at a specific time point:
1. yes, fully completed
2. yes, partly completed
3. no
Repeated measures model for continuous scores
To best utilize the repeated assessments of a given PRO score, a repeated measures model for 
longitudinal data will be used to estimate differences between treatment arms. This repeated 
measures model will include terms for treatment, the stratification factor (major cytogenetic 
response status), time, baseline value as main effects, and an interaction term for treatment by 
time. This analysis will be restricted to patients with an evaluable baseline score and at least 


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one evaluable post-baseline score. All data collected until end of treatment (including the end 
of treatment assessment) will be included in the analysis. Note that only data collected under 
treatment (i.e. while the patient is treated) will be included. The end of treatment assessment 
will be included if collected within 7 days of the last dose intake.
Time will be considered as a continuous variable expressed in weeks, i.e. considering that the 
PRO score follow a linear trend.
As a first approach, an unstructured correlation matrix will be used to model the correlation 
within patients. The structure of the correlation matrix will be investigated and simplified using 
likelihood ratio tested if appropriate.
2.11.1
MDASI-CML
The M.D. Anderson Symptom Inventory – Chronic Myeloid Leukemia (MDASI-CML)
questionnaire is planned to be administered during screening, at weeks 4, 8, 12, 16, 24, 36, 48 
and 96 after randomization.
The MDASI-CML is a 26 item self-administered questionnaire for adult CML patients. Twenty 
of the items measure the severity of disease-related symptoms and are scored from 0 (Not 
present) to 10 (As bad as you can imagine) and 6 items that measure symptom interference with 
daily life scored from 0 (Did not interfere) to 10 (Interfered completely). 
The severity score will be calculated when a patient scores at least 11 items out of the 20 
severity items using the formula: (sum of scores for the items answered) / (number of items 
answered). If a patient scores fewer than 11 items, the severity score will be missing.
The interference score will be calculated when a patient scores at least 4 items out of the 6 
interference items using the formula: (sum of scores for the items answered) / (number of 
items answered). If a patient scores fewer than 4 items, the interference score will be missing.
For the severity score and interference score, descriptive statistics (n, mean, SD, median, 25th 
and 75th percentiles) by treatment arm will be provided for the actual scores and changes from 
baseline scores at each scheduled assessment time point.
Between-treatment differences for the change in severity and interference scores will be 
evaluated using the above-mentioned repeated measures model. 
2.11.2
EQ-5D-5L
EQ-5D-5L is a two-part standardized instrument for measuring health outcomes in a wide range 
of health conditions and treatments. It consists of a descriptive system and a visual analogue 
scale (EQ VAS). The descriptive system comprises the following 5 dimensions: mobility, self-
care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems and extreme problems (or 
unable to perform the activity). The EQ VAS records the respondent’s self-rated health on a 
vertical, visual analogue scale where the endpoints are labeled ‘Best imaginable health state’ 
and ‘worst imaginable health state’.
The EQ-5D-5L data will be used to calcutae utility values for the economic evaluation of
asciminib and bosutinib in a separate analysis.


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The EQ-5D-5L questionnaire is planned to be administered during screening, at weeks 4, 8, 12, 
16, 24, 36, 48 and 96 after randomization.
Descriptive system
The number and percentage of subjects in the five levels of each EQ-5D demension will be 
presented by treatment group at each assessment time point.
EQ VAS
The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale from 
0, labeled as ‘worst imaginable health state’, to 100, labeled as ‘best imaginable health state’.
For the EQ VAS, descriptive statistics (n, mean, SD, median, 25th and 75th percentiles) by 
treatment arm will be provided for actual values and for the change from baseline at each 
assessment time point.
Between-treatment differences for the changes in EQ VAS score will be evaluated using the 
above-mentioned repeated measures model.
2.11.3
WPAI-CML
The Work Productivity and Activity Impairment Questionnaire – Chronic Myeloid Leukemia
(WPAI-CML) questionnaire is planned to be administered during screening, at weeks 4, 12, 24, 
48 and 96 after randomization.
The WPAI-CML is a six-item questionnaire which is intended to measure work and activity 
impairment associated with CML for those who self-identify as currently employed for pay. 
This questionnaire measures self-reported productivity loss associated with CML during the 
past seven days. It consists of questions about absence from work due to CML, hours spent at 
work, the reduction in productivity at work attributed to CML, and the reduction in productivity 
while performing regular activities. WPAI-CML outcomes are expressed as impairment 
percentages, with higher numbers indicating greater impairment and less productivity, i.e., 
worse outcomes. Scoring will be done according to WPAI-CML instrument guidance resulting 
in four scores including: Percent work time missed due to problem; percent impairment while 
working due to problem; Percent overall work impairment due to problem; and, percent activity 
impairment due to problem.
Descriptive statistics (n, mean, SD, median, 25th and 75th percentiles) for each of the four 
derived outcome scores and changes from baseline scores will be presented by treatment arm 
at each scheduled assessment time point with .
Between-treatment differences for the changes in each of the four outcome scores will be 
evaluated using the above-mentioned repeated measures model. 
2.11.4
PGIC
The Patient Global Impression of Change (PGIC) instrument is planned to be administered 
during at weeks 4, 8, 12, 16, 24, 36, 48 and 96 after randomization
The PGIC is comprised of a single question intended to measure a patient’s perspective of 
improvement or deterioration over time relative to treatment. The PGIC uses a seven-point scale 


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where one (1) equals very much improved and seven (7) equals very much worse. Missing 
values will not be imputed.
The number and percentage of subjects in each of the seven categories for PGIC will be 
presented by treatment group at each assessment time point.
2.12
Resource utilization
Data relating to resource utilization (described in trial protocol Section 7.2.5) from the FAS will 
be used for the purpose of economic evaluation, which will be carried out and reported as a 
separate activity outside the CSR. 
The measures of healthcare resource utilization (HCRU) include: hospitalization (H), 
emergency room (ER) visit, general practitioner (GP) visits, specialist (Sp) visit and urgent care 
(UC) visit. HCRU will be assessed as follows: frequency and duration of hospitalization from 
baseline up to end of treatment; frequency of emergency room visits from baseline up to end of 
treatment; frequency of additional outpatient office visits general practitioner, specialist, and 
urgent care visits from baseline up to end of treatment. Hospitalization visits will also record 
the number of days on ward and the type of ward (hospital unit) and the discharge status. At 
each HCRU collected, the reason for the visit, i.e. related to CML, AE related to CML therapy 
or other reason, will be collected, in order to quantify the impact of treatment on healthcare 
resources.
HCRU data by treatment arm will be summarized in the primary analysis CSR and the end of 
study treatment CSR, with descriptive statistics (n, mean, median, SD, min, max) for 
quantitative variables, and count and percentage for qualitative variables.
2.13
Biomarkers
As a project standard, Novartis will analyze only biomarkers collected in the clinical database.
For exploratory markers, since the studies are not adequately powered to assess specific
biomarker-related hypotheses, the goal of these exploratory statistical analyses should be
considered as the generation of new scientific hypotheses. No adjustment for multiple
comparisons is usually planned for exploratory analyses. Furthermore, additional post hoc
exploratory assessments are expected and may be performed.
There may be circumstances when  a decision is made to stop sample collection, or not 
perform or discontinue their analysis due to either practical or strategic reasons. Under such 
circumstances, the number of samples may be inadequate to perform a rigorous data analysis 
and the available data will only be listed and potentially summarized.
If not otherwise specified, the FAS will be used for all biomarker analyses on patients with 
biomarker data.
Exploratory biomarker objectives

To characterize mutations in the BCR-ABL1 gene at Week 1 Day 1, upon confirmed 
loss of molecular response and/or at end of treatment and examine their association 
with molecular and cytogenetic response for asciminib vs bosutinib


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
To understand biology of CML and bone marrow microenvironment on leukemic 
stem cells (LSCs) eradication, including patients’ immunogenicity

To assess clonal evolution during treatment with asciminib vs. bosutinib

To evaluate soluble/inflammatory factors that correlate with response to asciminib vs. 
bosutinib treatment 
Only some analyses for the first exploratory biomarker objective about BCR-ABL1 mutation
listed above are described here and the results will be included in the respective CSRs. 
Additional analyses for this and other exploratory biomarker objectives will be described in 
separate analyses plans, with results reported separately.
List of biomarkers evaluated and the collection time points
The biomarkers evaluated in the study are listed in Table 2-8 below.
Table 2-8
Sample biomarker summary table
Biomarker
Time point
Sample
Method
Immune markers PD-L1 
and CD8
Screening and 
end of treatment
Bone marrow biopsy
Immunohisto-
chemistry
Leukemic stem cells
characterization
Screening, week 
24 and end of 
treatment
Bone marrow aspirate
Flow cytometry
BCR-ABL1 gene mutation
W1D1 pre-dose 
and end of 
treatment. If 
mutation is 
present at 
baseline, then 
also every 12 
weeks after 
baseline
Peripheral blood
Sanger 
Sequencing
Low level mutations in 
BCR-ABL1 gene
W1D1 pre-dose 
and end of 
treatment
Peripheral blood
Mass 
spectrometry 
and NGS
Circulating cytokines in 
plasma
W1D1 pre-dose,
Week 48 and end 
of treatment
Peripheral blood
MSD and ELISA
Genetic variant analysis of 
the UGT2B7 and 
UGT2B17 gene
W1D1
Peripheral blood
Genechip
General data handling and preprocessing
For bone marrow samples the latest assessment during screening period will be used as the 
baseline value, while for blood samples the week 1 day 1 (W1D1) pre-dose assessment will be
used as the baseline value.


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When more than one biomarker data value are available for a subject at any time point, the 
mean of the replicate values will be used for all statistical analyses.
2.13.1
Somatic mutation biomarker data handling and analysis
Handling of somatic biomarker data
Overall, somatic mutation status (wild type or mutant) will be derived from the mutational 
status of the interrogated exons for the BCR-ABL1 gene by Sanger Sequencing. These may
be non-exclusive and the presence of mutation across more than one exon will be reported in 
separate categories.
Mutation summary statistics
All somatic mutation data will be reported using counts and percentages by the mutation type 
in the form of contingency tables with the rows containing the different mutations assayed, 
and the treatment groups in the columns. All the mutation categories for a gene will also be
aggregated into mutant, wild type or missing/unknown groups and counts/percentages will be
reported by these three categories as well. A summary table will be presented for baseline 
mutations and another summary table for post-baseline new mutations (not present at baseline).
All the mutation data will be listed for each subject ordered by treatment group.
Association between biomarkers and clinical outcome
This analysis does not adjust for multiple comparisons and results may have higher false 
positive rates.
The relationship between Week 1 Day 1 BCR-ABL1 gene mutation data (wild type or mutant)
and outcome data (with or without MMR at and by 24 and 96 weeks using FAS, with or without 
CCyR at and by 24 and 96 weeks using CCyR analysis set) will be explored by reporting
contingency tables and by applying a logistic regression including treatment group, Week 1 
Day 1 BCR-ABL1 gene mutation and their interaction as covariates. Treatment group will be
included in this summary table.
In addition, the same analysis will be performed for

the relationship between post-baseline new BCR-ABL1 mutation (with or without 
new mutation) up to 48 weeks and outcome data (with or without MMR at 48 and 96 
weeks using FAS, with or without CCyR at 48 and 96 weeks using CCyR analysis 
set).

the relationship between post-baseline new BCR-ABL1 mutation (with or without 
new mutation) up to end of treatment and outcome data (with or without MMR at 96 
weeks using FAS, with or without CCyR at 96 weeks using CCyR analysis set).
The odds ratios bewteen treatment groups with 95% confidence intervals will be reported, for 
each biomarker category and overall. If treatment by biomarker interaction is significant (e.g.
when p < 0.1), overall odds ratio for treatment will not be reported.


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2.14
Other exploratory analyses
MMR rate at 24 weeks
The FAS will be used for the following exploratory analyses:
1. A logistic regression model adjusted for the stratification factor (based on the 
randomization platform data IRT) will be fit to assess treatment effect. An adjusted 
odds ratio for the treatment effect with associated 95% confidence intervals will be 
presented. Mantel-Haenszel estimates of the common odds ratio and the 
corresponding 95% confidence interval will also be provided.
Some subjects were mistratified. To assess the impact of this mistratification on the 
treatment effect assessment, a logistic regression adjusting for major cytogenetic
status at baseline based on CRF data will also be run.
2. Based on the subgroups specified in Section 2.2.1, the following analyses will be 
performed for each subgroup:

Proportion of patients with MMR at 24 weeks and its 95% confidence interval 
based on the Pearson-Clopper method within each treatment group

The difference in MMR rate at 24 weeks between treatment groups and the 
corresponding Wald 95% confidence interval
Efficacy analyses in subgroups will be purely exploratory and are intended to explore 
the consistency of treatment effect. Forest plot (n, risk difference, Wald 95% 
confidence interval) will be produced to graphically depict the treatment effect 
estimates in different subgroups. No inferential statistics (p-values) will be 
produced for the subgroups.
3. A logistic regression model adjusted for the stratification factor (baseline major 
cytogenetic response status based on randomization data) and other important 
variables identified by the subgroup analyses above will be fit to assess treatment 
effect. An adjusted odds ratio for the treatment effect with associated 95% confidence 
intervals will be presented.
To assess the impact of mistratifications on the treatment effect assessment, the same 
analysis will be repeated, adjusting for major cytogenetic status at baseline based on 
CRF data instead of based on randomization data.
Influence of early molecular response levels on long term molecular response 
levels
The relationship between MMR status at 24 weeks and MMR status at 48 and 96 weeks will be 
explored using FAS by reporting contingency tables and by applying a logistic regression
including treatment group, MMR status at 24 weeks and their interaction as covariates. 
Treatment group will be included in this summary table. The odds ratios between treatment 
groups with 95% confidence intervals will be reported, for each category of MMR status at 24 
weeks and overall. If the interaction of treatment by MMR status at 24 weeks is significant
(e.g. when p < 0.1), overall odds ratio for treatment will not be reported.


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Efficacy Analysis on Switch Analysis Set
Efficacy analyses on the Switch Analysis Set will be performed at the time of the 96-week 
analysis. Unless otherwise specified, endpoints are defined and analyzed similarly as specified 
in Sections 2.5, 2.6, and 2.7 on Switch Analysis Set, but with baseline, FD, LD, and EoT 
replaced by baseline_switch, FDswitch, LDswitch, and S-EoT. The below are the efficacy endpoints 
to be analyzed:
1. MMR rate at and by all protocol-planned visits. 
2. CCyR rate at and by all protocol-planned visits. 
3. Time to MMR
4. Duration of MMR
5. Time to CCyR
6. Duration of CCyR
7. Time to Treatment Failure
The analysis of time-to-event endpoints will be conducted only if at least 5 events are observed.
2.15
Interim analysis
No formal interim analysis is planned for this trial.
Three to four analyses are planned with the analysis data cut-off dates and the scope of analyses 
as follows:

24-week Primary analysis: Formal testing of the primary endpoint with full alpha will be 
performed. Analyses of other efficacy endpoints at and by 24 weeks will also be 
performed.

96-week analysis: Formal statistical testing of the key secondary endpoint will be 
performed with = 0.05 (two-sided) only if the primary endpoint (i.e. MMR rate at 24 
weeks) is significant. Otherwise, no statistical testing will be performed, and any analysis
will be considered exploratory. Analyses of other efficacy endpoints will also be 
performed.

End of study treatment (EOsT) analysis (if required): similar to the 96-week analysis 
without formal statistical testing.
NOTE: This analysis may be conducted at the same time as 96-week analysis.

5-year PFS/OS update analysis: PFS and OS.
In addition, DMC safety analyses will be conducted. Prior to the database lock for the primary 
analysis, tables and figures aggregated by treatment arm for safety data review by the DMC or 
for other reporting activities will be produced by an independent statistician and independent 
statistical programmers.


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3
Sample size calculation
3.1
Primary analysis
To test the null hypothesis that the MMR rate at 24 weeks is equal in the two treatment arms, 
based on  two-sided 5% level of significance and with 90% power, 222 patients will be needed 
in total (i.e. 148 patients in the asciminib arm and 74 patients in the bosutinib arm based on 2:1 
randomization allocation). The calculations were made using the software package PASS 
(2008).
It is assumed that asciminib leads to a 20% improvement in the MMR rate at 24 weeks over 
bosutinib from 15% to 35% which corresponds to an odds ratio of 3.05. The assumed bosutinib 
MMR rate of 15% at 24 weeks is based on previous trials evaluating bosutinib therapy ([Kuoury 
et al. 2012], [Gambacorti-Passerini et al. 2014], [García-Gutiérrez et al. 2015]).
3.2
Power for analysis of key secondary variables
If the primary analysis of MMR rate at 24 weeks is statistically significant, then the key 
secondary endpoint MMR rate at 96 weeks will be tested, with the overall alpha controlled at 
the 5% two-sided level using a gatekeeping strategy.
Table 3-1 below summarizes the treatment effects of the key secondary endpoint which can be 
detected with 80% and 90% power, based on the specified assumptions regarding the bosutinib 
effect. The calculations were made using the software package PASS (2008).
Table 3-1
Detectable effect sizes for key secondary endpoint
Endpoint
Anticipated effect 
with bosutinib
2-sided alpha
Power
Detectable 
effect size§
MMR rate at 96 weeks
30%*
0.05
90%
80%
≥ 23%
≥ 20%
*: [Gambacorti-Passerini et al. 2014], Figure 1D.
§: Absolute difference from the anticipated effect with bosutinib.
For MMR rate at 96 weeks, if the anticipated effect with bosutinib is 30%, then the given sample 
size with 2-sided alpha=0.05 would allow to detect an absolute difference of at least 23% (i.e. 
MMR rate at 96 weeks with asciminib is at least 53%) for 90% power and of at least 20% (i.e. 
MMR rate at 96 weeks with asciminib is at least 50%) for 80% power.
4
Change to protocol specified analyses
Pharmacokinetic analysis set: Removal of the condition related to vomiting to consider a 
concentration evaluable as the occurrence and time of vomiting is not collected in the CRF.
The estimand langage was implemented in sections 2.5 and 2.6. Then, the PPS and analyses 
based on PPS were removed.
The subgroup considering historical BCR-ABL1 mutations was removed as not considered 
clinically relevant.
A definition for loss of CHR was provided.


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Definition of loss of MMR: removed any reference to confirmation of CHR and CCyR as 
confirmation of CHR and CCyR was not mandated by protocol and was therefore not performed 
in practise.
The following analyses were added:
ECOG status, time to event analyses for duration of MMR and CCyR, exposure adjusted AE 
incidence and yearly AE incidence, COVID-19 related sensitivity analyses. 
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 
treatment 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 missing and the EOT page is available:
The EOT completion date should be used.  

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 treatment 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. 
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


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Missing 
Element
Rule
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment 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 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
Stratum reported in the CRF


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This will be derived from the Bone Marrow Aspirate data recorded in the corresponding eCRF 
pages at baseline. In some case the baseline sample may be missing or not evaluable (i.e. <20 
metaphases). 
The following imputation rule will be applied to derive the missing or non evaluable values:

Major cytogenetic response (MCyR) (0 to 35% Ph+ metaphases) will be assumed if
BCR-ABL1 levels ≤10% (IS).
Rationale:
ELN 2013 recommendations are providing treatment milestones with response categories for 
cytogenetic and molecular response, which we can refer to for the imputation:
MCyR is roughly corresponding to BCR-ABL1 levels ≤10% (IS) (Ross et al 2009).
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 4.03. 
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 4.03. 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 v4.03 at the time of analysis will be 
used. For laboratory tests where grades are not defined by CTCAE v4.03, 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 high values, 


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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  
Hematology
Immature cells (promyelocytes, myelocytes, metamyelocytes and blasts) will not be displayed 
in shift tables and will only be listed.
Immature cells are manually counted only if anomalies are detected during the automatic testing. 
Therefore, when the automatic testing was performed but no data is transferred for immature 
cells, this means there was no immature cells and their values can be imputed to 0. Note that 
there should not be any imputation in case the automatic testing was not performed or the test 
of immature cells is present with missing value in the database (this would mean the test was to 
be performed but couldn’t).
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 (mmol/L) = Calcium (mmol/L) +0.02 (40 – [Albumin (g/L)]
For calculation of laboratory CTCAE grades 0 and 1, the normal range for derived corrected 
calcium is set to the same limits (in mmol/L) 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.


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Biochemistry
In order to avoid double reporting of the same information, all available values for BUN and 
UREA will be reported under the parameter name BUN (mmol/L) in listing using the following 
conversion rule: UREA (mmol/L)=2.14 BUN (mmol/L) ([Lamb E et al 2012]). 
5.4
Efficacy variables
5.4.1
Molecular response
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 PAXgeneTM Blood RNA tubes from MMD laboratory 
will be used in this study. The lab conversion factor for this assay was 1.1 until 1 June 2020 and 
1 thereafter.  
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
The BCR-ABL ratio in IS% provided by the central laboratory will be use in the analyses. 
However, to calculate the fold change in BCR-ABL1/ABL used to derive the loss of MMR 
criteria, in case the BCR-ABL number of copies is reported as a 0 value and the patient doesn’t 
have atypical transcript at baseline, then the value will be replaced by 1, and the BCR-ABL 
ratio will be calculated.
Molecular response is categorized as follows:

10% > BCR-ABL ratio

1% < BCR-ABL ratio ≤ 10%

0.1% < BCR-ABL ratio ≤ 1%

0.01% < BCR-ABL ratio ≤ 0.1%

0.0032% < BCR-ABL ratio ≤ 0.01%

BCR-ABL ratio ≤ 0.0032%
Major molecular response (MMR)
Major molecular response (MMR) is defined as a value of ≤ 0.1% of BCR-ABL ratio on the IS. 
This endpoint corresponds to a ≥ 3 log reduction in BCR-ABL transcripts from a standardized 
baseline value for untreated CML patients which was established in the IRIS study 
(STI5710106). MMR will be considered as a binary variable with patients achieving MMR 
grouped as ‘responders’ and patients not achieving MMR or patients with missing PCR 
evaluations grouped as ‘non-responders’.


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Loss of MMR
Loss of MMR is defined as an increase in BCR-ABL1/ABL to > 0.1% by international scale 
(IS) in association with a ≥ 5-fold rise in BCR-ABL1/ABL from the lowest value achieved up 
to that time point on study treatment and replicated by a second analysis of the same sample. 
Loss of MMR must be confirmed by a subsequent sample analysis within 4-6 weeks showing 
loss of MMR associated with a ≥ 5-fold rise in BCR-ABL1/ABL from the lowest value achieved
up to that time point on study treatment.
If there is any assessment in between indicating a BCR-ABL ratio of ≤ 0.1% or a < 5-fold 
increase in BCR-ABL ratio from the lowest value achieved up to that time point on study 
treatment, then the initial indication of loss of MMR cannot be confirmed. However, an 
assessment indicating (unconfirmed) loss of MMR will be considered as confirmed loss of 
MMR if the patient had loss of CHR or loss of complete cytogenetic response (CCyR) after the 
achievement of MMR. CML-related death or progression to AP or BC will be considered as 
confirmed loss of MMR in any case (if they occurred on treatment) (given that the patient 
achieved prior MMR). 
5.4.2
Cytogenetic response
Cytogenetic response will be based on the percentage of Ph+ metaphases in the bone marrow. 
Cytogenetic evaluations will be considered for response assessment only if the number of 
metaphases examined is ≥20 in each bone marrow sample. As per protocol, fluorescent in-situ
hybridization (FISH) assessments will not be considered for any evaluation of cytogenetic 
response during treatment.
Cytogenetic response is categorized as follows (a review of a minimum of 20 metaphases is 
required):

Complete response (CCyR): 0% Philadelphia chromosome positive (Ph+) metaphases

Partial response (PCyR): >0 to 35% Ph+ metaphases

Major response (MCyR = CCyR + PCyR): 0 to 35% Ph+ metaphases

Minor response (mCyR): >35 to 65% Ph+ metaphases

Minimal response: >65 to 95% Ph+ metaphases

None: >95 to 100% Ph+ metaphases.
If bone marrow aspirate blast percentage is provided as ‘<X’ (i.e. below limit of detection), the 
numeric value is set to X for summary tables. In the listing ‘<X’ will be presented.
Complete cytogenetic response (CCyR)
CCyR is defined as a value of 0% Ph+ metaphases in bone marrow.
CCyR will be considered as a binary variable with patients achieving CCyR grouped as 
‘responders’ and patients not achieving CCyR, patients with missing cytogenetic evaluations 
grouped as ‘non-responders’.
Loss of CCyR
Loss of CCyR is defined as an increase in the Ph+ bone marrow cells to > 0%.


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Loss of CCyR must have led to treatment discontinuation because of lack of efficacy (based on 
the “End of Treatment Phase Disposition” eCRF or “End of Treatment Disposition” eCRF 
during the Treatment switch phase with Subject status=”lack of efficacy” and Reason of 
treatment failure = “After start of therapy, loss of CHR, CCyR or PCyR”).
In addition, CML-related death or progression to AP or BC will be considered as loss of CCyR 
in any case (if they occurred on treatment).
Major cytogenetic response (MCyR)
MCyR is defined as a value of 0% to 35% Ph+ metaphases in bone marrow.
MCyR will be considered as a binary variable with patients achieving MCyR grouped as 
‘responders’ and patients not achieving MCyR, patients with missing cytogenetic evaluations 
grouped as ‘non-responders’.
Loss of MCyR is defined as an increase in the Ph+ bone marrow cells to > 35%. For patients 
with response = PCyR, this would constitute loss of PCyR.
CML-related death or progression to AP or BC will be considered as confirmed loss of MCyR
in any case (if they occurred on treatment).
5.4.3
Hematologic response
Loss of CHR
Loss of CHR is defined by meeting any of the following:

WBC count > 20 × 109/L

Platelet count ≥ 600 × 109/L

Appearance of blasts or promyelocytes in peripheral blood

Appearance of myelocytes + metamyelocytes ≥ 5% in peripheral blood

Progressive splenomegaly refractory to therapy (i.e. ≥5cm below left intercostal margin) 
Loss of CHR must have led to treatment discontinuation because of lack of efficacy (based on 
the “End of Treatment Phase Disposition” eCRF or “End of Treatment Disposition” eCRF 
during the Treatment switch phase with Subject status=”lack of efficacy” and Reason of 
treatment failure = “After start of therapy, loss of CHR, CCyR or PCyR”).
In addition, CML-related death or progression to AP or BC will be considered as loss of CHR 
in any case (if they occurred on treatment).
Complete hematologic response (CHR)
CHR is defined when all of the following criteria are present at any assessment which is
confirmed by another assessment at least after 4 weeks:

White blood cells (WBC) count < 10 × 109 /L

Platelet count < 450 × 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. As extramedullary
disease is evaluated less frequently than hematology, the results of these evaluations are
carried forward until the next assessment (unless extramedullary disease was not present
at the current assessment but present at the next).
The assessment is not considered CHR, if there are any values indicative of CML in AP or BC 
(i.e. by blasts in bone marrow). The information used for hematological assessment will be
obtained from the laboratory, extramedullary and bone marrow data, all merged by patient and 
date. To accommodate for missing parameters, specific laboratory results may be carried
forward up to 14 days such that assessments performed within a two-week period can combined 
into one complete evaluation of hematological response. A value will be carried forward for no 
more than up to the subsequent valid assessment of the respective laboratory parameter. If even 
after applying this carry-forward algorithm, any of the above laboratory parameters is not 
available at a given assessment date, the response assessment will be considered missing, unless 
any of the available values (including those carried forward) indicates that there is no response 
in which case the assessment will be ‘No response’.
For confirmation of CHR, both the initial CHR as well as the confirming assessment (at least 4 
weeks after the initial assessment) must satisfy all the criteria mentioned above and no
assessment in between indicates ‘No response’. The terms “confirmed CHR” and “CHR” are 
used as synonymous given that the definition of CHR mentioned above already includes a 
requirement for confirmation.
5.4.4
Treatment Failure
The following events will constitute ‘treatment failure’, and are based on the ELN criteria
(Baccarani et al 2013) defining failure of a second line treatment adapted to include 
discontinuation of randomized treatment as an event:

No CHR or > 95% Ph+ metaphases at three months after initiation of therapy or 
thereafter

BCR-ABL1 ratio > 10% IS and/or > 65% Ph+ metaphases at six months after 
initiation of therapy or thereafter

BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases at 12 months after 
initiation of therapy or thereafter

Loss of CHR, CCyR or PCyR at any time after initiation of therapy

Detection of new BCR-ABL1 mutations which potentially cause resistance to study 
treatment (T315I and V299L), at any time after initiation of therapy  

Confirmed loss of MMR in 2 consecutive tests

New clonal chromosome abnormalities in Ph+ cells: CCA/Ph+: at any time after 
initiation of therapy

Discontinuation from randomized treatment for any reason* (Note that Reason for 
treatment discontinuation=”completed” doesn’t indicate a premature treatment 
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5.4.5
CML progression to accelerated phase (AP) or blast crisis (BC)
For the evaluation of CML progression to AP or BC, the following criteria will be used.
Accelerated phase (AP) is defined by any of the following:

≥ 15% blasts in the peripheral blood or bone marrow aspirate, but < 30% blasts in 
both the peripheral blood and bone marrow aspirate

≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow aspirate, but < 
30% blasts in both the peripheral blood and bone marrow aspirate

≥ 20% basophils in the peripheral blood

Thrombocytopenia (<100 x 109/L) that is unrelated to therapy*
*As thrombocytopenia is a known adverse reaction to CML therapy, platelets <100 × 109/L are 
only considered as CML-AP if the patient had these values within 30 days of treatment 
discontinuation due to disease progression. In this case, comments are to be provided on the 
termination page that thrombocytopenia is indicative of progression to AP and an adverse event 
(AE) entered with relationship to study treatment = ‘Not suspected’
Blast crisis (BC) is defined by any of the following:

≥ 30% blasts in peripheral blood or bone marrow aspirate

Appearance of extramedullary involvement other than hepatosplenomegaly proven by 
biopsy (i.e., chloroma).
The second bullet criteria can’t be considered in this study as this information was not 
collected.
5.4.6
CML-related deaths
CML-related death is considered as any death during treatment or follow-up (safety or survival)

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.
With respect to the second bullet, as “unknown” cause of death will be coded to the Medical 
Dictionary for Regulatory Activities (MedDRA) preferred term ‘Death’, this MedDRA coding 
will be used in the derivation of CML-related death.
5.4.7
Disease progression
The following events are considered disease progression

CML-related deaths

Accelerated phase (AP)

Blast crisis (BC)
5.4.8
Overall survival
This includes all-cause deaths.


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5.5
Derivation of response rates and categories 
5.5.1
Response rate at a specific time point
The molecular and cytogenetic response evaluations will be summarized by the following 
mutually exclusive categories which are based on the respective assessment within the time 
window:

Response categories (sections 5.4.1 and 5.4.2 ): Patients with an available assessment at 
that time point (+/- time window) indicating any of the response categories.

No response: Patients with assessment at that time point (+/- time window) indicating 'no 
response'

Missing: Patients without an evaluable response assessment at that time point (+/- time 
window). This category is then further split into patients who are ongoing without 
treatment failure at the beginning of the relevant time window, patients who are ongoing
with treatment failure at the beginning of the relevant time window, patients who 
discontinued due to lack of efficacy, disease progression (PD) or death and patients who 
discontinued due to other reasons.
5.5.2
Response rate by a specific time point (best response)
In this analysis, patients who had achieved any response at or before the time point will be 
displayed in their best response category, no matter if they lost the response/discontinued or not. 
Therefore this response rate represents the best observed response rate up to that specific time 
point (including the time window). 
Patients for whom an evaluable response assessment was never provided will be classified as 
‘Missing’. 
5.6
Statistical models
5.6.1
Primary analysis
The null hypothesis of equality of MMR rate at 24 weeks in the two treatment arms will be 
tested against two-sided alternative. The statistical hypotheses are:
H0: RA24wk = RB24wk versus HA: RA24wk ≠ RB24wk, for a two-sided test
where RA24wk is the probability of MMR rate at 24 weeks in asciminib arm and RB24wk is the 
probability of MMR rate at 24 weeks in bosutinib arm.
The Cochran-Mantel-Haenszel chi-square test X2
CMH(implemented via SAS procedure FREQ
with CMH option in the TABLES statement), stratified by the randomization stratification 
factor, i.e. cytogenetic response status (MCyR vs no MCyR) at screening, will be used to test
the difference in response rates between the treatment arms. The p-value corresponding to the 
CMH test for “general association” will be used which follows a Chi-square distribution with 
one degree of freedom.
The 95% confidence interval for the unstratified difference in MMR rate at 24 weeks between 
treatment groups will be provided using the Wald method (implemented via SAS procedure
FREQ
with RISKDIFF option
in
the
TABLES
statement, under the default 


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METHOD=WALD and VAR=SAMPLE). If the 2×2 table is with asciminib in row 1, 
bosutinib in row 2, MMR in column 1 and No MMR in column 2, then the SAS output will 
give the estimate of (risk for MMR at 24 weeks in asciminib – risk for MMR at 24 weeks in 
bosutinib). The corresponding Mantel-Haenszel estimate of common risk difference and 95% 
confidence interval will also be presented (with RISKDIFF(COMMON) option in the
TABLES statement, taking the Mantel-Haenszel estimate from the SAS output table).
If the sampling assumptions for chi-square test is not met (i.e. the expected frequencies should
exceed 5 for all of table cells), the exact Cochran-Mantel-Haenszel test will be used 
(implemented via SAS procedure MULTTEST). The test is performed by running a stratified
version of the Cochran-Armitage permutation test [Armitage et al. 1969]. In studies with
stratified randomization, the chi-square approximation is considered appropriate for the 
X2
CMH statistics if the rule of Mantel and Fleiss [Mantel and Fleiss 1980] is satisfied.
Confidence interval for MMR rate within each treatment arm
MMR will be summarized in terms of percentage rates with 95% confidence interval using
exact binomial confidence interval (implemented using SAS procedure FREQ with EXACT
statement for one-way table [Clopper and Pearson 1934]).
5.6.2
Key secondary analysis
The null hypothesis of equality of MMR rate at 96 weeks in the two treatment arms will be 
tested against two-sided alternative. The statistical hypotheses are:
H0: RA96wk = RB96wk versus HA: RA96wk ≠ RB96wk, for a two-sided test
where RA96wk is the probability of MMR rate at 96 weeks in asciminib arm and RB96wk is the 
probability of MMR rate at 96 weeks in bosutinib arm.
The same approaches as for the primary endpoint (Section 5.5.1) will be applied here for the 
Cochran-Mantel-Haenszel chi-square test X2
CMH, the 95% Wald confidence interval for the 
difference in MMR rate at 96 weeks between treatment groups, the Mantel-Haenszel estimate 
of common risk difference with 95% confidence interval, and the confidence interval for MMR 
rate within each treatment arm.
Multiplicity adjustment
Formal statistical testing of the key secondary endpoint will be performed with = 0.05 (two-
sided) only if the primary endpoint is significant by means of a gatekeeping procedure to control 
the overall alpha level.
5.6.3
Other analyses
Mantel-Haenszel common odds ratio
To obtain Mantel-Haenszel estimates of the common odds ratio and the corresponding 95% 
confidence interval in exploratory analyses,  it requires SAS procedure FREQ with CMH and 
RELRISK options in the TABLES statement. 


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Logistic Regression 
Odds ratio will be used as a measure of association between treatment and response in 
exploratory analyses (Section 2.14). The odds ratio will be derived from the logistic regression
model (implemented using SAS procedure LOGISTIC, with treatment specified as an
explanatory variable in the CLASS statement) which allows for including not only the
stratification factor but also for adjustments for other covariates (both categorical and
continuous). The odds ratio will be presented with 95% Wald confidence limits.
In cases where an exact test has been used to compare response rates, the odds ratio should be 
determined using exact logistic regression, and the odds ratio presented with exact 95% 
confidence limits. In these cases, SAS PROC LOGISTIC with EXACTONLY option will be 
used.
Kaplan-Meier estimates
An estimate of the survival function in each treatment group will be constructed using Kaplan-
Meier (product-limit) method as implemented in PROC LIFETEST with METHOD=KM
option. The PROC LIFETEST statement will use the option CONFTYPE=LOGLOG.
Median survival for each treatment group will be obtained along with 95% confidence 
intervals calculated from PROC LIFETEST output using the method of [Brookmeyer and 
Crowley 1982]. Kaplan-Meier estimates of the survival function with 95% confidence
intervals at specific time points will be summarized. The standard error of the Kaplan-
Meier estimate will be calculated using Greenwood’s formula [Collett 1994].
Hazard ratio
Hazard ratio will be estimated by fitting the Cox proportional hazards model using SAS 
procedure PHREG (with TIES=EXACT option in the MODEL statement). 
A stratified unadjusted Cox model will be, i.e. the MODEL statement will include the
treatment group variable as the only covariate and the STRATA statement will include
stratification variable(s). Hazard ratio with two-sided 95% confidence interval will be based 
on Wald test.
5.6.4
Calculation of exposure-adjusted incidence rate
To adjust for different durations of exposure across treatment arms, the incidence rate per 100 
patient-years of exposure (exposure-adjusted incidence rates of adverse events) will be 
calculated.
The IR/100 pyr is defined as numerator/denominator, where

Numerator = number of patients with the adverse events of interest (not the number of 
events; one patient may have more than one event).

Denominator = patient-years = total time at risk in years = among all patients in the 
population, sum of the duration of exposure (in days) until the first onset of the event 
of interest, if the patient experienced the event, or until the date of last dose if the 
patient did not experience the event / 365.25.
The patient-years (i.e. total time at risk in years) will be calculated as the sum of times at risk 
in days over all patients in the population / 365.25.


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The time at risk for a patient in days will be calculated as follows:

If the patient experienced the event of interest, the time at risk for this patient is the 
duration of exposure from the first dose of treatment until the first onset of the event.

For patients without an event of interest, the time at risk is the total duration of 
exposure during core study, as applicable.
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. Lamb E, et al (2012) Kidney Function Tests  In Elsevier Health Sciences (Ed), Tietz 
Textbook of Clinical Chemistry and Molecular Diagnostics (Chapter 25). Also retrieved 
from 
https://books.google.es/books?id=BBLRUI4aHhkC&lpg=PA685&hl=es&pg=PA685#v=o
nepage&q&f=false
11. 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.
12. Ross DM, Branford S, Moore S, et al (2006) Limited clinical value of regular bone 
marrow cytogenetic analysis in imatinib-treated chronic phase CML patients monitored by 
RQ-PCR for BCR-ABL. Leukemia; 20(4):664-70.


Clinical Development
ABL001/asciminib
CABL001A2301
A phase 3, multi-center, open-label, randomized study of 
oral ABL001 (asciminib) versus bosutinib in patients with 
Chronic Myelogenous Leukemia in chronic phase (CML-
CP), previously treated with 2 or more tyrosine kinase 
inhibitors
Statistical Analysis Plan (SAP) – Addendum 1
Document type:
SAP Documentation
Document status:
Addendum 1 
Release date:
14-October-2020
Number of pages:
75
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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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)
25-
Aug-
2017
Prior 
to 
DB 
lock
for 
primary 
analysis
Creation 
of 
final version
N/A - First version
NA
26-
Mar-
2020
Prior 
to 
DB 
lock 
for 
primary 
analysis
Implementation 
of 
protocol 
amendments 2 
and 3. 
ABL001 has been replaced by 
International Nonproprietary 
Name (INN) asciminib.
Introduction of the switch to 
asciminib option for patients 
experiencing treatment failure 
on bosutinib treatment
Update of the definition of 
end of study treatment
Added a potential End-of-
Study-Treatment analysis 
different from the 96-week 
analysis
Addition/removal of
secondary safety objectives 
and exploratory efficacy 
objectives
Throughout the 
SAP amendment
Section 
 
1.1, 
Figure 
1-1
Sections 2.1, 2.3
Analyses added 
throughout 
the 
document
Section 1.1
Table 1-1
Additional 
analyses, 
clarification
Clarification on which data are 
included in 
the analyses, 
which 
assessments 
are 
considered for safety
and 
efficacy analyses
Addition of the treatment arms 
and definition of the date of 
end 
of 
study 
treatment
Removal of windows defined 
for ECGs, LVEF and PK 
assessments as they are not 
needed.
Section 
2.1
Section 
2.1.1


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As per Health Authorities 
request, 
addition 
of 
the 
breakdown per different time 
points of the number (%) of 
patients who discontinued the 
study treatment phase and of 
the primary reason for study 
treatment 
phase 
discontinuation
PAS: 
Removal 
of 
the 
condition related to vomiting 
to consider a concentration 
evaluable as the occurrence 
and time of vomiting is not 
collected in the CRF.
Addition 
of 
a
subgroup 
“Stratum reported in the CRF” 
for the analysis by subgroup of 
the primary endpoint (to take 
into 
account 
the 
mistratification cases)
Removal of the subgroup 
“with or without historical 
BCR-ABL1 mutation by local 
lab” as this is not considered 
clinically relevant
Additional analyses of prior 
TKI 
and 
non 
TKI 
antineoplastic therapies
Implementation 
of 
the 
estimand language for the 
primary and key secondary 
objectives
Addition 
of 
a 
sensitivity 
analysis 
of 
the 
primary 
estimand stratifying by the 
stratum recorded in the CRF to 
take into account that many 
stratification errors occurred
Addition of 
Time-to-event 
analyses for time to MMR and 
time to CCyR
Section 
2.3.1
Section 2.2
Section 
2.2.1
Section
2.4.2
Sections 2.5 and 
2.6
Section 
2.5.5
Section 
2.7.2


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Added how time is censored 
for time to MMR/CCyR, 
clarification on how to handle 
missing BMA assessments 
due to MMR being achieved
Added analyses AEs and 
SAEs 
incidence 
rates 
by 
adjusting for exposure and by 
reporting by time intervals to 
account 
for 
potential 
difference 
in 
exposure 
between the treatment arms
Clarified 
handling 
of 
unscheduled 
ECG 
measurements in the analyses 
Section 
2.7.3
Section 
2.8.1
Section 2.8.4.1
4-
June-
2020
Prior 
to 
DB 
lock 
for 
primary 
analysis
Creation 
of 
amendment 2.0
Clarified 
baseline 
for 
mutations
Clarified EOT is mapped to 
defined time points
Modified age subgroup, added 
Line of therapy subgroup and 
moved Without T315I/V299L 
to 
Supplementary 
analysis
(All 
patients 
with 
T315I/V299L 
mutations 
identified at the Week 1 Day 1 
visit are discontinued from 
study treatment when the 
mutation 
results 
become 
available).
Clarified Mutation subgroup 
doesn’t include T315I/V299L 
mutations.
Modified age categories
Added COVID-19 related PDs 
analysis
Added definitions of time on 
treatment, 
duration 
of 
exposure in patient-years and 
average daily dose
Section 
2.1.1
Section 
2.2.1
Section 2.3
Section 
2.3.1
Section 
2.4.1


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Additional analyses of prior 
TKI therapy
Added 
summary 
of 
concomitant therapies for on-
switched treatment period.
Added COVID-19 sensitivity 
analyses for the primary and 
key secondary endpoints
Added 
a 
supplementary 
analysis 
to 
the 
primary 
endpoint 
(Patients 
without 
T315I/V299L mutations at 
Week 1 Day 1 visit)
Added new graph for Ctrough
values of asciminib
Updated the list of changes to 
the protocol specified analyses
Added imputation rules for 
immature cells
Removed imputation rules for 
corrected calcium as corrected 
calcium is collected
Clarified all available values 
for BUN and UREA will be 
reported under the parameter 
name BUN in listing to avoid 
double reporting of same 
information
Definition of loss of MMR: 
Removed 
reference 
to 
confirmation 
of 
loss 
of 
CHR/CCyR
Loss 
of 
CHR: 
clarified 
“Progressive 
splenomegaly 
refractory to therapy” is ≥ 5cm
below left intercostal margin”
Implemented 
change 
to 
definition of treatment failure 
(Protocol amendment 3)
Section 
2.4.2
Sections 
2.5.5, 
2.6.5
Section 
2.5.6
Section 
2.9
Section 
4
Section 
5.3
Section 
5.4.1
Section 
5.4.3
Section 
5.4.4
Section 
5.4.5 


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Clarified 
what 
“Thrombocytopenia (<100 x 
109/L) that is unrelated to 
therapy” is.
Added derivation of response 
rates and categories section
Section 5.5.
7-
Aug-
2020
Prior 
to 
DB 
lock 
for 
primary 
analysis
Creation 
of 
amendment 3.0
after FDA type 
C 
teleconference 
on 28 July 2020
As agreed with FDA, added 
sensitivity analyses of the 
primary and key secondary 
endpoints
without 
the 
imputation rule used in the 
main analyses
in case of 
missing PCR evaluations at 
24/96 weeks. 
Per 
FDA 
request, 
added 
another subgroup of interest: 
BCR-ABL ratio at baseline ≥
1% or <1%.
Added calculation rules for 
duration of interrruption.
Added derivation rule for 
corrected calcium using the 
reported total calcium value 
and albumin.
Aligned the definition of loss 
of CCyR with the definition of 
loss of CHR by adding the 
requirement that loss of CCyR 
(Ph+ bone marrow cells to > 
0%) must have led to treatment 
discontinuation because of 
lack of efficacy.
Section 
2.5.5
Section 
2.2.1
Section 
2.4.1
Section 
5.3
Section 5.4.2
14-
Oct-
2020
Post
DB 
lock 
for 
primary 
analysis
Creation 
of 
addendum 1.0 
to include post-
hoc 
analyses
added after FIR 
results review
Added that protocol deviations 
during the treatment switch 
period 
will 
be 
reported 
separately and clarified .
Clarified how to identify 
prohibited 
concomitant 
medications.
Added an analysis of time to 
MMR 
considering 
Section 
2.3.1
Section 
2.4.2
Sections 
2.7.2 
and 
5.6.3


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discontinuation 
from 
treatment due to any reason, 
without prior achievement of 
MMR as a competing risk.
Added an analysis of the 
MMR rate using the number of 
subjects with adequate follow-
up as the denominator, i.e. for 
each time point (week x), only 
patients randomized at least x 
weeks prior to the cut-off date 
will be considered.
Added
that 
post-hoc 
exploration of the treatment 
effect in different subgroups 
and assessment of the possible 
effect 
of 
differences 
in 
distribution 
of 
baseline 
characteristics were conducted 
(e.g. distribution of reasons for 
discontinuation of last prior 
TKI by gender and treatment, 
distribution of MCyR status at 
baseline 
by 
reasons 
for 
discontinuation of last prior 
TKI, distribution of mutation 
status at Week 1 Day 1 by 
reasons for discontinuation of 
last prior TKI).
Section 
2.14


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Table of contents
Table of contents .................................................................................................................8
1
Introduction .......................................................................................................................13
1.1
Study design...........................................................................................................13
1.2
Study objectives and endpoints .............................................................................14
2
Statistical methods.............................................................................................................16
2.1
Data analysis general information .........................................................................16
2.1.1
General definitions................................................................................18
2.2
Analysis sets ..........................................................................................................26
2.2.1
Subgroup of interest ..............................................................................27
2.3
Patient disposition, demographics and other baseline characteristics ...................29
2.3.1
Patient disposition.................................................................................30
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................32
2.4.1
Study treatment / compliance................................................................32
2.4.2
Prior, concomitant and post therapies...................................................34
2.5
Analysis of the primary objective/estimand ..........................................................36
2.5.1
Primary endpoint/estimand ...................................................................36
2.5.2
Statistical hypothesis, model, and method of analysis..........................37
2.5.3
Handling of remaining intercurrent events of primary estimand..........37
2.5.4
Handling of missing values not related to intercurrent event ...............37
2.5.5
Sensitivity analyses ...............................................................................37
2.5.6
Supplementary analyses........................................................................38
2.6
Analysis of the key secondary objective/estimand................................................38
2.6.1
Key secondary endpoint/estimand ........................................................39
2.6.2
Statistical hypothesis, model, and method of analysis..........................39
2.6.3
Handling of remaining intercurrent events of primary estimand..........40
2.6.4
Handling of missing values not related to intercurrent event ...............40
2.6.5
Sensitivity analysis................................................................................40
2.7
Analysis of secondary efficacy objective(s)..........................................................40
2.7.1
Secondary endpoints .............................................................................40
2.7.2
Statistical hypothesis, model, and method of analysis..........................42
2.7.3
Handling of missing values/censoring/discontinuations.......................45
2.8
Safety analyses.......................................................................................................46
2.8.1
Adverse events (AEs)............................................................................46
2.8.2
Deaths....................................................................................................47


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2.8.3
Laboratory data .....................................................................................48
2.8.4
Other safety data ...................................................................................49
2.8.5
Additional Analyses..............................................................................51
2.9
Pharmacokinetic endpoints....................................................................................51
2.10
PD and PK/PD analyses.........................................................................................53
2.11
Patient-reported outcomes .....................................................................................53
2.11.1
MDASI-CML........................................................................................54
2.11.2
EQ-5D-5L .............................................................................................54
2.11.3
WPAI-CML...........................................................................................55
2.11.4
PGIC......................................................................................................55
2.12
Resource utilization ...............................................................................................56
2.13
Biomarkers.............................................................................................................56
2.13.1
Somatic mutation biomarker data handling and analysis......................58
2.14
Other exploratory analyses ....................................................................................59
2.15
Interim analysis......................................................................................................60
3
Sample size calculation .....................................................................................................61
3.1
Primary analysis.....................................................................................................61
3.2
Power for analysis of key secondary variables......................................................61
4
Change to protocol specified analyses ..............................................................................61
5
Appendix ...........................................................................................................................62
5.1
Imputation rules.....................................................................................................62
5.1.1
Study drug.............................................................................................62
5.1.2
AE, ConMeds and safety assessment date imputation..........................62
5.2
AEs coding/grading ...............................................................................................64
5.3
Laboratory parameters derivations ........................................................................64
5.4
Efficacy variables ..................................................................................................66
5.4.1
Molecular response ...............................................................................66
5.4.2
Cytogenetic response ............................................................................67
5.4.3
Hematologic response ...........................................................................68
5.4.4
Treatment Failure..................................................................................69
5.4.5
CML progression to accelerated phase (AP) or blast crisis (BC) .........70
5.4.6
CML-related deaths...............................................................................70
5.4.7
Disease progression...............................................................................70
5.4.8
Overall survival.....................................................................................71
5.5
Derivation of response rates and categories ..........................................................71
5.5.1
Response rate at a specific time point...................................................71


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5.5.2
Response rate by a specific time point (best response).........................71
5.6
Statistical models...................................................................................................71
5.6.1
Primary analysis....................................................................................71
5.6.2
Key secondary analysis.........................................................................72
5.6.3
Other analyses .......................................................................................73
5.6.4
Calculation of exposure-adjusted incidence rate...................................74
6
Reference...........................................................................................................................74


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List of abbreviations
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AP
Accelerated phase
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic classification
AUC
Area under the curve
BC
Blast crisis
bid
bis in diem/twice a day
CCyR
Complete cytogenetic response
CHR
Complete hematologic response
CMH
Cochrane-Mantel-Haenszel
CML
Chronic myelogenous leukemia
CML-CP
Chronic myelogenous leukemia in chronic phase
CRO
Contract research organization
CSP
Clinical study protocol
CSR
Clinical study report
CTCAE
Common terminology criteria for adverse events
CV
Coefficient of variation
DAR
Dosage administration record
DI
Dose intensity
DMC
Data monitoring committee 
DRL
Drug reference  listing
DSUR
Development safety update report
ECG
Electrocardiogram
eCRF
Electronic case report form
EOT
End of treatment in the treatment phase (patient level)
EOsT
End of study treatment (study level)
ER
Emergency room
FAS
Full analysis set
FD
First dose date of study treatment during the treatment phase
FDswitch
First dose date of asciminib during the treatment switch phase
GP
General practitioner
H
Hospitalization
HCRU
Health care resource utilization
HLT
High level term
HLGT
High level group term
IRT
Interactive response technology
IS
International scale
LD
Last dose date of study treatment during the treatment phase
LDswitch
Last dose date of asciminib during the treatment switch phase


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LLOQ
Lower limit of quantitation
LPFT
Last patient first treatment
LSC
Leukemic stem cell
LVEF
Left ventricular ejection fraction
MCyR
Major cytogenetic response
mCyR
Minor cytogenetic response
MedDRA
Medical dictionary for regulatory activities
MMR
Major molecular response
NCI
National Cancer Institute
NGS
Next generation sequencing
NMQ
Novartis MedDRA Query
OS
Overall survival
PAS
Pharmacokinetic analysis set
PCR
Polymerase chain reaction
PCyR
Partial cytogenetic response
PD
Pharmacodynamic
PDI
Planned dose intensity
PFS
Progression-free rurvival
Ph+
Philadelphia chromosome positive
PK
Pharmacokinetics
PPS
Per-protocol set
PRO
Patient-reported outcomes
PSUR
Periodic safety update report
PT
Preferred term
qd
Qua’que di’e / once a day
RDI
Relative dose intensity
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
S-EoT
End of treatment in the treatment switch phase (patient level)
SMQ
Standardized MedDRA query
SOC
System organ class
Sp
Specialist
TBL
Total bilirubin
TKI
Tyrosine kinase inhibitor
TTF
Time to treatment failure
UC
Urgent care
ULN
Upper limit of norm
VAS
Visual analogue scale
W1D1
Week 1 Day 1
WBC
White blood cells
WHO-DD
World Health Organization Drug Dictionary


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses of primary objective,
secondary objectives and selected exploratory objectives for the clinical study reports (CSR) of 
study CABL001A2301, a phase 3, multi-center, open-label, randomized study of oral asciminib
versus bosutinib in patients with Chronic Myelogenous Leukemia in chronic phase (CML-CP), 
previously treated with 2 or more tyrosine kinase inhibitors. 
The content of this SAP is based on protocol CABL001A2301 version 03. All decisions 
regarding safety monitoring analysis for the data monitoring committee, 24-week primary
analysis, 96-week analysis, end of study treatment analysis, 5-year progression-free survival 
(PFS)/overall survival (OS) update analysis, and postings for ClinTrial.gov and EudraCT, as 
defined in this SAP document, have been made prior to the first database lock of the study data
for the primary analysis.
1.1
Study design
This is a randomized,  Phase III , open-label,  active-controlled, multi-center study  comparing  
safety and efficacy of asciminib to bosutinib in patients with CML-CP, previously treated with 
2 or more tyrosine kinase inhibitors (Figure 1-1). Approximately 220 patients will be 
randomized to one of the following treatment arms in 2:1 ratio:

asciminib 40 mg BID

Bosutinib 500 mg QD
Randomization will be stratified by the following factor: cytogenetic response status (with or 
without major cytogenetic response).
Figure 1-1
Schematic of Study Design
Patients with documented treatment failure (as per the 2013 ELN guidelines, Baccarani et al 
2013) while on bosutinib treatment will have the option to switch to asciminib treatment within 


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96 weeks after the last patient has been randomized on study. The patients who switch to 
asciminib will be able to receive asciminib up to the end of study treatment (EOsT) period.
Patients will be treated up to the EOsT defined as up to 96 weeks after the last patient received 
the first study dose (LPFT) or up to 48 weeks after the last patient has switched to asciminib 
treatment whichever is longer, if they do not discontinue study treatment earlier. After the EOsT, 
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.
Major Molecular Response (MMR) rate at 24 weeks is the primary endpoint in this study. MMR 
rate at 96 weeks is the key secondary endpoint.
Four analyses are planned for this study, including the 24-week primary analysis, the 96-week 
analysis, the End-of-Study-Treatment (EOsT) analysis, and Progression-Free survival/Overall 
survival (PFS/OS) update analysis The timing when those analyses are conducted is 
summarized in Section 2.1. 
No formal interim efficacy analysis is planned in this study. A data monitoring committee 
(DMC) will monitor unblinded safety data approximately 6 months after the first randomized 
patient has started study treatment. Subsequent reviews will be conducted approximately every 
6 months and when needed thereafter (ie. if significant safety findings are noted) until the 
primary analysis.
1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Primary
To compare the MMR rate at 24 weeks of
asciminib versus bosutinib 
Major Molecular Response (MMR) rate at 24 weeks
Key secondary
To compare additional parameters of the 
efficacy of asciminib versus bosutinib 
MMR rate at 96 weeks
Other secondary
To compare additional parameters of the 
efficacy of asciminib versus bosutinib

Cytogenetic response rate (Complete, Partial, Major, 
Minor, Minimal, no response) at and by all scheduled 
data collection time points including 24, 48 and 96 weeks

MMR rate at all scheduled data collection time points  
(except 24 and 96 weeks which are already covered by 
primary and key secondary endpoints)

MMR rate by all scheduled data collection time points 
including 24, 48 and 96 weeks

Time to MMR

Duration of MMR

Time to CCyR

Duration of CCyR

Time to treatment failure

Progression free survival


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Objective
Endpoint

Overall survival
To compare the safety and tolerability 
profile of asciminib versus bosutinib
Type, frequency and severity of adverse events,
changes in laboratory values that fall outside the pre-
determined ranges and clinically notable ECG and other 
safety data (vital signs)
To characterize the PK of asciminib in the 
CML-CP population
Trough plasma concentrations,
PK parameters in full PK group: Cmax, Tmax, AUC0-12h, 
CL/F 
To assess the safety of asciminib when 
administered as treatment after bosutinib 
failure according to the 2013 ELN 
Guidelines
Type, frequency and severity of adverse events, changes in 
laboratory values that fall outside the pre-determined ranges 
and clinically notable ECG and other safety data (vital signs)


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Objective
Endpoint
Exploratory
To evaluate the influence of factors such 
as cytogenetic response at baseline, 
failure/intolerance to prior TKIs, line of 
therapy, gender, race and age on the 
effect of asciminib with respect to the 
primary efficacy endpoint 
Major Molecular Response (MMR) rate at 24 weeks
To explore the exposure-response 
relationships of asciminib; evaluate the 
effect of population covariates
Exposure-safety, exposure-PD analyses
To characterize mutations in the BCR-
ABL1 gene at Week 1 Day 1, upon 
confirmed loss of MMR and/or at end of 
treatment and examine their association 
with molecular and cytogenetic response 
for asciminib vs bosutinib
BCR-ABL1 gene mutations at Week 1 Day 1, upom confirmed 
loss of MMR and/or at end of treatment as determined by 
Sanger Sequencing
To understand biology of CML and bone 
marrow microenvironment on leukemic 
stem cells (LSCs) eradication, including 
patients’ immunogenicity
Bone marrow biopsies characterization for adaptive immune 
response by immunohistochemistry (IHC); bone marrow 
aspirates to evaluate the effect of treatments on LSCs burden 
and immune cells subsets changes by flow cytometry
To assess clonal evolution during 
treatment with asciminib vs. bosutinib
Low level BCR-ABL1 mutation profiles assessed by mass 
spectrometry at Week 1 Day 1, upon confirmed loss of MMR
and/or at EOT.  
Clonal evolution of several genes implicated in CML assessed 
by Next Generation Sequencing (NGS) methods 
To evaluate soluble/inflammarory factors 
that correlate with response to asciminib
vs. bosutinib treatment
Baseline and changes from baseline of cytokine expression in 
plasma  
To compare the impact of treatment on 
patient reported outcomes (PRO) 
including CML-specific symptoms, patient 
quality of life, and impact on work 
productivity and activity impairment from 
baseline and EOT between  treatment 
arms in all patients
Change in symptom burden and interference from baseline 
over time according to the MDASI-CML PRO instrument
Change in patient’s impression of CML symptoms according 
to Patient Global Impression of Change (PGIC)
Change in health utility from baseline over time according to 
EQ-5D-5L
Change in work productivity and activity impairment over time 
according to WPAI
To compare the impact of treatment on 
health care resource utilization between 
treatment arms in all patients
Health care resource burden over time
2
Statistical methods
2.1
Data analysis general information
The planned analyses will be performed by Novartis and/or a designated CRO. SAS version 9.4 
or later will be used to perform all data analyses and to generate tables, figures and listings.
There is no planned interim efficacy analysis. Prior to the database lock for the primary analysis, 
tables and figures aggregated by treatment arm for safety data review by the data monitoring 
committee or for other reporting activities will be produced by an independent statistician and 
independent statistical programmers.


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For between-treatment comparisons of efficacy endpoints, randomization stratification factor, 
i.e. cytogenetic response status (MCyR vs no MCyR) at screening, will be included in respective
stratified statistical tests.
Data included in the analyses
The analysis data cut-off dates for the planned analyses are:

Primary analysis: After all randomized patients have been on study treatment for 24
weeks or  discontinued earlier, i.e., LPFT + 24 weeks. 

96-week analysis: After all randomized patients have been on study treatment for 96
weeks or  discontinued earlier, i.e., LPFT + 96 weeks

End of study treatment analysis: 30 days after the EOsT. (Note: After the study 
treatment period, the assigned study treatment will be made available, may be outside 
of this study, to patients who in the opinion of the investigators are still deriving 
clinical benefit.) 

PFS/OS update analysis: 5 years from the date when the last randomized patient 
received the first study dose (irrespective of treatment switch for patients failing 
bosutinib).
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. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
by treatment group; a missing category will be included as applicable. Percentages will be
calculated using the number of patients in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum) by treatment group.
For pharmacokinetics (PK) concentration and parameters descriptive statistics also include 
coefficient of variation (CV)%, geo-mean and geo-CV%.


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2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, will refer to the asciminib only. Whereas, study treatment will refer to
asciminib or control treatment, i.e. bosutinib, received during the treatment phase. Switched 
treatment will refer to asciminib received during treatment switch phase.
Treatment arms

Asciminib (Subjects randomized to asciminib arm at the beginning of the study)

Bosutinib (Subjects randomized to bosutinib arm at the beginning of the study)
Date of end of study treatment (EOsT)
The EOsT date is the date that the study treatment is ended for the entire study. On this date, 
patients are treated for at least 96 weeks if they are not eligible to switch study treatment or are 
treated for at least 48 weeks after they have switched to asciminib treatment, unless patients 
have discontinued study treatment earlier
Date of first administration of randomized study treatment 
The date of first administration of randomized study treatment (FD) is derived as the first date 
when a non-zero dose of study treatment was administered as per the Dosage Administration
Record (DAR) electronic case report form (eCRF). The date of first administration of study 
treatment will also be referred as start of study treatment.
The date of first administration of randomized study treatment is the same as the date of first 
administration of investigational drug or control drug. 
Date of first administration of switched treatment 
For subjects switching from bosutinib to asciminib, the date of first administration of switched 
treatment (FDswitch) is derived as the first date when a non-zero dose of asciminib was 
administered as per the DAR eCRF. The date of first administration of switched treatment 
(asciminib) will also be referred as start of switched treatment.
Date of last administration of randomized study treatment 
The date of last administration of randomized study treatment (LD) is defined as the last date 
when a non-zero dose of study treatment was administered as per DAR eCRF. For subjects 
switching from bosutinib to asciminib, this includes the dose of bosutinib administered as 
bridging therapy between their treatment failure and the first dose of asciminib administered.
The date of last administration of randomized study treatment is the same as the date of last 
administration of investigational drug or control drug.


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Date of last administration of switched treatment 
The date of last administration of switched treatment (LDswitch) is defined as the last date when 
a non-zero dose of switched treatment (asciminib) was administered as per DAR eCRF.
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:

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, PK, etc.) is the start of study treatment.
The reference start date for all other, non-safety assessments (e.g. molecular response, survival 
time, disease progression, ECOG performance status, patient reported outcomes (PRO), etc.) is
the date of randomization.
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.
Switch study day
The switch study day, describes the day of the event or assessment date, relative to the start of 
switched treatment.
Switch study day = date of event – start of switched treatment + 1, if event is on or after the
start of switched treatment
Switch study day = date of event – start of switched treatment, if event precedes the start of
switched treatment
The switch study day will be displayed in the data listings if an event starts on or after the start 
of switched treatment.
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 
divided by 7.
Baseline for the treatment period
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of randomization is taken as “baseline” value or “baseline” assessment. In 


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the context of baseline definition, the efficacy evaluations also include PRO and performance 
status. 
For safety evaluations, the last available assessment, including unscheduled assessments before 
the date of start of study treatment 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 theses 
measurements would be calculated for baseline (if not already available in the database).
For mutations, the Week 1 Day 1 assessment is taken as “baseline” assessment.
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.
Baseline for the treatment switch period
For subjects switching from bosutinib to asciminib, the last non-missing assessment, including
unscheduled assessments before the date of first administration of asciminib is taken as
‘‘baseline” assessment for the switched treatment period, and denoted as baseline_switch for 
short.
On-treatment assessment/event and observation periods
For adverse event reporting the overall observation period will be divided into three mutually 
exclusive segments for subjects without treatment switching and into up to five mutually 
exclusive segments for subjects switching treatment: 
For subjects without treatment switching:
1. pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment (FD)
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last actual administration of study treatment (including start and stop date) (LD). 
Note: Patients will be treated up to the end of study treatment period (EOsT). This will 
be the last actual administration of study treatment for each patient if the patient has not 
discontinued study treatment earlier. On this date, all patients without treatment 
switching will have been treated for at least 96 weeks unless patients have discontinued 
study treatment earlier. After this period, the assigned study treatment will be made 
available, may be outside of this study, to patients who in the opinion of the investigators 
are still deriving clinical benefit.
3. post-treatment period: starting at day 31 after last administration of study treatment.
For subjects with treatment switching from bosutinib to asciminib:


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
pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment (FD)

on-treatment period: from date of first administration of study treatment to either the day 
before the first administration of asciminib (FDswitch) or  30 days after the date of last actual 
administration of bosutinib (LD), whichever comes first. 

post-treatment period: from day 31 after last administration of bosutinib to the day before  
the first administration of asciminib (FDswitch). If the end date is before the start date, this 
period is not applicable.

on-switched treatment period: from date of first administration of asciminib (FDswitch) to 
30 days after date of last actual administration of asciminib (LD switch).
NOTE: Subjects are treated in the study up to end of study treatment period (EOsT). On 
this date, all subjects with treatment switching will have been treated for at least 48 weeks 
after switching unless they have discontinued the switched treatment earlier.

Post-switched treatment period: from day 31 after last actual administration of asciminib 
(LD switch). 
If dates are incomplete in a way that clear assignment to pre-, on-, post-, on-switched-, post-
switched-treatment period cannot be made, then the respective data will be assigned to the on-
treatment period.
Safety summaries (tables, figures) on the Safety set (respectively on the Switch Analysis Set) 
include only data from the on-treatment (resp. on-switched treatment) period with the exception 
of baseline data which will also be summarized where appropriate (e.g. change from baseline 
summaries). In particular, summary tables for adverse events (AEs) will summarize only on-
treatment (resp. on-switched treatment) events, with a start date during the on-treatment (resp. 
on-switched treatment) period (treatment-emergent AEs) (resp. switched-treatment-emergent 
AEs). In addition, a separate summary for death including on-treatment and post-treatment 
deaths will be provided.
However, all safety data (including those from the pre-treatment, post-treatment and post-
switched treatment period) will be listed and flagged as appropriate.
Efficacy summaries on the FAS (apart from OS and PFS) include data from baseline up to either 
the last assessment on or before the EoT visit or before or on treatment failure, whichever is the 
earliest.
Efficacy summaries on the Switch Analysis Set include data from baseline_switch up to the last 
assessment on or before the S-EoT visit or before or on treatment failure during the switched
treatment period, whichever is the earliest.
The efficacy assessments collected post-treatment failure, post-EoT or post S-EoT visit are not 
included in any efficacy analyses (except for OS and PFS analyses). However, they will be 
listed and flagged as appropriate.


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Windows for multiple assessments 
Data such as molecular response, cytogenetic response collected over time (including 
unscheduled visits) will be summarized by scheduled time point. As patients do not always 
adhere to the visit schedule, visits will be remapped according to visit windows defined in 
Tables 2-1 to Table 2-4 of this document to enable by-visit analysis. Only those protocol-
defined visits will have the visit window defined. Each assessment (including the end of 
treatment assessment), either scheduled or unscheduled, will have a mapped visit assigned, as 
long as study day is available, according to the defined visit window up to the date with data 
included. 
If more than one assessment is assigned to the same time window, the assessment performed 
closest to the target date will be used for by-visit statistical analyses. If 2 assessments within a 
visit window are equidistant from the target date, then the average of the 2 assessments will be 
used. If multiple assessments on the same date, then the the average will be used. Data from all 
assessments (scheduled and unscheduled), including multiple assessments, will be listed.
Table 2-1
Time windows for molecular response
Assessment
Target day of assessment
Time Interval
Baseline
≤1
≤ Day 1#
Week 4
29
Day 2 to day 43
Week 8
57
Day 44 - 71
Week 12
85
Day 72 - 99
Week 16
113
Day 100 to day 141
Week 24
169
Day 142 to day 211
Week k (k=36, 48, …)
kx7 + 1
Day kx7-40 – kx7+43
# Day 1 = Date of randomization
EOT assessments are mapped to the time points as needed.


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Table 2-2
Time windows for cytogenetic response
Assessment
Target day of assessment
Time Interval
Baseline
1
≤ Day 1#
Week 24
169
Day 2 to day 253
Week 48
337
Day 254 to day 421
Week 72
505
Day 422 to day 589
Week 96
673
Day 590 to day 700
# Day 1 = Date of randomization
EOT assessments are mapped to the time points as needed.
For PRO data time windows will be defined for descriptive summary by visit and longitudinal 
data analysis. If more than one assessment is available in the same time window, the assessment 
closest to the planned date will be considered. If two assessments are obtained with the same 
time difference compared to the scheduled visit day, the assessment obtained prior to visit will 
be considered.  
Table 2-3
Time windows for PRO: MDASI-CML, EQ-5D-5L, PGIC
Assessment
Target day of assessment
Time Interval
Baseline
1
≤ Day 1#
Week 4
29
Day 2 - 43
Week 8
57
Day 44 - 71
Week 12
85
Day 72 - 99
Week 16
113
Day 100 - 141
Week 24
169
Day 142 - 211
Week 36
253
Day 212 - 295
Week 48
337
Day 296 - 505
Week 96
673
Day 506 - 700
# Day 1 = Date of randomization
Table 2-4
Time windows for PRO: WPAI-CML
Assessment
Target day of assessment
Time Interval
Baseline
1
≤ Day 1#
Week 4
29
Day 2 - 57
Week 12
85
Day 58 -127
Week 24
169
Day 128- 253
Week 48
337
Day 254 - 505
Week 96
673
Day 506 - 700
# Day 1 = Date of randomization
Here’s the general rule for the target day of assessment and time interval: For Week k visit, 
target day of assessment is defined as k*7+1. For the time interval, “Lower limit” = “upper limit 


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of prior applicable visit” +1. “Upper limit” = “target day of current visit” + integer part of 
(“target day of next applicable visit” – “target day of current visit”)/2. 
Visit window for the switched treatment period will use the same rules as described above but 
with Day 1 being the date of first administration of asciminib. Visit name for the switched 
treatment period will be defined similarly with annotated by beginning with “S-“ (e.g. S-Week 
4) to differentiate from those used for the randomized treatment period.


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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 randomization 
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/PK 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 the 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
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, patients will be analyzed according 
to the treatment and stratum they have been assigned to during the randomization procedure.
Safety Set
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment actually received.
The actual treatment received corresponds to:

the randomized treatment if patients took at least one dose of that treatment;

the first treatment received if the randomized treatment was never received.
Pharmacokinetic Analysis Set
The Pharmacokinetic Analysis Set (PAS) includes all patients who provide at least one 
evaluable PK concentration. For a concentration to be evaluable, patients are required to:

Take a dose of asciminib prior to sampling

Take the same dose of asciminib for at least 3 consecutive days without dose 
interruption or dose modification prior to sampling

Have the pre-dose sample collected before the next dose administration
Other analysis sets

For duration of MMR and time to MMR (descriptive analysis), the MMR Responder 
Set will be used that is a subset of FAS and includes patients who achieve MMR at 
any time on study treatment.

For CCyR rates at and by scheduled time points and time to CCyR (Kaplan-Meier 
analysis), the CCyR Analysis Set will be used that is a subset of FAS and includes 
patients who are not in CCyR at baseline.

For duration of CCyR and time to CCyR (descriptive analysis), the CCyR Responder 
Set will be use that is a subset of FAS and includes patients who do not have CCyR at 
baseline and achieve CCyR at any time on study treatment.

For analyses of patients switched to asciminib, the Switch Analysis Set will be used 
that is a subset of FAS and includes patients who switched from bosutinib to 
asciminib and received at least one dose of asciminib.
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 subject classification rules defined in Table 
2-6. 


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Table 2-6
Subject classification based on protocol deviations and non protocol 
deviation criteria
Analysis set
Protocol deviations leading 
to exclusion
Non 
protocol 
deviation 
leading to exclusion
FAS 
No written inform consent
Not applicable
Safety set
No written inform consent
No dose of study medication 
PK analysis set
No written inform consent
See definition of PAS
MMR Responder Set
Not applicable
See definition
of MMR 
Responder Set
CCyR Analysis Set
Not applicable
See definition
of CCyR 
Analysis Set
CCyR Responder Set
Not applicable
See definition of 
CCyR
Responder Set
Switch Analysis Set
Not applicable
See definition of 
Switch 
Analysis Set
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the eCRF. 
2.2.1
Subgroup of interest
Subgroup analyses will use the same method as for the analysis in the respective overall analysis 
set. 
The objective for carrying out these subgroup analyses is to identify potential issues that
may be limited to a subgroup of patients, or that are more commonly observed in a subgroup 
of patients.
Summary tables and figures will be generated only for subgroups with at least 15 patients. 
Efficacy
The primary efficacy endpoint will be summarized by the following subgroups to examine the 
homogeneity of treatment effect provided that the primary efficacy analysis based on the FAS 
is statistically significant: 

Stratification factor (based on randomization data from Interactive Response 
Technology [IRT]): “Major Cytogenetic Response” or “No Major Cytogenetic 
Response”

Stratum reported in the CRF (derived using the data collected on the Bone Marrow 
Aspirate eCRF at baseline: see Appendix): “Major Cytogenetic Response” or “No 
Major Cytogenetic Response”


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
Sex: Female or male

Race: Asian, Caucasian, or others

Age category (≥18-< 65 years, ≥65 years, ≥75 years,)

Reason for discontinuation of the last prior Tyrosine Kinase Inhibitor (TKI): 
Failure (i.e. lack of efficacy) or intolerance (i.e. adverse event, lack of tolerability). 
Note: Only one reason for discontinuation is allowed for each prior therapy.

Number of prior TKI therapies: 2, 3 or ≥4

Line of therapy of randomized treatment: 3rd, 4th or ≥5th

With or without Week 1 Day 1 BCR-ABL1 mutation (other than T315I or V299L) by 
Sanger Sequencing at central lab: Wild type or  mutant

BCR-ABL ratio at baseline ≥1% or <1%
No formal statistical test of hypotheses will be performed for the subgroups, only point estimate 
of the treatment effect and 95%-confidence intervals will be provided (see Section 2.14 for 
further analysis details). The objective of the efficacy subgroup analysis is to demonstrate 
homogeneity of treatment effect in the above subgroups.
Safety
Subgroup analyses for selected safety endpoints will be defined when required.
Japan-specific subgroup analyses
Two subgroups will be formed based on geographic region: Japan or other region (this is not 
based on ethinicity). These subgroup analyses will be only used for submission to Japan health 
authority.
Summary tables and figures will be presented for the two subgroups for the following outcome 
measures:

Baseline characteristics: Tables of demographics, diagnosis and extent of cancer,
extramedullary involvement, bone marrow analysis, molecular response, prior TKI 
and non-TKI, patient disposition, analysis sets by stratum

Exposure: Tables of duration of exposure, dose received

Tables of concomitant medications as well as surgical and medical procedures

PK (only in asciminib arm): Table and figure of asciminib concentration by time, 
table of asciminib PK parameters (patients with full PK sampling), figure of average 
trough asciminib concentration from week 2, 4, 12 and 24 vs. BCR-ABL ratio IS (%)
at 24 weeks

AEs: Tables of all AEs, treatment-related AEs, AEs requiring dose adjustment or 
interruption, AEs requiring additional therapies, serious adverse events (SAEs), 
adverse events of special interest (AESIs), overview table of AEs and death

ECG: Tables of Notable ECG values, change from baseline in ECG parameters values

Lab: Hematology shift table, biochemistry shift table

Efficacy: Tables of molecular response categories at and by each time point, MMR 
rate at and by each time point, time to MMR, duration of MMR, cytogenetic response 


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categories at and by each time point, time to CCyR, duration of CCyR, TTF, PFS, OS. 
Figures of cumulative incidence of MMR and of CCyR, association between Week 1 
Day 1 BCR-ABL1 gene mutation and clinical outcome.
2.3
Patient disposition, demographics and other baseline 
characteristics
The FAS will be used for all baseline and demographic summaries and listings unless otherwise 
specified. Summaries will be reported by treatment arm and for all patients, and listings will be 
reported by treatment arm to assess baseline comparability. No inferential statistics will be 
provided.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment arm. Categorical data (e.g. age groups: 18 - <65, 65 - <75, and ≥ 75 years and 18 -
<65, ≥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.
For the Switch Analysis Set, the initial baseline and “baseline_switch” value will be 
summarized. Weight, BMI, age and ECOG performance status will be summarized using the 
“baseline_switch” value defined in Section 2.1.2.
In addition, a summary table by sex, age group (18 - <65, 65 - <85, and ≥ 85 years) and treatment 
group and another summary table by race and treatment group will be generated using the safety 
set for DSUR/PSUR.
Baseline stratification factors
The number (%) of patients in each stratum (“Major Cytogenetic Response” or “No Major 
Cytogenetic Response”) based on data obtained from the IRT system will be summarized 
overall and by treatment arm for the FAS. Discordances between the stratum recorded in IRT 
at the time of randomization and the stratum recorded in the clinical database through the data 
collected on eCRF will be cross-tabulated and listed. In case the baseline bone marrow aspirate 
is missing or not evaluable (i.e. < 20 metaphases), the stratum recorded in the clinical database 
will be imputed following the rule described in Appendix 5.1.2.1.
Baseline cytogenetic response and molecular response
Baseline and Baseline_switch will be summarized for cytogenetic response and molecular 
response for the FAS and Switch Analysis Set respectively.
Diagnosis and extent of cancer
All diagnosis and extent of cancer data will be summarized and listed by treatment arm. One
summary table will include time (years) since initial diagnosis (descriptive statistics with N,
mean, median, standard deviation, minimum and maximum) and historical mutation: present 


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(unknown, yes, no), historical CML-associated mutation status (E225K, E255V, E355G, etc.)
(frequency counts and percentages). Another table will include extramedullary involvement: 
any extramedullary involvement (Yes/No) and location of extramedullary involvement (Spleen, 
Liver) (frequency counts and percentages).
For the Switch Analysis Set, the above information will be based on the last observation prior 
to the Baseline_switch.
Medical history
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on eCRF will be summarized and listed by treatment arm. The summary will be 
presented by primary system organ class (SOC), preferred term (PT) and treatment arm. 
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 listings will be produced for medical history possibly contributing to liver 
dysfunction, and medical history of protocol solicited cardiovascular events.
The cardiovascular risk factors, heavy smoking, low physical activity, unhealthy diet, and other, 
are collected prior to randomization and the EoT visit. A listing by treatment arm will be 
presented. 
Family medical history of each patient for ischemic heart disease, cardiac arrhythmia, sudden 
death, high cholesterol, diabetes mellitus, heart defects (congenital heart disease), and heart 
failure is also collected prior to randomization and at the EoT visit. A listing by treatment arm 
will be presented.
Other
All data collected at baseline, including child bearing potential as well as informed consent for 
additional research on study data and biological samples, will be listed.
2.3.1
Patient disposition
Enrollment by country and center will be summarized for all screened patients and also by 
treatment arm using the FAS. The number (%) of randomized patients included in the FAS will 
be presented overall and by treatment group. The number (%) of screened and not-randomized 
patients and the reasons for screening failure will also be displayed. The eligibility criteria will 
be also summarized. 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 treatment group.
The following summaries will be provided (with % based on the total number of FAS patients):

Number (%) of patients who were randomized (based on data from IRT system)

Number (%) of patients who were randomized but not treated (based on DAR eCRF 
page not completed for any study treatment component)

Primary reason for not being treated (based on “End of Treatment Phase Disposition” 
eCRF page)


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
Number (%) of patients who were treated (based on DAR eCRF pages of each study 
treatment completed with non-zero dose administered)

Number (%) of patients who are still on-treatment (based on the “End of Treatment 
Phase Disposition” page not completed); 

Number (%) of patients who discontinued the study treatment phase overall, before 
Week 24,  Week 48 and Week 96 (based on the “End of Treatment Phase 
Disposition” page) 

Primary reason for study treatment phase discontinuation overall, before Week 24,  
Week 48 and Week 96 (based on the “End of Treatment Phase Disposition” page)

Number (%) of patients who have entered the survival follow-up (based on the “End 
of Treatment Phase Disposition” page)

Number (%) of patients in the FAS randomized to the bosutinib arm who switched to 
receive asciminib (based on DAR – ABL0001 eCRF page completed with non-zero 
dose administered during the Treatment switch phase);
The following summaries will be provided with % based on the total number patients in the 
Switch Analysis Set:

Number (%) of patients who switched from bosutinib arm to receive asciminib and are 
still receiving asciminib (based on the “End of Treatment Disposition” eCRF not 
completed during the Treatment switch phase);Number (%) of patients who switched from 
bosutinib arm to receive asciminib and discontinued asciminib (based on the “End of 
Treatment Disposition” eCRF during the Treatment switch phase);

Primary reason for  treatment switch phase discontinuation (based on the “End of 
Treatment Disposition” eCRF during the Treatment switch phase)

Number (%) of patients who have entered the survival follow-up (based on the “End of 
Treatment Disposition” eCRF during the Treatment switch phase)
Protocol deviations
The number (%) of patients in the FAS with any protocol deviation during the randomized 
treatment period will be tabulated by deviation category (as specified in the Study Specification 
Document) overall and by treatment group for the FAS. All protocol deviations will be listed.
In addition, the number (%) of patients in the FAS with any COVID-19 related protocol 
deviation (COVID-19 specific protocol deviations as well as non-specific COVID-19 protocol 
deviations with a COVID-19 relationship) during the randomized treatment period will be 
tabulated by deviation category (as specified in the Study Specification Document) overall and 
by treatment group. The same information will be tabulated for protocol deviations occuring 
during the treatment switch period for the switch analysis set.
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized  by 
treatment group and stratum. Reasons leading to exclusion from analysis sets will be listed by 
treatment group and stratum as well as tabulated overall and by treatment group.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure, actual cumulative dose, average daily dose, dose intensity (DI) and 
relative dose intensity (RDI) will be summarized by treatment arm. Duration of exposure will 
be categorized into time intervals; frequency counts and percentages will be presented for the 
number (%) of subjects in each interval. The number (%) of subjects who have dose reductions 
or interruptions, and the reasons, will be summarized by treatment group. 
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.  
The safety set and Switch Analysis Set will be used for all summaries and listings of randomized 
and switched treatments respectively. 
To summarize exposure data for the randomized treatment period, this will be based on patients 
in the Safety set with the date of last administration of study treatment and the date of first 
administration of study treatment being FD and LD respectively.
To summarize exposure data for the switched treatment period, this will be based on patients in 
the Switch Analysis Set with the date of last administration of  study treatment and the date of 
first administration of study treatment being FDswitch and LDswitch respectively.
Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug or control:
Duration of exposure to study treatment (weeks) = ((date of last administration of  study 
treatment) – (date of first administration of study treatment) + 1) / 7. 
The duration of exposure in patient-years is the total of the duration of exposure in years 
from all the patients in a treatment group. 
The date of last administration of study treatment is defined in Section 2.1.1.
Summary of duration of exposure to study treatment will include categorical summaries based 
on intervals (<24 weeks, ≥24 weeks, ≥48 weeks, ≥96 weeks) and continuous summaries (i.e. 
mean, standard deviation etc.).
Cumulative dose
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure. 
The planned cumulative dose for a study treatment refers to the total planned dose as per the 
protocol up to the last date of study treatment administration. The calculations for the two study 
treatments are:

ABL001: 40 mg/administration × 2 (administration/day) × duration of exposure (day) 


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
Bosutinib:  500 mg/day × duration of exposure prior to dose escalation (day) 
+ 600 mg/day × duration of exposure since dose escalation (day),
where the starting day of dose escalation is identified as the first record in the DAR 
eCRF with dose increased and reason “As per protocol”.
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment 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 study treatment.
Dose intensity and relative dose intensity
Average Daily Dose (ADD) is defined as:
ADD (mg/day) = Actual cumulative dose (mg) / Time on treatment (day).
Time on treatment (weeks) = ((date of last administration of  study treatment) – (date of first 
administration of study treatment) + 1 – number of days with dose interruption*) / 7
*For subjects in the asciminib arm, this includes the half days before and after the period with 
0 dose if the treatment was interrupted after the morning dose and/or resumed in the evening (1 
day record with QD dose administered before or after a record with 0 dose).
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 (day).
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 (day).
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg/day)  / PDI (mg/day).  
ADD, DI and RDI will be summarized separately for the two study treatments. 
Dose changes, interruptions or permanent discontinuations
The number of subjects who have dose increase (allowed for bosutinib starting week 8, see 
protocol Section 6.2), dose reductions, dose interruptions or permanent discontinuations, and 
the reasons, as well as the duration of dose interruption due to any reason will be summarized 
separately for the two study treatments. For any subjects, duration of dose interruption will be 
calculated by adding all individual episodes of dose interruption for that patient. For subjects in 
the asciminb arm, this includes the half days before and after the period with 0 dose if the 
treatment was interrupted after the morning dose and/or resumed in the evening (1 day record 
with QD dose administered before or after a record with 0 dose). 
‘Dose Changed’, ‘Dose Interrupted’ and ‘Dose Permanently Discontinued’ fields from the DAR 
eCRF pages will be used to determine the dose changes, dose interruptions, and permanent 
discontinuations, respectively.


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The corresponding fields ‘Reason for Dose Change/Dose Interrupted’ 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 asciminib arm, there is only one planned dose, i.e. 80 mg/day. For patients in 
bosutinib arm, the initial planned dose is 500 mg/day and could be changed to 600 mg/day in 
week 8 or later.
For the purpose of 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 change where the actual total daily dose is lower than the most recently
planned dose. Therefore any dose change to correct a dosing error will not be considered a dose 
reduction. Only dose change is collected in the eCRF, while number of reductions will be 
derived programmatically based on the change and the direction of the change.
Increase: A dose change where the actual total daily dose is greater than the most recently
planned dose. Therefore any dose change to correct a dosing error will not be considered a dose 
increase. Only dose change is collected in the eCRF, while number of increase will be derived 
programmatically based on the change and the direction of the change.
2.4.2
Prior, concomitant and post therapies
Prior anti-cancer therapy
The number and percentage of patients who received any prior anti-neoplastic medications will 
be summarized by treatment arm for the lowest anatomical therapeutic classification (ATC)
class and preferred term. A listing will also be produced. 
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 FAS.
The following information will be summarized for the FAS and Switch Analysis Set:

Prior TKI by medication (e.g. imatinib, dasatinib, nilotinib, ponatinib, bosutinib, etc.) 

Number of prior TKI (e.g. 2, 3, 4, etc.) 

Number of lines of prior TKI therapy (2, 3, 4, 5+)
A new line of therapy is considered each time a change in TKI occured. Multiple entries 
for the same TKI will be counted as separate lines of therapy if a different TKI is received 
between the different entries.

Time on each line of prior TKI therapy (in years)

Time on last prior TKI (in years)

Reason to discontinue the most recent TKI therapy at the time of screening

Prior non-TKI therapies (Yes, No). 
A Sankey-like plot showing the sequence of prior TKIs will be provided.


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Note: In case the last TKI given prior to enrollment in the study was a bridging therapy (i.e. 
reason for discontinuation includes a wording related to bridging), it will not be considered in 
the analysis of prior TKIs. In particular, it will not be considered as the last or most recent TKI 
therapy at the time of screening and will not count as an additional line of therapy.
For the Switch Analysis Set, bosutinib received during the randomized treatment period and 
other TKIs received since discontinuation of bosutinib and before first administration of 
asciminib (FDswitch) should be considered as prior TKIs.
Post treatment anti-cancer therapy
Anti-neoplastic therapies since discontinuation of study treatment will be listed and summarized 
by the lowest anatomical therapeutic classification (ATC) class, preferred term, overall and by 
treatment group by means of frequency counts and percentages using FAS.
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. 
Concomitant therapies
Concomitant therapies are defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapies include medications (other than study drugs) and medical 
procedures starting on or after the start date of study treatment, or starting prior to the start date 
of study treatment and continuing after the start date of study treatment. 
Concomitant 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. 
The summaries for the on-treatment period using the Safety Set will include:

Therapies starting on or after the start of randomized study treatment but no later than 
the end of the on-treatment period and

Therapies starting prior to start of randomized study treatment and continuing after 
the start of randomized study treatment.
These summaries for the on-switched treatment period using the Switch Analysis Set will 
include:

Medications starting on or after the start of switched treatment but no later than the 
end of the on-switched treatment period and

Medications starting prior to start of switched treatment and continuing after the start 
of switched treatment.
All concomitant therapies will be listed using the Safety Set. Any concomitant therapies
starting and ending prior to the start of randomized study treatment or starting beyond end of 
the on-treatment period if not switched, or starting beyond end of on-switched treatment
period if switched will be flagged in the listing. 


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The prohibited concomitant medications will be summarized by lowest ATC class and preferred 
term up to the end of on-treatment and on-switched treatment periods, respectively. Prohibited 
medications will be concomitant medications that led to the protocol deviation “Use of 
prohibited concomitant medication”.
2.5
Analysis of the primary objective/estimand
In this section, the targeted treatment effect corresponding to the primary objective as well as 
the primary objective is clarified using the estimand language.
The primary clinical question of interest is: Is the efficacy of asciminib (40 mg bid) superior to 
bosutinib (500 mg qd) in CML patients in chronic phase, previously treated with 2 or more 
tyrosine kinase inhibitors, with regards to achieving MMR at 24 weeks while on study treatment
and without meeting any treatment failure criteria (defined in section 5.4.4) prior to 24 weeks, 
regardless of dose modification,  dose interruption, or deviation in any intake of concomitant 
medications.
The primary estimand is described by the following attributes:
Population: CML patients in chronic phase, previously treated with 2 or more tyrosine kinase 
inhibitors. Further details about the population are provided in Section 5 of the protocol.
Endpoint: Major Molecular Response (MMR) achieved at 24 weeks while on study treatment
without meeting any treatment failure criteria (defined in section 5.4.4) prior to 24 weeks. A 
patient will be counted as having achieved MMR at 24 weeks if he/she meets the MMR criterion
(BCR-ABL ratio ≤0.1%) at 24 weeks while on study treatment unless the patient met any 
treatment failure criteria (defined in section 5.4.4) prior to 24 weeks.
Intercurrent events: 

Treatment discontinuation (i.e. having performed an EOT visit) prior to 24 weeks due to 
any reason (e.g. intolerance, treatment failure, death, etc.): non response

Meeting any treatment failure criteria (defined in section 5.4.4) prior to 24 weeks: non 
response

Dose modification,  dose interruption, or deviation in any intake of concomitant 
medications: ignore (treatment policy strategy)
Treatment of interest: the randomized treatment (the investigational treatment asciminib or the 
control treatment bosutinib) received for at least 24 weeks with or without dose modification, 
dose interruption or deviation in any intake of concomitant medications. Further details about 
the investigational treatment and control treatment are provided in Section 6 of the protocol.
Handling of remaining intercurrent events : no other IE foreseen
The summary measure: difference in MMR rate and its 95% confidence interval at week 24 
between the two treatment arms.
2.5.1
Primary endpoint/estimand
The primary endpoint is Major Molecular Response (MMR) achieved at 24 weeks while on 
study treatment without meeting any treatment failure criteria (defined in section 5.4.4) prior to 
24 weeks. A patient will be counted as having achieved MMR at 24 weeks if he/she meets the 


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MMR criterion (BCR-ABL ratio ≤0.1%) at 24 weeks while on study treatment unless the 
patient met any treatment failure criteria (defined in section 5.4.4) prior to 24 weeks.
MMR will be considered as a binary variable with patients achieving MMR grouped as 
‘responders’ and patients not achieving MMR grouped as ‘non responders’. Only patients with 
MMR at 24 weeks are considered responders. In other words, any patient who achieves MMR 
before 24 weeks, but is no longer in MMR at 24 weeks, will be considered as a non-responder 
in this primary analysis.
Patients discontinuing treatment (i.e. having performed an EOT visit) prior to 24 weeks due to 
any reason (e.g. intolerance, treatment failure, death, etc.) and patients meeting any treatment 
failure criteria (defined in section 5.4.4) prior to 24 weeks will be considered as not having 
achieved MMR at 24 weeks.
Details of derivation of Polymerase Chain Reaction (PCR) results and calculation of BCR-ABL 
ratio are presented in Section 5.4.
2.5.2
Statistical hypothesis, model, and method of analysis
The MMR rate at 24 weeks will be calculated based on the FAS and according to the Intent To
Treat (ITT) principle. MMR rate and its 95% confidence interval based on the Pearson-Clopper 
method will be presented by treatment group. The 95% confidence interval for the unstratified 
difference in MMR rate between treatment groups will be provided using the Wald method.
The null hypothesis is that there is no difference between the treatment groups with respect to 
MMR rate at 24 weeks. The Cochrane-Mantel-Haenszel (CMH) chi-square test, stratified by 
the randomization stratification factor, i.e. cytogenetic response status (MCyR vs no MCyR) at 
screening, will be used to compare MMR rate between the two treatment groups, at the two-
sided 5% level of significance. The Mantel-Haenszel estimate of the common risk difference 
and the corresponding 95% confidence interval will be presented. 
2.5.3
Handling of remaining intercurrent events of primary estimand
No remaining intercurrent events.
2.5.4
Handling of missing values not related to intercurrent event
Patients with missing PCR evaluations at 24 weeks will be considered as non-responders. 
However, if the 24-week PCR evaluation is missing, but both a PCR evaluation at 16 weeks 
and a PCR evaluation at 36 weeks indicate MMR, the 24-week assessment is imputed as a 
‘Response’, assuming that MMR is maintained between 16 and 36 weeks.
2.5.5
Sensitivity analyses
The following sensitivity analyses will be performed:

The CMH chi-square test of MMR rate at 24 weeks will be repeated stratifying by the 
stratum recorded in the CRF (MCyR vs no MCyR at baseline).

Due to the COVID-19 (Coronavirus) pandemic, there is a risk that planned hospital visits 
are cancelled, potentially resulting in missing PCR evaluations. In order to assess the 
impact of COVID-19 (including potential missing data) on the primary endpoint, the 


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CMH chi-square test of MMR rate at 24 weeks will be repeated on the FAS excluding the 
patients with planned 24-week visit (start of study treatment + 161 days ) after the start 
date of COVID-19 epidemic. As per Novartis guidance, the start date, in a given country 
or region, is being defined as the approximate time point at which, according to the WHO 
situation reports and the Johns Hopkins database, the number of confirmed COVID-19 
infections started to increase significantly (around 100 confirmed cases) and/or 
governments started to take measures (such as stay-at-home orders) to contain the
epidemic, whichever occurred first (China: January 1, 2020; South Korea: February 20, 
2020; Japan: February 21, 2020; Italy: February 23, 2020 and Rest of the World: March 1, 
2020).

The CMH chi-square test of MMR rate at 24 weeks will be repeated without the 
imputation rule used in the main analysis in case of missing PCR evaluations at 24 weeks.
2.5.6
Supplementary analyses
Additional supplemental logistic regression and subgroup analyses are described in Section 
2.14.
Assess whether the efficacy of asciminib (40 mg bid) is superior to bosutinib (500 mg qd) in 
CML patients in chronic phase, without T315I or V299L mutation detected at Week 1 Day 1 
visit and previously treated with 2 or more tyrosine kinase inhibitors, with regards to achieving 
MMR at 24 weeks while on study treatment and without meeting any treatment failure criteria 
(defined in section 5.4.4) prior to 24 weeks, regardless of dose modification,  dose interruption, 
or deviation in any intake of concomitant medications.
The corresponding estimand attributes are the same as the ones of the primary estimand except 
that the population excludes patients detected with T315I or V299L at Week 1 Day 1 visit (As 
per protocol, these patients were discontinued from study treatment when the mutation results 
became available). 
The CMH chi-square test of MMR rate at 24 weeks will be repeated on the FAS excluding 
patients detected with T315I or V299L at Week 1 Day 1 visit.
2.6
Analysis of the key secondary objective/estimand
The key secondary clinical question of interest is: Is the efficacy of asciminib (40 mg bid) 
superior to bosutinib (500 mg qd) in CML patients in chronic phase, previously treated with 2 
or more tyrosine kinase inhibitors, with regards to achieving MMR at 96 weeks while on study 
treatment and without meeting any treatment failure criteria (defined in section 5.4.4) prior to 
96 weeks, regardless of dose modification,  dose interruption, or deviation in any intake of 
concomitant medications.
The key secondary estimand is described by the following attributes:
Population: CML patients in chronic phase, previously treated with 2 or more tyrosine kinase 
inhibitors. Further details about the population are provided in Section 5 of the protocol.
Endpoint: Major Molecular Response (MMR) achieved at 96 weeks while being treated without 
meeting any treatment failure criteria (defined in section 5.4.4) prior to 96 weeks. A patient will 
be counted as having achieved MMR at 96 weeks if he/she meets the MMR criterion (BCR-


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ABL ratio ≤0.1%) at 96 weeks while on study treatment unless the patient met any treatment 
failure criteria (defined in section 5.4.4) prior to 96 weeks. 
Intercurrent events: 

Treatment discontinuation (i.e. having performed an EOT visit) prior to 96 weeks due to 
any reason (e.g. intolerance, treatment failure, death, etc.): non response

Meeting any treatment failure criteria (defined in section 5.4.4) prior to 96 weeks: non 
response

Dose modification,  dose interruption, or deviation in any intake of concomitant 
medications: ignore (treatment policy strategy)
Treatment of interest: the randomized treatment (the investigational treatment asciminib or the 
control treatment bosutinib) received for at least 96 weeks with or without dose modification, 
dose interruption or deviation in any intake of concomitant medications. Further details about 
the investigational treatment and control treatment are provided in Section 6 of the protocol.
Handling of remaining intercurrent events : no other IE foreseen
The summary measure: difference in MMR rate and its 95% confidence interval at week 96 
between the two treatment arms
The analysis of the key secondary objective will be performed at the time of the 96-week 
analysis.
2.6.1
Key secondary endpoint/estimand
The key secondary endpoint is MMR achieved at 96 weeks while on study treatment without 
meeting any treatment failure criteria (defined in section 5.4.4) prior to 96 weeks. A patient will 
be counted as having achieved MMR at 96 weeks if he/she meets the MMR criterion (BCR-
ABL ratio ≤0.1%) at 96 weeks while on study treatment unless the patient met any treatment 
failure criteria (defined in section 5.4.4) prior to 96 weeks.
MMR will be considered as a binary variable with patients achieving MMR grouped as 
‘responders’ and patients not achieving MMR grouped as ‘non responders’. Only patients with 
MMR at 96 weeks are considered responders. In other words, any patient who achieves MMR 
before 96 weeks, but is no longer in MMR at 96 weeks, will be considered as a non-responder 
in this key secondary analysis.
Patients discontinuing treatment (i.e. having performed an EOT visit) prior to 96 weeks due to 
any reason (e.g. intolerance, treatment failure, death, etc.) and patients meeting any treatment 
failure criteria (defined in section 5.4.4) prior to 96 weeks will be considered as not having 
achieved MMR at 96 weeks.
2.6.2
Statistical hypothesis, model, and method of analysis
The null hypothesis is that there is no difference between the treatment groups with respect to 
MMR rate at 96 weeks. Following a gatekeeping procedure to control the overall alpha level, 
only if the primary endpoint is significant, formal statistical testing of the key secondary 
endpoint with two-sided 5% level of significance will be performed using the CMH chi-square 


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test, stratified by the randomization stratification factor, i.e. cytogenetic response status (MCyR 
vs no MCyR) at screening.
MMR rate and its 95% confidence interval based on the Pearson-Clopper method will be 
presented by treatment group. The 95% confidence interval for the difference in MMR rate 
between treatment groups will be provided using the Wald method. The Mantel-Haenszel 
estimate of the common risk difference and the corresponding 95% confidence interval will 
also be presented.
2.6.3
Handling of remaining intercurrent events of primary estimand
No remaining intercurrent events.
2.6.4
Handling of missing values not related to intercurrent event
Patients with missing PCR evaluations at 96 weeks will be considered as non-responders. 
However, if the 96-week PCR evaluation is missing, but both a PCR evaluation at 84 weeks 
and a PCR evaluation at 108 weeks indicate MMR, the 96-week assessment is imputed as a 
‘Response’, assuming that MMR is maintained between 84 and 108 weeks.
2.6.5
Sensitivity analysis

In order to assess the impact of COVID-19 (including potential missing data) on the key 
secondary endpoint, the CMH chi-square test of MMR rate at 96 weeks will be repeated 
on the FAS excluding the patients with planned 96-week visit (start of study treatment + 
665 days) between the start date of the COVID-19 epidemic (China: January 1, 2020; 
South Korea: February 20, 2020; Japan: February 21, 2020; Italy: February 23, 2020 and 
Rest of the World: March 1, 2020) and its end date (to be defined in the future). 

The CMH chi-square test of MMR rate at 96 weeks will be repeated without the 
imputation rule used in the main analysis in case of missing PCR evaluations at 96 weeks.
2.7
Analysis of secondary efficacy objective(s)
The other secondary efficacy objective is to compare additional parameters (defined below) of 
the efficacy of asciminib versus bosutinib.
2.7.1
Secondary endpoints
2.7.1.1
Molecular response
MMR rates at all scheduled data collection time points, i.e., the protocol-planned visits 
except for 24 weeks and 96 weeks which are already covered by primary and key secondary 
endpoints. Such rates are defined as the proportion of patients with MMR at the respective time 
points.
MMR rates by all scheduled data collection time points, i.e., the protocol-planned visits.
These are cumulative MMR rates by time points and are defined as the proportion of patients 
who achieve MMR at or before specified visits, i.e. if a patient achieves an MMR but then loses 
it before or at a specific visit, he/she will still be classed as achieving MMR by that specific 
time point.


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Molecular response category at specific time points, i.e., the protocol-planned visits. 
Categories of molecular response are defined in Appendix. 
Molecular response category by specific time points, i.e., the protocol-planned visits. This is 
defined as the best (lowest) molecular response category up to the specific time points.
Time to MMR (in weeks) is defined as: (date of first documented MMR - date of randomization 
+ 1)/7.
Duration of MMR is defined for patients in the MMR Responder Set as the time between the 
date of the first documented MMR and the end date of MMR, i.e. the earliest date of confirmed 
loss of MMR, progression to accelerated phase (AP)/blast crisis (BC), or CML-related death. 
Loss of MMR and progression to accelerated phase (AP)/blast crisis (BC) are defined in 
Appendix.
For patients for whom none of the events above is reported, the duration will be censored (see 
Section 2.7.3). The duration of MMR (in weeks) is calculated as: (end date or censoring date of 
MMR - date of first MMR + 1)/7.
2.7.1.2
Cytogenetic response
At each assessment time point the cytogenetic response status of each patient is classified as 
complete, partial, major, minor, minimal response and none (a review of a minimum of 20 
metaphases is required):

Complete response (CCyR): 0% Philadelphia chromosome positive (Ph+) metaphases

Partial response (PCyR): >0 to 35% Ph+ metaphases

Major response (MCyR = CCyR + PCyR): 0 to 35% Ph+ metaphases

Minor response (mCyR): >35 to 65% Ph+ metaphases

Minimal response: >65 to 95% Ph+ metaphases

None: >95 to 100% Ph+ metaphases.
As per protocol, bone marrow aspirate for cytogenetic analyses will be performed as long as 
subjects have not achieved MMR. Therefore, in case no bone marrow aspirate was performed 
but the subject is in MMR at a specific time-point, the subject is considered to have achieved
CCyR at that time-point. The date of CCyR is imputed by the date of MMR at the same 
scheduled time-point.
CCyR rates at all scheduled data collection time points, i.e., the protocol-planned visits. 
Such rates are defined as the proportion of patients in CCyR at the respective time points among 
patients in the CCyR Analysis Set, which excludes patients who are in CCyR at baseline.
CCyR rates by all scheduled data collection time points, i.e., the protocol-planned visits.
Such rates are defined as the proportion of patients who achieve CCyR at or before the 
respective time points among patients in the CCyR Analysis Set.
Cytogenetic response category at specific time points, i.e., the protocol-planned visits. At 
each assessment time point the cytogenetic response status of each patient is classified as 
complete, partial, major, minor, minimal response and none (a review of a minimum of 20 
metaphase is required) as defined in Appendix.


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Cytogenetic response category by specific time points, i.e., the protocol-planned visits. This 
is defined as the best (lowest) cytogenetic response category up to the specific time points.
Time to CCyR (in weeks) is defined for patients as: (date of first documented CCyR - date of 
randomization + 1)/7.
Duration of CCyR is defined for patients in the CCyR Responder Set as the time between date 
of first documented CCyR and the end date of CCyR, i.e. the earliest date of loss of CCyR, 
progression to AP/BC, or CML-related death. Loss of CCyR and progression to AP/BC are 
defined in Appendix. For patients for whom none of the events above is reported, the duration
will be censored (see Section 2.7.3). The duration of CCyR (in weeks) is calculated as: (end
date or censoring date of CCyR - date of first CCyR + 1)/7.
2.7.1.3
Other secondary efficacy endpoints
Time to treatment failure (TTF) is defined for patients in FAS as the time from date of 
randomization to an event of treatment failure. The events that constitute ‘treatment failure’ are 
described in the Appendix. They are based on the ELN criteria [Baccarani et al. 2013] defining 
failure of a second line treatment adapted to include discontinuation of randomized treatment 
as an event.
TTF (in months) is calculated as: (date of treatment failure or censoring date (see Section 2.7.3) 
- date of randomization + 1)/30.4375.
Progression-Free-Survival (PFS) is defined for patients in FAS as the time from the date of 
randomization to the earliest occurrence of documented disease progression to AP/BC or the 
date of death from any cause (including progressions and deaths observed during the survival 
follow-up period). 
PFS (in months) is calculated as: (date of disease progression/death or censoring date (see 
Section 2.7.3) - date of randomization + 1)/30.4375.
Overall survival (OS) is defined for patients in FAS as the time from the date of randomization 
to the date of death (including the survival follow-up period).
OS (in months) is calculated as: (date of death or censoring date (see Section 2.7.3) - date of 
randomization + 1)/30.4375, regardless whether the patient switched from bosutinib to 
asciminib.
2.7.2
Statistical hypothesis, model, and method of analysis
No confirmatory statistical testing of non-key secondary efficacy endpoints will be performed, 
however, nominal p-values will be presented for exploratory purposes (as specified in protocol 
Section 10.5.2).
MMR rates at and by time points
The FAS will be used for these endpoints. For each time point the MMR rate and the associated 
95% confidence interval based on the Pearson-Clopper method will be presented by treatment 
group. The descriptive p-value obtained via CMH chi-square tests stratified by the 
randomization strata, i.e. MCyR vs no MCyR at screening, will be presented. A 95% confidence 


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interval for the difference in each MMR rate between treatment groups will be provided using 
the Wald method. The Mantel-Haenszel estimate of the common risk difference and the 
corresponding 95% confidence interval will also be provided.
A post-hoc analysis of the MMR rate will be performed using the number of subjects with 
adequate follow-up as the denominator. Subjects will be included in the analysis at a timepoint 
whenever their time between the date of randomization and the cut-off date is equal or above 
this timepoint, regardless of whether they discontinued before.
The cumulative incidence of MMR by treatment group will be graphically displayed by an 
increasing step function. Each curve will increase each time (after randomization) at which a 
new responder is observed and thus will increase up to the best observed response rate (e.g. up 
to 50% if half of the patients in the analysis population are able to achieve MMR).
Molecular response at and by time points
Frequency and percentage of all molecular response categories (defined in Appendix) by 
treatment arm using FAS will be presented for each time point.
For the by-time-points summary, the within-patient best molecular response category up to the 
specific time points is used to calculate the frequency and percentage.
Time to MMR
The MMR Responder Set will be used. Descriptive statistics (minimum, maximum, median, 
quartiles, mean, sd) of time to MMR will be provided for the two treatment groups separately.
The FAS will be also used to perform similar Time-to-Event analyses as described below for 
duration of MMR.
A post-hoc analysis of time to MMR will also be performed considering discontinuation from 
treatment due to any reason, without prior achievement of MMR as a competing risk.
Time to MMR will be censored at the last molecular assessment (PCR) date on treatment prior 
to or at the cut-off date, if no events/competing risk occurred before or at the cut-off date or the 
EOT. 
The estimated cumulative incidence rates and 95% confidence intervals at 12, 24, 48, 72 and 
96 weeks will be presented for each treatment group. The cumulative incidence curve will be 
plotted. 
Duration of MMR
The MMR Responder Set will be used. The survival distribution of duration of MMR will be 
estimated using the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% 
confidence intervals [Brookmeyer and Crowley 1982] of the medians, along with the proportion 
of patients who are still in MMR at 24, 48, 72 and 96 weeks and the associated 95% confidence 
intervals, will be presented for each treatment group.
CCyR rates at and by time points
The CCyR Analysis Set will be used for these endpoints. 


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For each time point the CCyR rate and the associated 95% confidence interval based on the 
Pearson-Clopper method will be presented by treatment group. The descriptive p-value 
obtained via CMH chi-square tests stratified by the randomization strata, i.e. MCyR vs no 
MCyR at screening, will be presented. A 95% confidence interval for the difference in each
CCyR rate between treatment groups will be provided using the Wald method. The Mantel-
Haenszel estimate of the common risk difference and the corresponding 95% confidence 
interval will also be provided.
The cumulative incidence of CCyR by treatment group will be graphically displayed by an 
increasing step function. Each curve will increase each time (after randomization) at which a 
new responder is observed and thus will increase up to the best observed response rate (e.g. up 
to 50% if half of the patients in the analysis population are able to achieve CCyR).
Cytogenetic response at and by time points
Frequency and percentage of all cytogenetic response categories (defined in Section 2.7.1.2) by 
treatment arm using FAS will be presented for each time point. A shift table comparing baseline 
and best post-baseline cytogenetic response categories by treatment will also be presented. All 
assessments of cytogenetic response categories will also be listed by treatment arm.
For the by-time-points summary, the within-patient best cytogenetic response category up to 
the specific time points is used to calculate the frequency and percentage.
Assessments of bone marrow aspirate at different time points will also be summarized.
Time to CCyR
The CCyR Responder Set will be used. Descriptive statistics (minimum, maximum, median, 
quartiles, mean, sd) of time to CCyR will be provided for the two treatment groups separately.
The CCyR analysis set will be also used to perform similar Time-to-Event analyses as described 
below for duration of CCyR. 
Duration of CCyR
The CCyR Responder Set will be used. The survival distribution of duration of CCyR will be 
estimated using the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% 
confidence intervals [Brookmeyer and Crowley 1982] of the medians, along with the proportion 
of patients who are still in CCyR at 24, 48, 72 and 96 weeks and the associated 95% confidence 
intervals, will be presented for each treatment group.
TTF, PFS and OS
For each endpoint the survival distribution will be estimated using the Kaplan-Meier method, 
and Kaplan-Meier curves, medians and 95% confidence intervals [Brookmeyer and Crowley 
1982] of the medians, along with the proportion of patients who have not experienced the 
respective events at 1, 3 and 5 years and the associated 95% confidence intervals, will be 
presented for each treatment group. The hazard ratio between the two treatments will be 
calculated, along with its 95% confidence interval, using a stratified Cox model. The descriptive 
p-value obtained using a stratified log-rank test will be also presented. The stratification will be 


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based on the randomization stratification factor, i.e. cytogenetic response status (MCyR vs no 
MCyR) at screening.
2.7.3
Handling of missing values/censoring/discontinuations
MMR rates at specific time points: Patients discontinuing the randomized treatment prior to 
a specific time point due to any reason or patients without an available assessment at that time 
point will be considered as non-responders for that time point.
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 at specific time points: The category “Missing” will be assigned to

Ongoing cases, i.e. patients without assessment at the specific time point who have 
not discontinued study treatment and have not been treated sufficiently long for a 
specific time point

Discontinued due to progressive disease/death prior to a specific time point

Discontinued due to other reasons prior to a specific 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 in the MMR responder set 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.
CCyR rates at specific time points: Patients discontinuing the randomized treatment prior to 
a specific time point due to any reason will be considered as non-responders for that time point.
CCyR rates by specific time points: This will be handled similarly as MMR, but with CCyR 
instead.


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Cytogenetic response at specific time points: This will be handled similarly as molecular 
response category.
Cytogenetic response category by specific time points: This will be handled similarly as 
molecular response category.
Time to CCyR: For patients in the CCyR analysis set who have not experienced any CCyR, 
the time will be censored in the same manner as Time to MMR.
Duration of CCyR: For patients in the CCyR responder set who have not experienced any 
event (loss of CCyR, progression to AP/BC, or CML-related death) the duration will be 
censored at the last cytogenetic assessment date on treatment or the last PCR evaluation on 
treatment indicating MMR, whichever is the latest. 
TTF: For patients in the FAS who have not reached treatment failure, their TTFs will be 
censored at the time of their last study assessment (PCR, cytogenetic, hematologic or 
extramedullary) before the cut-off date.
PFS: For patients who have not experienced an event (disease progression to AP/BC or death 
from any cause), their PFS times will be censored at the date of last study assessment (PCR, 
cytogenetic, hematologic or extramedullary) before the cut-off date, regardless of subsequent 
intake of treatment(s) after randomization.
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, regardless of subsequent intake 
of treatment(s) after randomization.
2.8
Safety analyses
All safety analyses will be based on the safety set, except that the summary of safety data during 
the switched treatment period will be based on the Switch Analysis Set. All listings and tables 
will be presented by treatment group.
2.8.1
Adverse events (AEs)
AE summaries will include all AEs occurring during the on-treatment period (or the on-
switched 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 the on-treatment period will be flagged in the listings.
AEs will be summarized by number and percentage of subjects 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 subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades or 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.
In AE 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 asciminib arm.


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The following adverse event summaries will be produced by treatment arm for the Safety set 
and Switch Analysis Set: overview of adverse events and deaths, AEs by SOC and PT,
summarized by relationship, seriousness, leading to treatment discontinuation, leading to dose 
interruption/adjustment, requiring additional therapy, and leading to fatal outcome. The study 
treatment-related AEs/SAEs/AEs leading to treatment discontinuation as well as SAE with fatal 
outcome are summarized for the Safety set and Switch Analysis set. 
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.
In order to account for differences in exposure between the treatment arms, incidence rates of 
AEs and SAEs will be presented by adjusting for duration of treatment period in patient-years. 
They will also be reported by time intervals (i.e. period of emergence: the event is assigned to 
the interval when it first started): 0 to 2 months, > 2 months to 6 months, > 6 months to 12 
months, >12 months and more after the start of study treatment. 
2.8.1.1
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
An adverse event of special interest (AESI) is a grouping of adverse events that are of scientific 
and medical concern specific to compound asciminib. These groupings are defined using 
MedDRA terms, SMQs (standardized MedDRA queries), HLGTs (high level group terms), 
HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA 
queries, NMQ) may also be used. A NMQ is a customized group of search terms which defines 
a medical concept for which there is no official SMQ available or the available SMQ does not 
completely fit the need. It may include a combination of single terms and/or an existing SMQ, 
narrow or broad. 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 (or the on-switched treatment period) will be 
summarized.
Summaries of these AESIs will be provided by treatment arm (specifying grade, SAE, 
relationship, leading to treatment discontinuation, leading to dose adjustment/interruption, 
death, etc.). 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.
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment deaths) will be 
produced on the Safety set by treatment arm, system organ class and preferred term. 
Similarly, a separate summary for on-switched treatment deaths will be produced on the Switch 
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All deaths will be listed, where deaths occurring during the post-treatment, the on-switched 
treatment or post-switched treatment periods will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened subjects.
2.8.3
Laboratory data
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.  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 v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
On analyzing laboratory data, all sources (central and local laboratories) will be combined. The 
summaries will include all assessments available for the lab parameter collected no later than
30 days after the last study treatment administration date.
The following summaries will be produced on the Safety set separately for hematology and 
biochemistry laboratory data (by laboratory parameter and treatment):

Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline in the on-treatment period.

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value. 

For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.
The same summaries will be produced on the Switch Analysis Set for the on-switched treatment 
period.
The following listings will be produced separately for hematology and biochemistry for the 
laboratory data:

Listings of all laboratory data, with CTCAE grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.

Listing of all CTCAE grade 3 or 4 laboratory toxicities
Liver function parameters
Liver function parameters of interest are total bilirubin (TBL), Alanine aminotransferase
(ALT), Aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The number (%)
of patients with worst post-baseline values as per Novartis DILI Clinical safety guidelines will 
be summarized for the criteria defined by single lab parameter. For combination of various 
parameters, the worst post-baseline values from each single parameter are taken into 
consideration, i.e. it may not come from the concurrent measurement (i.e. same assessment). :
The following summaries will be produced:


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
ALT or AST > 3x upper limit of norm (ULN)

ALT or AST > 5xULN

ALT or AST > 10xULN

ALT or AST > 20xULN

TBL > 2xULN

TBL > 3xULN

ALT or AST > 3xULN & TBL > 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP >= 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN  
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
12-lead ECGs including PR, QRS, QT, QTcF and RR intervals will be obtained centrally for 
each subject during the study. ECG data will be read and interpreted centrally. 
The echocardiogram will be performed and evaluated locally to assess the left ventricular 
ejection fraction (LVEF).
Data handling
The average of the triplicate ECG parameters at each time point will be used in the analyses.
For unscheduled visits, ECGs that are reported on the same day and within 30 minutes apart 
from each other will be assumed to be sequential ECGs and thus will be used to compute the 
mean of the ECG parameters.
Unscheduled ECG measurements will not be used in computing the summary statistics for 
change from Baseline at each post-baseline time point. However, they will be used in the outlier 
analyses (e.g. QTc > 450 ms, > 480 ms, or > 500 ms at any time point, or an increase from 
Baseline in QTc > 30 ms or > 60 ms). End of treatment ECG measurements for discontinued 
patients will be considered as an unscheduled measurement in case it occurs outside a scheduled 
visit.
Data analysis
The number and percentage of subjects with notable ECG values will be presented by treatment 
arm for the Safety set and Switched Analysis Set. Notable values are defined below:

QT, QTcF

New value of > 450 and ≤ 480 ms

New value of > 480 and ≤ 500 ms

New value of > 500 ms

Increase from Baseline of > 30 ms to ≤  60ms

Increase from Baseline of > 60 ms

HR


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
Increase from baseline >25% and to a value > 100 bpm

Decrease from baseline >25% and to a value < 50 bpm

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 all ECG assessments will be produced by treatment arm and notable values will be 
flagged. A separate listing of only the subjects with notable ECG values will also be produced.
In each listing the assessments collected during the post-treatment period will be flagged.
Change from baseline ECG parameters by timepoint will also be summarized by treatment.
A listing of all LVEF assessments will be produced by treatment arm. In the listing, the 
assessments collected outside of on-treatment period will be flagged.
A summary table by treatment arm with descriptive statistics for LVEF at different timepoints
(baseline, week 20) and for change from baseline will be presented. A shift table for LVEF 
categories (≤40%, 41-49%, ≥50%) at baseline versus worst value on treatment will also be 
presented.
2.8.4.2
Cardiovascular risk factor assessment
Prior to randomization and at the end of treatment, for each patient information of the following 
risk factors is collected: heavy smoking, low physical activity, unhealthy diet, and other. A 
listing by treatment arm will be presented. 
Family medical history of each patient for ischemic heart disease, cardiac arrhythmia, sudden 
death, high cholesterol, diabetes mellitus, heart defects (congenital heart disease), and heart 
failure is also collected prior to randomization and at the end of treatment. A listing by treatment 
arm will be presented.
2.8.4.3
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute), systolic and diastolic blood pressure (mmHg).
Data handling
Vital signs collected on treatment will be summarized. Values measured outside of on treatment 
period will be flagged in the listings.


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Data analysis
The number and percentage of subjects with notable vital sign values (high/low) in systolic 
blood pressure, diastolic blood pressure, pulse rate, weight and temperature will be presented 
by treatment arm.         
A listing of all vital sign assessments will be produced by treatment arm and notable values will 
be flagged. In the listing, the assessments collected outside of on-treatment period will be 
flagged. 
2.8.4.4
Liver events
There are separate eCRF pages to collect acetaminophen/paracetamol, autoimmune, drug use 6 
months prior to liver event, immunoglobulin, liver function tests, pathology, related imaging, 
viral serology and potential impact of alcohol use, and an overview eCRF page. Data on the 
overview eCRF page will be listed by treatment arm. Assessments collected during the post-
treatment period will be flagged.
2.8.4.5
Pulmonary function tests
Data of pulmonary function tests will be listed by treatment arm. Assessments collected during 
the post-treatment period will be flagged.
2.8.5
Additional Analyses
2.8.5.1
ECOG performance status
ECOG performance status collected on treatment will be summarized. Shift tables will be 
provided comparing baseline with best and worst values during study for each treatment group.
2.9
Pharmacokinetic endpoints
PK parameters
The PK parameters that will be determined are shown in Table 2-7. The PK parameters for
asciminib are derived based on the non-compartmental methods using Phoenix WinNonlin®
software version 6.4 in patients with full PK sampling in PAS.


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Table 2-7
Non-compartmental PK parameters for asciminib in full PK group
AUC0-12h
The area under the plasma concentration-time curve from time zero to 12 
hours (ng*hr*mL-1)
AUClast
The AUC from time zero to the last measurable plasma concentration 
sampling time (Tlast) (ng*hr*mL-1)
Ctrough
Trough plasma concentration (measured concentration at the end of a 
dosing interval at steady state [taken directly before next administration])
Cmax
The maximum (peak) observed plasma concentration after
dose 
administration (ng/mL)
Tmax
The time to reach maximum (peak) plasma concentration after dose 
administration (hr)
Tlast
The time to reach the last measurable plasma concentration after dose 
administration (hr)
CL/F
The total apparent body clearance of drug from the plasma after oral 
administration (L*hr-1)
Descriptive statistics (n, arithmetic mean, CV% mean, standard deviation (SD), median, 
geometric mean, CV% geo-mean, minimum and maximum) will be presented by treatment for 
PAS for all PK parameters defined in Table 2-7 except Tmax, where only n, median, minimum 
and maximum will be presented. 
All individual PK parameters will be listed for patients treated with asciminib and with full PK 
sampling in the safety set.
PK concentrations 
Descriptive statistics (n, m (number of non-zero concentrations), arithmetic mean, CV% mean, 
SD, median, geometric mean, CV% geo-mean, minimum and maximum) for asciminib
concentration will be presented at each scheduled time point for the PAS.
The mean (+/- SD) and geometric mean concentration-time profiles for asciminib over time will 
be displayed graphically for PAS on the linear and semi-log view (Week 2 Day 1; for patients 
with full PK sampling only).
The mean (±SD) and median Ctrough values of asciminib over time will be displayed 
graphically for PAS on the linear scale only (Patients with full and sparse PK sampling).
All individual plasma asciminib concentration data will be listed for patients treated with
asciminib in the Safety Set.
Handling of PK data below LLOQ or missing
All concentration values below the lower limit of quantitation (LLOQ, 1 ng/mL) are set to zero 
by the Bioanalyst, and will be displayed in the listings as zero and flagged. LLOQ values will 
be treated as zero in any calculations of summary statistics, and treated as missing for the 


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calculation of the geometric means and their CV%. The number of non-zero concentrations will 
also be reported in the summary statistics.
Missing values for any PK data will not be imputed and will be treated as missing.
2.10
PD and PK/PD analyses
The potential relationship between asciminib exposure (e.g. trough concentration) and efficacy,
pharmacodynamics (PD) or safety endpoints may be assessed by graphic exploration and/or 
statistical modeling, as appropriate, including effect of population covariates. Additional 
exposure-response analyses for ECG may be conducted. The concentration data may be 
analyzed by a population approach to evaluate the influence of covariates on drug exposure. If 
applicable, the details of the above-mentioned analyses will be described in a separate analysis 
plan and reported separately.
The relationship between average trough plasma concentration up to 24 weeks and BCR-ABL 
ratio IS (%) at 24 weeks will be assessed by graphic exploration. 
2.11
Patient-reported outcomes
The FAS will be used for analyzing PRO data unless specified differently. The MDASI CML, 
PGIC along with EQ-5D-5L will be used to assess patient’s disease-related symptoms and 
health-related quality of life from baseline to EOT; and the WPAI-CML will be used to assess 
work productivity and activity impairment related to the patient’s CML. All tools require 
patient’s direct completion and will be administered utilizing electronic device for data 
collection at scheduled time points from screening to end of treatment.
The baseline is defined in Section 2.1.1. Patients with an evaluable baseline score and at least 
one evaluable post-baseline score during the treatment period will be included in the change 
from baseline analyses. Missing data items in a scale will be handled according to the manual 
for each instrument. No imputation will be applied if the total or subscale scores are missing 
at a visit. All measures will assess differences between the treatment arms.
Compliance to the schedule of administration of each PRO questionnaire will be summarized 
by treatment group, for baseline and scheduled post-baseline assessment time points. The 
following categories, as collected on the eCRF, will be used to describe whether the 
questionnaire was completed at a specific time point:
1. yes, fully completed
2. yes, partly completed
3. no
Repeated measures model for continuous scores
To best utilize the repeated assessments of a given PRO score, a repeated measures model for 
longitudinal data will be used to estimate differences between treatment arms. This repeated 
measures model will include terms for treatment, the stratification factor (major cytogenetic 
response status), time, baseline value as main effects, and an interaction term for treatment by 
time. This analysis will be restricted to patients with an evaluable baseline score and at least 


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one evaluable post-baseline score. All data collected until end of treatment (including the end 
of treatment assessment) will be included in the analysis. Note that only data collected under 
treatment (i.e. while the patient is treated) will be included. The end of treatment assessment 
will be included if collected within 7 days of the last dose intake.
Time will be considered as a continuous variable expressed in weeks, i.e. considering that the 
PRO score follow a linear trend.
As a first approach, an unstructured correlation matrix will be used to model the correlation 
within patients. The structure of the correlation matrix will be investigated and simplified using 
likelihood ratio tested if appropriate.
2.11.1
MDASI-CML
The M.D. Anderson Symptom Inventory – Chronic Myeloid Leukemia (MDASI-CML)
questionnaire is planned to be administered during screening, at weeks 4, 8, 12, 16, 24, 36, 48 
and 96 after randomization.
The MDASI-CML is a 26 item self-administered questionnaire for adult CML patients. Twenty 
of the items measure the severity of disease-related symptoms and are scored from 0 (Not 
present) to 10 (As bad as you can imagine) and 6 items that measure symptom interference with 
daily life scored from 0 (Did not interfere) to 10 (Interfered completely). 
The severity score will be calculated when a patient scores at least 11 items out of the 20 
severity items using the formula: (sum of scores for the items answered) / (number of items 
answered). If a patient scores fewer than 11 items, the severity score will be missing.
The interference score will be calculated when a patient scores at least 4 items out of the 6 
interference items using the formula: (sum of scores for the items answered) / (number of 
items answered). If a patient scores fewer than 4 items, the interference score will be missing.
For the severity score and interference score, descriptive statistics (n, mean, SD, median, 25th 
and 75th percentiles) by treatment arm will be provided for the actual scores and changes from 
baseline scores at each scheduled assessment time point.
Between-treatment differences for the change in severity and interference scores will be 
evaluated using the above-mentioned repeated measures model. 
2.11.2
EQ-5D-5L
EQ-5D-5L is a two-part standardized instrument for measuring health outcomes in a wide range 
of health conditions and treatments. It consists of a descriptive system and a visual analogue 
scale (EQ VAS). The descriptive system comprises the following 5 dimensions: mobility, self-
care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems and extreme problems (or 
unable to perform the activity). The EQ VAS records the respondent’s self-rated health on a 
vertical, visual analogue scale where the endpoints are labeled ‘Best imaginable health state’ 
and ‘worst imaginable health state’.
The EQ-5D-5L data will be used to calcutae utility values for the economic evaluation of
asciminib and bosutinib in a separate analysis.


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The EQ-5D-5L questionnaire is planned to be administered during screening, at weeks 4, 8, 12, 
16, 24, 36, 48 and 96 after randomization.
Descriptive system
The number and percentage of subjects in the five levels of each EQ-5D demension will be 
presented by treatment group at each assessment time point.
EQ VAS
The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale from 
0, labeled as ‘worst imaginable health state’, to 100, labeled as ‘best imaginable health state’.
For the EQ VAS, descriptive statistics (n, mean, SD, median, 25th and 75th percentiles) by 
treatment arm will be provided for actual values and for the change from baseline at each 
assessment time point.
Between-treatment differences for the changes in EQ VAS score will be evaluated using the 
above-mentioned repeated measures model.
2.11.3
WPAI-CML
The Work Productivity and Activity Impairment Questionnaire – Chronic Myeloid Leukemia
(WPAI-CML) questionnaire is planned to be administered during screening, at weeks 4, 12, 24, 
48 and 96 after randomization.
The WPAI-CML is a six-item questionnaire which is intended to measure work and activity 
impairment associated with CML for those who self-identify as currently employed for pay. 
This questionnaire measures self-reported productivity loss associated with CML during the 
past seven days. It consists of questions about absence from work due to CML, hours spent at 
work, the reduction in productivity at work attributed to CML, and the reduction in productivity 
while performing regular activities. WPAI-CML outcomes are expressed as impairment 
percentages, with higher numbers indicating greater impairment and less productivity, i.e., 
worse outcomes. Scoring will be done according to WPAI-CML instrument guidance resulting 
in four scores including: Percent work time missed due to problem; percent impairment while 
working due to problem; Percent overall work impairment due to problem; and, percent activity 
impairment due to problem.
Descriptive statistics (n, mean, SD, median, 25th and 75th percentiles) for each of the four 
derived outcome scores and changes from baseline scores will be presented by treatment arm 
at each scheduled assessment time point with .
Between-treatment differences for the changes in each of the four outcome scores will be 
evaluated using the above-mentioned repeated measures model. 
2.11.4
PGIC
The Patient Global Impression of Change (PGIC) instrument is planned to be administered 
during at weeks 4, 8, 12, 16, 24, 36, 48 and 96 after randomization
The PGIC is comprised of a single question intended to measure a patient’s perspective of 
improvement or deterioration over time relative to treatment. The PGIC uses a seven-point scale 


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where one (1) equals very much improved and seven (7) equals very much worse. Missing 
values will not be imputed.
The number and percentage of subjects in each of the seven categories for PGIC will be 
presented by treatment group at each assessment time point.
2.12
Resource utilization
Data relating to resource utilization (described in trial protocol Section 7.2.5) from the FAS will 
be used for the purpose of economic evaluation, which will be carried out and reported as a 
separate activity outside the CSR. 
The measures of healthcare resource utilization (HCRU) include: hospitalization (H), 
emergency room (ER) visit, general practitioner (GP) visits, specialist (Sp) visit and urgent care 
(UC) visit. HCRU will be assessed as follows: frequency and duration of hospitalization from 
baseline up to end of treatment; frequency of emergency room visits from baseline up to end of 
treatment; frequency of additional outpatient office visits general practitioner, specialist, and 
urgent care visits from baseline up to end of treatment. Hospitalization visits will also record 
the number of days on ward and the type of ward (hospital unit) and the discharge status. At 
each HCRU collected, the reason for the visit, i.e. related to CML, AE related to CML therapy 
or other reason, will be collected, in order to quantify the impact of treatment on healthcare 
resources.
HCRU data by treatment arm will be summarized in the primary analysis CSR and the end of 
study treatment CSR, with descriptive statistics (n, mean, median, SD, min, max) for 
quantitative variables, and count and percentage for qualitative variables.
2.13
Biomarkers
As a project standard, Novartis will analyze only biomarkers collected in the clinical database.
For exploratory markers, since the studies are not adequately powered to assess specific
biomarker-related hypotheses, the goal of these exploratory statistical analyses should be
considered as the generation of new scientific hypotheses. No adjustment for multiple
comparisons is usually planned for exploratory analyses. Furthermore, additional post hoc
exploratory assessments are expected and may be performed.
There may be circumstances when  a decision is made to stop sample collection, or not 
perform or discontinue their analysis due to either practical or strategic reasons. Under such 
circumstances, the number of samples may be inadequate to perform a rigorous data analysis 
and the available data will only be listed and potentially summarized.
If not otherwise specified, the FAS will be used for all biomarker analyses on patients with 
biomarker data.
Exploratory biomarker objectives

To characterize mutations in the BCR-ABL1 gene at Week 1 Day 1, upon confirmed 
loss of molecular response and/or at end of treatment and examine their association 
with molecular and cytogenetic response for asciminib vs bosutinib


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
To understand biology of CML and bone marrow microenvironment on leukemic 
stem cells (LSCs) eradication, including patients’ immunogenicity

To assess clonal evolution during treatment with asciminib vs. bosutinib

To evaluate soluble/inflammatory factors that correlate with response to asciminib vs. 
bosutinib treatment 
Only some analyses for the first exploratory biomarker objective about BCR-ABL1 mutation
listed above are described here and the results will be included in the respective CSRs. 
Additional analyses for this and other exploratory biomarker objectives will be described in 
separate analyses plans, with results reported separately.
List of biomarkers evaluated and the collection time points
The biomarkers evaluated in the study are listed in Table 2-8 below.
Table 2-8
Sample biomarker summary table
Biomarker
Time point
Sample
Method
Immune markers PD-L1 
and CD8
Screening and 
end of treatment
Bone marrow biopsy
Immunohisto-
chemistry
Leukemic stem cells
characterization
Screening, week 
24 and end of 
treatment
Bone marrow aspirate
Flow cytometry
BCR-ABL1 gene mutation
W1D1 pre-dose 
and end of 
treatment. If 
mutation is 
present at 
baseline, then 
also every 12 
weeks after 
baseline
Peripheral blood
Sanger 
Sequencing
Low level mutations in 
BCR-ABL1 gene
W1D1 pre-dose 
and end of 
treatment
Peripheral blood
Mass 
spectrometry 
and NGS
Circulating cytokines in 
plasma
W1D1 pre-dose,
Week 48 and end 
of treatment
Peripheral blood
MSD and ELISA
Genetic variant analysis of 
the UGT2B7 and 
UGT2B17 gene
W1D1
Peripheral blood
Genechip
General data handling and preprocessing
For bone marrow samples the latest assessment during screening period will be used as the 
baseline value, while for blood samples the week 1 day 1 (W1D1) pre-dose assessment will be
used as the baseline value.


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When more than one biomarker data value are available for a subject at any time point, the 
mean of the replicate values will be used for all statistical analyses.
2.13.1
Somatic mutation biomarker data handling and analysis
Handling of somatic biomarker data
Overall, somatic mutation status (wild type or mutant) will be derived from the mutational 
status of the interrogated exons for the BCR-ABL1 gene by Sanger Sequencing. These may
be non-exclusive and the presence of mutation across more than one exon will be reported in 
separate categories.
Mutation summary statistics
All somatic mutation data will be reported using counts and percentages by the mutation type 
in the form of contingency tables with the rows containing the different mutations assayed, 
and the treatment groups in the columns. All the mutation categories for a gene will also be
aggregated into mutant, wild type or missing/unknown groups and counts/percentages will be
reported by these three categories as well. A summary table will be presented for baseline 
mutations and another summary table for post-baseline new mutations (not present at baseline).
All the mutation data will be listed for each subject ordered by treatment group.
Association between biomarkers and clinical outcome
This analysis does not adjust for multiple comparisons and results may have higher false 
positive rates.
The relationship between Week 1 Day 1 BCR-ABL1 gene mutation data (wild type or mutant)
and outcome data (with or without MMR at and by 24 and 96 weeks using FAS, with or without 
CCyR at and by 24 and 96 weeks using CCyR analysis set) will be explored by reporting
contingency tables and by applying a logistic regression including treatment group, Week 1 
Day 1 BCR-ABL1 gene mutation and their interaction as covariates. Treatment group will be
included in this summary table.
In addition, the same analysis will be performed for

the relationship between post-baseline new BCR-ABL1 mutation (with or without 
new mutation) up to 48 weeks and outcome data (with or without MMR at 48 and 96 
weeks using FAS, with or without CCyR at 48 and 96 weeks using CCyR analysis 
set).

the relationship between post-baseline new BCR-ABL1 mutation (with or without 
new mutation) up to end of treatment and outcome data (with or without MMR at 96 
weeks using FAS, with or without CCyR at 96 weeks using CCyR analysis set).
The odds ratios bewteen treatment groups with 95% confidence intervals will be reported, for 
each biomarker category and overall. If treatment by biomarker interaction is significant (e.g.
when p < 0.1), overall odds ratio for treatment will not be reported.


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2.14
Other exploratory analyses
MMR rate at 24 weeks
The FAS will be used for the following exploratory analyses:
1. A logistic regression model adjusted for the stratification factor (based on the 
randomization platform data IRT) will be fit to assess treatment effect. An adjusted 
odds ratio for the treatment effect with associated 95% confidence intervals will be 
presented. Mantel-Haenszel estimates of the common odds ratio and the 
corresponding 95% confidence interval will also be provided.
Some subjects were mistratified. To assess the impact of this mistratification on the 
treatment effect assessment, a logistic regression adjusting for major cytogenetic
status at baseline based on CRF data will also be run.
2. Based on the subgroups specified in Section 2.2.1, the following analyses will be 
performed for each subgroup:

Proportion of patients with MMR at 24 weeks and its 95% confidence interval 
based on the Pearson-Clopper method within each treatment group

The difference in MMR rate at 24 weeks between treatment groups and the 
corresponding Wald 95% confidence interval
Efficacy analyses in subgroups will be purely exploratory and are intended to explore the 
consistency of treatment effect. Forest plot (n, risk difference, Wald 95% confidence 
interval) will be produced to graphically depict the treatment effect estimates in 
different subgroups. No inferential statistics (p-values) will be produced for the 
subgroups.
Post-hoc exploration of the treatment effect in different subgroups and assessment of 
the possible effect of differences in distribution of baseline characteristics were 
conducted (e.g. distribution of reasons for discontinuation of last prior TKI by gender 
and treatment, distribution of MCyR status at baseline by reasons for discontinuation 
of last prior TKI, distribution of mutation status at Week 1 Day 1 by reasons for 
discontinuation of last prior TKI).
3. A logistic regression model adjusted for the stratification factor (baseline major 
cytogenetic response status based on randomization data) and other important 
variables identified by the subgroup analyses above will be fit to assess treatment 
effect. An adjusted odds ratio for the treatment effect with associated 95% confidence 
intervals will be presented.
To assess the impact of mistratifications on the treatment effect assessment, the same 
analysis will be repeated, adjusting for major cytogenetic status at baseline based on 
CRF data instead of based on randomization data.


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Influence of early molecular response levels on long term molecular response 
levels
The relationship between MMR status at 24 weeks and MMR status at 48 and 96 weeks will be 
explored using FAS by reporting contingency tables and by applying a logistic regression
including treatment group, MMR status at 24 weeks and their interaction as covariates. 
Treatment group will be included in this summary table. The odds ratios between treatment 
groups with 95% confidence intervals will be reported, for each category of MMR status at 24 
weeks and overall. If the interaction of treatment by MMR status at 24 weeks is significant
(e.g. when p < 0.1), overall odds ratio for treatment will not be reported.
Efficacy Analysis on Switch Analysis Set
Efficacy analyses on the Switch Analysis Set will be performed at the time of the 96-week 
analysis. Unless otherwise specified, endpoints are defined and analyzed similarly as specified 
in Sections 2.5, 2.6, and 2.7 on Switch Analysis Set, but with baseline, FD, LD, and EoT 
replaced by baseline_switch, FDswitch, LDswitch, and S-EoT. The below are the efficacy endpoints 
to be analyzed:

MMR rate at and by all protocol-planned visits. 

CCyR rate at and by all protocol-planned visits. 

Time to MMR

Duration of MMR

Time to CCyR

Duration of CCyR

Time to Treatment Failure
The analysis of time-to-event endpoints will be conducted only if at least 5 events are observed.
2.15
Interim analysis
No formal interim analysis is planned for this trial.
Three to four analyses are planned with the analysis data cut-off dates and the scope of analyses 
as follows:

24-week Primary analysis: Formal testing of the primary endpoint with full alpha will be 
performed. Analyses of other efficacy endpoints at and by 24 weeks will also be 
performed.

96-week analysis: Formal statistical testing of the key secondary endpoint will be 
performed with = 0.05 (two-sided) only if the primary endpoint (i.e. MMR rate at 24 
weeks) is significant. Otherwise, no statistical testing will be performed, and any analysis
will be considered exploratory. Analyses of other efficacy endpoints will also be 
performed.

End of study treatment (EOsT) analysis (if required): similar to the 96-week analysis 
without formal statistical testing.
NOTE: This analysis may be conducted at the same time as 96-week analysis.


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
5-year PFS/OS update analysis: PFS and OS.
In addition, DMC safety analyses will be conducted. Prior to the database lock for the primary 
analysis, tables and figures aggregated by treatment arm for safety data review by the DMC or 
for other reporting activities will be produced by an independent statistician and independent 
statistical programmers.
3
Sample size calculation
3.1
Primary analysis
To test the null hypothesis that the MMR rate at 24 weeks is equal in the two treatment arms, 
based on  two-sided 5% level of significance and with 90% power, 222 patients will be needed 
in total (i.e. 148 patients in the asciminib arm and 74 patients in the bosutinib arm based on 2:1 
randomization allocation). The calculations were made using the software package PASS 
(2008).
It is assumed that asciminib leads to a 20% improvement in the MMR rate at 24 weeks over 
bosutinib from 15% to 35% which corresponds to an odds ratio of 3.05. The assumed bosutinib
MMR rate of 15% at 24 weeks is based on previous trials evaluating bosutinib therapy ([Kuoury 
et al. 2012], [Gambacorti-Passerini et al. 2014], [García-Gutiérrez et al. 2015]).
3.2
Power for analysis of key secondary variables
If the primary analysis of MMR rate at 24 weeks is statistically significant, then the key 
secondary endpoint MMR rate at 96 weeks will be tested, with the overall alpha controlled at 
the 5% two-sided level using a gatekeeping strategy.
Table 3-1 below summarizes the treatment effects of the key secondary endpoint which can be 
detected with 80% and 90% power, based on the specified assumptions regarding the bosutinib 
effect. The calculations were made using the software package PASS (2008).
Table 3-1
Detectable effect sizes for key secondary endpoint
Endpoint
Anticipated effect 
with bosutinib
2-sided alpha
Power
Detectable 
effect size§
MMR rate at 96 weeks
30%*
0.05
90%
80%
≥ 23%
≥ 20%
*: [Gambacorti-Passerini et al. 2014], Figure 1D.
§: Absolute difference from the anticipated effect with bosutinib.
For MMR rate at 96 weeks, if the anticipated effect with bosutinib is 30%, then the given sample 
size with 2-sided alpha=0.05 would allow to detect an absolute difference of at least 23% (i.e. 
MMR rate at 96 weeks with asciminib is at least 53%) for 90% power and of at least 20% (i.e. 
MMR rate at 96 weeks with asciminib is at least 50%) for 80% power.
4
Change to protocol specified analyses
Pharmacokinetic analysis set: Removal of the condition related to vomiting to consider a 
concentration evaluable as the occurrence and time of vomiting is not collected in the CRF.


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The estimand langage was implemented in sections 2.5 and 2.6. Then, the PPS and analyses 
based on PPS were removed.
The subgroup considering historical BCR-ABL1 mutations was removed as not considered 
clinically relevant.
A definition for loss of CHR was provided.
Definition of loss of MMR: removed any reference to confirmation of CHR and CCyR as 
confirmation of CHR and CCyR was not mandated by protocol and was therefore not performed 
in practise.
The following analyses were added:
ECOG status, time to event analyses for duration of MMR and CCyR, exposure adjusted AE 
incidence and yearly AE incidence, COVID-19 related sensitivity analyses. 
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 
treatment 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 missing and the EOT page is available:
The EOT completion date should be used.  

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 treatment 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 treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment 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. 


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5.1.2.1
Other imputations
Incomplete date of initial diagnosis of cancer 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
Stratum reported in the CRF
This will be derived from the Bone Marrow Aspirate data recorded in the corresponding eCRF
pages at baseline. In some case the baseline sample may be missing or not evaluable (i.e. <20 
metaphases). 
The following imputation rule will be applied to derive the missing or non evaluable values:

Major cytogenetic response (MCyR) (0 to 35% Ph+ metaphases) will be assumed if
BCR-ABL1 levels ≤10% (IS).
Rationale:
ELN 2013 recommendations are providing treatment milestones with response categories for 
cytogenetic and molecular response, which we can refer to for the imputation:
MCyR is roughly corresponding to BCR-ABL1 levels ≤10% (IS) (Ross et al 2009).
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 4.03. 
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 4.03. 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 


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for CTCAE grading of laboratory parameters (embedded below). The latest available version 
of the document based on the underlying CTCAE version v4.03 at the time of analysis will be 
used. For laboratory tests where grades are not defined by CTCAE v4.03, 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 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  
Hematology
Immature cells (promyelocytes, myelocytes, metamyelocytes and blasts) will not be displayed 
in shift tables and will only be listed.
Immature cells are manually counted only if anomalies are detected during the automatic testing. 
Therefore, when the automatic testing was performed but no data is transferred for immature 
cells, this means there was no immature cells and their values can be imputed to 0. Note that 
there should not be any imputation in case the automatic testing was not performed or the test 
of immature cells is present with missing value in the database (this would mean the test was to 
be performed but couldn’t).
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 (mmol/L) = Calcium (mmol/L) +0.02 (40 – [Albumin (g/L)]


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For calculation of laboratory CTCAE grades 0 and 1, the normal range for derived corrected 
calcium is set to the same limits (in mmol/L) 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.
Biochemistry
In order to avoid double reporting of the same information, all available values for BUN and 
UREA will be reported under the parameter name BUN (mmol/L) in listing using the following 
conversion rule: UREA (mmol/L)=2.14 BUN (mmol/L) ([Lamb E et al 2012]). 
5.4
Efficacy variables
5.4.1
Molecular response
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 PAXgeneTM Blood RNA tubes from MMD laboratory 
will be used in this study. The lab conversion factor for this assay was 1.1 until 1 June 2020 and 
1 thereafter.  
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
The BCR-ABL ratio in IS% provided by the central laboratory will be use in the analyses. 
However, to calculate the fold change in BCR-ABL1/ABL used to derive the loss of MMR 
criteria, in case the BCR-ABL number of copies is reported as a 0 value and the patient doesn’t 
have atypical transcript at baseline, then the value will be replaced by 1, and the BCR-ABL 
ratio will be calculated.
Molecular response is categorized as follows:

10% > BCR-ABL ratio

1% < BCR-ABL ratio ≤ 10%

0.1% < BCR-ABL ratio ≤ 1%

0.01% < BCR-ABL ratio ≤ 0.1%

0.0032% < BCR-ABL ratio ≤ 0.01%

BCR-ABL ratio ≤ 0.0032%
Major molecular response (MMR)
Major molecular response (MMR) is defined as a value of ≤ 0.1% of BCR-ABL ratio on the IS. 
This endpoint corresponds to a ≥ 3 log reduction in BCR-ABL transcripts from a standardized 
baseline value for untreated CML patients which was established in the IRIS study 
(STI5710106). MMR will be considered as a binary variable with patients achieving MMR 


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grouped as ‘responders’ and patients not achieving MMR or patients with missing PCR 
evaluations grouped as ‘non-responders’.
Loss of MMR
Loss of MMR is defined as an increase in BCR-ABL1/ABL to > 0.1% by international scale 
(IS) in association with a ≥ 5-fold rise in BCR-ABL1/ABL from the lowest value achieved up 
to that time point on study treatment and replicated by a second analysis of the same sample. 
Loss of MMR must be confirmed by a subsequent sample analysis within 4-6 weeks showing 
loss of MMR associated with a ≥ 5-fold rise in BCR-ABL1/ABL from the lowest value achieved
up to that time point on study treatment.
If there is any assessment in between indicating a BCR-ABL ratio of ≤ 0.1% or a < 5-fold 
increase in BCR-ABL ratio from the lowest value achieved up to that time point on study 
treatment, then the initial indication of loss of MMR cannot be confirmed. However, an 
assessment indicating (unconfirmed) loss of MMR will be considered as confirmed loss of 
MMR if the patient had loss of CHR or loss of complete cytogenetic response (CCyR) after the 
achievement of MMR. CML-related death or progression to AP or BC will be considered as 
confirmed loss of MMR in any case (if they occurred on treatment) (given that the patient 
achieved prior MMR). 
5.4.2
Cytogenetic response
Cytogenetic response will be based on the percentage of Ph+ metaphases in the bone marrow. 
Cytogenetic evaluations will be considered for response assessment only if the number of 
metaphases examined is ≥20 in each bone marrow sample. As per protocol, fluorescent in-situ
hybridization (FISH) assessments will not be considered for any evaluation of cytogenetic 
response during treatment.
Cytogenetic response is categorized as follows (a review of a minimum of 20 metaphases is 
required):

Complete response (CCyR): 0% Philadelphia chromosome positive (Ph+) metaphases

Partial response (PCyR): >0 to 35% Ph+ metaphases

Major response (MCyR = CCyR + PCyR): 0 to 35% Ph+ metaphases

Minor response (mCyR): >35 to 65% Ph+ metaphases

Minimal response: >65 to 95% Ph+ metaphases

None: >95 to 100% Ph+ metaphases.
If bone marrow aspirate blast percentage is provided as ‘<X’ (i.e. below limit of detection), the 
numeric value is set to X for summary tables. In the listing ‘<X’ will be presented.
Complete cytogenetic response (CCyR)
CCyR is defined as a value of 0% Ph+ metaphases in bone marrow.
CCyR will be considered as a binary variable with patients achieving CCyR grouped as 
‘responders’ and patients not achieving CCyR, patients with missing cytogenetic evaluations 
grouped as ‘non-responders’.


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Loss of CCyR
Loss of CCyR is defined as an increase in the Ph+ bone marrow cells to > 0%.
Loss of CCyR must have led to treatment discontinuation because of lack of efficacy (based on 
the “End of Treatment Phase Disposition” eCRF or “End of Treatment Disposition” eCRF 
during the Treatment switch phase with Subject status=”lack of efficacy” and Reason of 
treatment failure = “After start of therapy, loss of CHR, CCyR or PCyR”).
In addition, CML-related death or progression to AP or BC will be considered as loss of CCyR 
in any case (if they occurred on treatment).
Major cytogenetic response (MCyR)
MCyR is defined as a value of 0% to 35% Ph+ metaphases in bone marrow.
MCyR will be considered as a binary variable with patients achieving MCyR grouped as 
‘responders’ and patients not achieving MCyR, patients with missing cytogenetic evaluations 
grouped as ‘non-responders’.
Loss of MCyR is defined as an increase in the Ph+ bone marrow cells to > 35%. For patients 
with response = PCyR, this would constitute loss of PCyR.
CML-related death or progression to AP or BC will be considered as confirmed loss of MCyR
in any case (if they occurred on treatment).
5.4.3
Hematologic response
Loss of CHR
Loss of CHR is defined by meeting any of the following:

WBC count > 20 × 109/L

Platelet count ≥ 600 × 109/L

Appearance of blasts or promyelocytes in peripheral blood

Appearance of myelocytes + metamyelocytes ≥ 5% in peripheral blood

Progressive splenomegaly refractory to therapy (i.e. ≥5cm below left intercostal margin) 
Loss of CHR must have led to treatment discontinuation because of lack of efficacy (based on 
the “End of Treatment Phase Disposition” eCRF or “End of Treatment Disposition” eCRF 
during the Treatment switch phase with Subject status=”lack of efficacy” and Reason of 
treatment failure = “After start of therapy, loss of CHR, CCyR or PCyR”).
In addition, CML-related death or progression to AP or BC will be considered as loss of CHR 
in any case (if they occurred on treatment).
Complete hematologic response (CHR)
CHR is defined when all of the following criteria are present at any assessment which is
confirmed by another assessment at least after 4 weeks:

White blood cells (WBC) count < 10 × 109 /L

Platelet count < 450 × 109 /L


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
Basophils < 5%

No blasts and promyelocytes in peripheral blood

Myelocytes + metamyelocytes < 5% in peripheral blood

No evidence of extramedullary disease, including spleen and liver. As extramedullary
disease is evaluated less frequently than hematology, the results of these evaluations are
carried forward until the next assessment (unless extramedullary disease was not present
at the current assessment but present at the next).
The assessment is not considered CHR, if there are any values indicative of CML in AP or BC 
(i.e. by blasts in bone marrow). The information used for hematological assessment will be
obtained from the laboratory, extramedullary and bone marrow data, all merged by patient and 
date. To accommodate for missing parameters, specific laboratory results may be carried
forward up to 14 days such that assessments performed within a two-week period can combined 
into one complete evaluation of hematological response. A value will be carried forward for no 
more than up to the subsequent valid assessment of the respective laboratory parameter. If even 
after applying this carry-forward algorithm, any of the above laboratory parameters is not 
available at a given assessment date, the response assessment will be considered missing, unless 
any of the available values (including those carried forward) indicates that there is no response 
in which case the assessment will be ‘No response’.
For confirmation of CHR, both the initial CHR as well as the confirming assessment (at least 4 
weeks after the initial assessment) must satisfy all the criteria mentioned above and no
assessment in between indicates ‘No response’. The terms “confirmed CHR” and “CHR” are 
used as synonymous given that the definition of CHR mentioned above already includes a 
requirement for confirmation.
5.4.4
Treatment Failure
The following events will constitute ‘treatment failure’, and are based on the ELN criteria
(Baccarani et al 2013) defining failure of a second line treatment adapted to include 
discontinuation of randomized treatment as an event:

No CHR or > 95% Ph+ metaphases at three months after initiation of therapy or 
thereafter

BCR-ABL1 ratio > 10% IS and/or > 65% Ph+ metaphases at six months after 
initiation of therapy or thereafter

BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases at 12 months after 
initiation of therapy or thereafter

Loss of CHR, CCyR or PCyR at any time after initiation of therapy

Detection of new BCR-ABL1 mutations which potentially cause resistance to study 
treatment (T315I and V299L), at any time after initiation of therapy  

Confirmed loss of MMR in 2 consecutive tests

New clonal chromosome abnormalities in Ph+ cells: CCA/Ph+: at any time after 
initiation of therapy


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
Discontinuation from randomized treatment for any reason* (Note that Reason for 
treatment discontinuation=”completed” doesn’t indicate a premature treatment 
discontinuation)
5.4.5
CML progression to accelerated phase (AP) or blast crisis (BC)
For the evaluation of CML progression to AP or BC, the following criteria will be used.
Accelerated phase (AP) is defined by any of the following:

≥ 15% blasts in the peripheral blood or bone marrow aspirate, but < 30% blasts in 
both the peripheral blood and bone marrow aspirate

≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow aspirate, but < 
30% blasts in both the peripheral blood and bone marrow aspirate

≥ 20% basophils in the peripheral blood

Thrombocytopenia (<100 x 109/L) that is unrelated to therapy*
*As thrombocytopenia is a known adverse reaction to CML therapy, platelets <100 × 109/L are 
only considered as CML-AP if the patient had these values within 30 days of treatment 
discontinuation due to disease progression. In this case, comments are to be provided on the 
termination page that thrombocytopenia is indicative of progression to AP and an adverse event 
(AE) entered with relationship to study treatment = ‘Not suspected’
Blast crisis (BC) is defined by any of the following:

≥ 30% blasts in peripheral blood or bone marrow aspirate

Appearance of extramedullary involvement other than hepatosplenomegaly proven by 
biopsy (i.e., chloroma).
The second bullet criteria can’t be considered in this study as this information was not 
collected.
5.4.6
CML-related deaths
CML-related death is considered as any death during treatment or follow-up (safety or survival)

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.
With respect to the second bullet, as “unknown” cause of death will be coded to the Medical 
Dictionary for Regulatory Activities (MedDRA) preferred term ‘Death’, this MedDRA coding 
will be used in the derivation of CML-related death.
5.4.7
Disease progression
The following events are considered disease progression

CML-related deaths

Accelerated phase (AP)

Blast crisis (BC)


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5.4.8
Overall survival
This includes all-cause deaths.
5.5
Derivation of response rates and categories 
5.5.1
Response rate at a specific time point
The molecular and cytogenetic response evaluations will be summarized by the following 
mutually exclusive categories which are based on the respective assessment within the time 
window:

Response categories (sections 5.4.1 and 5.4.2 ): Patients with an available assessment at 
that time point (+/- time window) indicating any of the response categories.

No response: Patients with assessment at that time point (+/- time window) indicating 'no 
response'

Missing: Patients without an evaluable response assessment at that time point (+/- time 
window). This category is then further split into patients who are ongoing without 
treatment failure at the beginning of the relevant time window, patients who are ongoing
with treatment failure at the beginning of the relevant time window, patients who 
discontinued due to lack of efficacy, disease progression (PD) or death and patients who 
discontinued due to other reasons.
5.5.2
Response rate by a specific time point (best response)
In this analysis, patients who had achieved any response at or before the time point will be 
displayed in their best response category, no matter if they lost the response/discontinued or not. 
Therefore this response rate represents the best observed response rate up to that specific time 
point (including the time window). 
Patients for whom an evaluable response assessment was never provided will be classified as 
‘Missing’. 
5.6
Statistical models
5.6.1
Primary analysis
The null hypothesis of equality of MMR rate at 24 weeks in the two treatment arms will be 
tested against two-sided alternative. The statistical hypotheses are:
H0: RA24wk = RB24wk versus HA: RA24wk ≠ RB24wk, for a two-sided test
where RA24wk is the probability of MMR rate at 24 weeks in asciminib arm and RB24wk is the 
probability of MMR rate at 24 weeks in bosutinib arm.
The Cochran-Mantel-Haenszel chi-square test X2
CMH(implemented via SAS procedure FREQ
with CMH option in the TABLES statement), stratified by the randomization stratification 
factor, i.e. cytogenetic response status (MCyR vs no MCyR) at screening, will be used to test
the difference in response rates between the treatment arms. The p-value corresponding to the 
CMH test for “general association” will be used which follows a Chi-square distribution with 
one degree of freedom.


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The 95% confidence interval for the unstratified difference in MMR rate at 24 weeks between 
treatment groups will be provided using the Wald method (implemented via SAS procedure
FREQ
with RISKDIFF option
in
the
TABLES
statement, under the default 
METHOD=WALD and VAR=SAMPLE). If the 2×2 table is with asciminib in row 1, 
bosutinib in row 2, MMR in column 1 and No MMR in column 2, then the SAS output will 
give the estimate of (risk for MMR at 24 weeks in asciminib – risk for MMR at 24 weeks in 
bosutinib). The corresponding Mantel-Haenszel estimate of common risk difference and 95% 
confidence interval will also be presented (with RISKDIFF(COMMON) option in the
TABLES statement, taking the Mantel-Haenszel estimate from the SAS output table).
If the sampling assumptions for chi-square test is not met (i.e. the expected frequencies should
exceed 5 for all of table cells), the exact Cochran-Mantel-Haenszel test will be used 
(implemented via SAS procedure MULTTEST). The test is performed by running a stratified
version of the Cochran-Armitage permutation test [Armitage et al. 1969]. In studies with
stratified randomization, the chi-square approximation is considered appropriate for the 
X2
CMH statistics if the rule of Mantel and Fleiss [Mantel and Fleiss 1980] is satisfied.
Confidence interval for MMR rate within each treatment arm
MMR will be summarized in terms of percentage rates with 95% confidence interval using
exact binomial confidence interval (implemented using SAS procedure FREQ with EXACT
statement for one-way table [Clopper and Pearson 1934]).
5.6.2
Key secondary analysis
The null hypothesis of equality of MMR rate at 96 weeks in the two treatment arms will be 
tested against two-sided alternative. The statistical hypotheses are:
H0: RA96wk = RB96wk versus HA: RA96wk ≠ RB96wk, for a two-sided test
where RA96wk is the probability of MMR rate at 96 weeks in asciminib arm and RB96wk is the 
probability of MMR rate at 96 weeks in bosutinib arm.
The same approaches as for the primary endpoint (Section 5.5.1) will be applied here for the 
Cochran-Mantel-Haenszel chi-square test X2
CMH, the 95% Wald confidence interval for the 
difference in MMR rate at 96 weeks between treatment groups, the Mantel-Haenszel estimate 
of common risk difference with 95% confidence interval, and the confidence interval for MMR 
rate within each treatment arm.
Multiplicity adjustment
Formal statistical testing of the key secondary endpoint will be performed with = 0.05 (two-
sided) only if the primary endpoint is significant by means of a gatekeeping procedure to control 
the overall alpha level.


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5.6.3
Other analyses
Mantel-Haenszel common odds ratio
To obtain Mantel-Haenszel estimates of the common odds ratio and the corresponding 95% 
confidence interval in exploratory analyses,  it requires SAS procedure FREQ with CMH and 
RELRISK options in the TABLES statement. 
Logistic Regression 
Odds ratio will be used as a measure of association between treatment and response in 
exploratory analyses (Section 2.14). The odds ratio will be derived from the logistic regression
model (implemented using SAS procedure LOGISTIC, with treatment specified as an
explanatory variable in the CLASS statement) which allows for including not only the
stratification factor but also for adjustments for other covariates (both categorical and
continuous). The odds ratio will be presented with 95% Wald confidence limits.
In cases where an exact test has been used to compare response rates, the odds ratio should be 
determined using exact logistic regression, and the odds ratio presented with exact 95% 
confidence limits. In these cases, SAS PROC LOGISTIC with EXACTONLY option will be 
used.
Kaplan-Meier estimates
An estimate of the survival function in each treatment group will be constructed using Kaplan-
Meier (product-limit) method as implemented in PROC LIFETEST with METHOD=KM
option. The PROC LIFETEST statement will use the option CONFTYPE=LOGLOG.
Median survival for each treatment group will be obtained along with 95% confidence 
intervals calculated from PROC LIFETEST output using the method of [Brookmeyer and 
Crowley 1982]. Kaplan-Meier estimates of the survival function with 95% confidence
intervals at specific time points will be summarized. The standard error of the Kaplan-
Meier estimate will be calculated using Greenwood’s formula [Collett 1994].
Hazard ratio
Hazard ratio will be estimated by fitting the Cox proportional hazards model using SAS 
procedure PHREG (with TIES=EXACT option in the MODEL statement). 
A stratified unadjusted Cox model will be, i.e. the MODEL statement will include the
treatment group variable as the only covariate and the STRATA statement will include
stratification variable(s). Hazard ratio with two-sided 95% confidence interval will be based 
on Wald test.
Cumulative incidence
The cumulative incidence proportion (CIP) will be estimated using SAS procedure LIFETEST 
or PHREG with EVENTCODE=Code for event of interest (e.g. MMR) as option in the 
MODEL statement, whereas code=0 for censored subjects and any other code (e.g. code=2) 
for subjects who dropped out due to a competing risk. The estimated CIP at the defined time 
points will be presented with 95% CI together with number of subjects with events, number of 
subjects with competing risks, and number of subjects censored.


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5.6.4
Calculation of exposure-adjusted incidence rate
To adjust for different durations of exposure across treatment arms, the incidence rate per 100 
patient-years of exposure (exposure-adjusted incidence rates of adverse events) will be 
calculated.
The IR/100 pyr is defined as numerator/denominator, where

Numerator = number of patients with the adverse events of interest (not the number of 
events; one patient may have more than one event).

Denominator = patient-years = total time at risk in years = among all patients in the 
population, sum of the duration of exposure (in days) until the first onset of the event 
of interest, if the patient experienced the event, or until the date of last dose if the 
patient did not experience the event / 365.25.
The patient-years (i.e. total time at risk in years) will be calculated as the sum of times at risk 
in days over all patients in the population / 365.25.
The time at risk for a patient in days will be calculated as follows:

If the patient experienced the event of interest, the time at risk for this patient is the 
duration of exposure from the first dose of treatment until the first onset of the event.

For patients without an event of interest, the time at risk is the total duration of 
exposure during core study, as applicable.
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.


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10. Lamb E, et al (2012) Kidney Function Tests  In Elsevier Health Sciences (Ed), Tietz 
Textbook of Clinical Chemistry and Molecular Diagnostics (Chapter 25). Also retrieved 
from 
https://books.google.es/books?id=BBLRUI4aHhkC&lpg=PA685&hl=es&pg=PA685#v=o
nepage&q&f=false
11. 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.
12. Ross DM, Branford S, Moore S, et al (2006) Limited clinical value of regular bone 
marrow cytogenetic analysis in imatinib-treated chronic phase CML patients monitored by 
RQ-PCR for BCR-ABL. Leukemia; 20(4):664-70.




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Date 
Time point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
25-
Aug-
2017 
Prior 
to 
DB 
lock 
for 
primary 
analysis 
Creation 
of 
final version 
N/A - First version 
NA 
 
 
 
 
 
26-
Mar-
2020 
Prior 
to 
DB 
lock 
for 
primary 
analysis 
Implementation 
of 
protocol 
amendments 2 
and 3.  
ABL001 has been replaced by 
International Nonproprietary 
Name (INN) asciminib. 
Introduction of the switch to 
asciminib option for patients 
experiencing treatment failure 
on bosutinib treatment 
 
 
Update of the definition of 
end of study treatment 
Added a potential End-of-
Study-Treatment analysis 
different from the 96-week 
analysis 
Addition/removal of 
secondary safety objectives 
and exploratory efficacy 
objectives 
Throughout the 
SAP amendment 
 
Section  1.1, 
Figure 1-1 
Sections 2.1, 2.3 
Analyses added 
throughout the 
document 
Section 1.1 
 
 
 
 
Table 1-1 
 
 
 
Additional 
analyses, 
clarification 
Clarification on which data are 
included 
in 
the 
analyses, 
which 
assessments 
are 
considered for safety and 
efficacy analyses 
Addition of the treatment arms 
and definition of the date of 
end 
of 
study 
treatment 
Removal of windows defined 
for ECGs, LVEF and PK 
assessments as they are not 
needed. 
As per Health Authorities 
Section 2.1 
 
 
 
 
Section 2.1.1 
 
 
 
 
 
 
Section 2.3.1  


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request, 
addition 
of 
the 
breakdown per different time 
points of the number (%) of 
patients who discontinued the 
study treatment phase and of 
the primary reason for study 
treatment 
phase 
discontinuation 
PAS: 
Removal 
of 
the 
condition related to vomiting 
to consider a concentration 
evaluable as the occurrence 
and time of vomiting is not 
collected in the CRF. 
Addition 
of 
a 
subgroup 
“Stratum reported in the CRF” 
for the analysis by subgroup of 
the primary endpoint (to take 
into 
account 
the 
mistratification cases) 
Removal of the subgroup 
“with or without historical 
BCR-ABL1 mutation by local 
lab” as this is not considered 
clinically relevant 
Additional analyses of prior 
TKI 
and 
non 
TKI 
antineoplastic therapies 
Implementation 
of 
the 
estimand language for the 
primary and key secondary 
objectives 
Addition 
of 
a 
sensitivity 
analysis 
of 
the 
primary 
estimand stratifying by the 
stratum recorded in the CRF to 
take into account that many 
stratification errors occurred 
Addition 
of 
Time-to-event 
analyses for time to MMR and 
time to CCyR 
 
 
 
 
 
 
 
 
Section 2.2 
 
 
 
 
 
Section 2.2.1 
 
 
 
 
 
 
 
 
 
 
Section 2.4.2 
 
 
Sections 2.5 and 
2.6 
 
 
Section 2.5.5 
 
 
 
 
 
Section 2.7.2 
 
 


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Added how time is censored 
for time to MMR/CCyR, 
clarification on how to handle 
missing BMA assessments 
due to MMR being achieved 
Added analyses AEs and 
SAEs 
incidence 
rates 
by 
adjusting for exposure and by 
reporting by time intervals to 
account 
for 
 
potential 
difference 
in 
exposure 
between the treatment arms 
Clarified 
handling 
of 
unscheduled 
ECG 
measurements in the analyses  
Section 2.7.3 
 
 
 
 
Section 2.8.1 
 
 
 
 
 
 
Section 2.8.4.1 
 
4-
June-
2020 
Prior 
to 
DB 
lock 
for 
primary 
analysis 
 Creation 
of 
amendment 2.0 
Clarified 
baseline 
for 
mutations 
Clarified EOT is mapped to 
defined time points 
Modified age subgroup, added 
Line of therapy subgroup and 
moved Without T315I/V299L 
to 
Supplementary 
analysis 
(All 
patients 
with 
T315I/V299L 
mutations 
identified at the Week 1 Day 1 
visit are discontinued from 
study treatment when the 
mutation 
results 
become 
available). 
Clarified Mutation subgroup 
doesn’t include T315I/V299L 
mutations. 
Modified age categories 
Added COVID-19 related PDs 
analysis 
Added definitions of time on 
treatment, 
duration 
of 
exposure in patient-years and 
average daily dose  
Section 2.1.1 
 
 
 
Section 2.2.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 2.3 
Section 2.3.1 
 
Section 2.4.1 
 
 
 


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Additional analyses of prior 
TKI therapy 
Added 
summary 
of 
concomitant therapies for on-
switched treatment period. 
Added COVID-19 sensitivity 
analyses for the primary and 
key secondary endpoints 
Added 
a 
supplementary 
analysis 
to 
the 
primary 
endpoint 
(Patients 
without 
T315I/V299L mutations at 
Week 1 Day 1 visit) 
Added new graph for Ctrough 
values of asciminib 
Updated the list of changes to 
the protocol specified analyses 
Added imputation rules for 
immature cells 
Removed imputation rules for 
corrected calcium as corrected 
calcium is collected 
Clarified all available values 
for BUN and UREA will be 
reported under the parameter 
name BUN in listing to avoid 
double reporting of same 
information 
Definition of loss of MMR: 
Removed reference to 
confirmation of loss of 
CHR/CCyR 
Loss of CHR: clarified 
“Progressive splenomegaly 
refractory to therapy” is ≥ 
5cm below left intercostal 
margin” 
Implemented change to 
definition of treatment failure 
(Protocol amendment 3) 
Section 2.4.2 
 
Sections 2.5.5, 
2.6.5 
 
Section 2.5.6 
 
 
Section 2.9 
 
 
 
Section 4 
 
Section 5.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.4.1 
 
 
 
Section 5.4.3 
 
 
 
 
Section 5.4.4 
 
 


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Clarified what 
“Thrombocytopenia (<100 x 
109/L) that is unrelated to 
therapy” is. 
Added derivation of response 
rates and categories section 
Section 5.4.5  
 
 
 
Section 5.5. 
7-
Aug-
2020 
Prior 
to 
DB 
lock 
for 
primary 
analysis 
 Creation 
of 
amendment 3.0 
after FDA type 
C 
teleconference 
on 28 July 020 
As agreed with FDA, added 
sensitivity analyses of the 
primary and key secondary 
endpoints 
without 
the 
imputation rule used in the 
main analyses in case of 
missing PCR evaluations at 
24/96 weeks.  
Per 
FDA 
request, 
added 
another subgroup of interest: 
BCR-ABL ratio at baseline ≥ 
1% or <1%. 
Added calculation rules for 
duration of interrruption. 
Added derivation rule for 
corrected calcium using the 
reported total calcium value 
and albumin. 
Aligned the definition of loss 
of CCyR with the definition of 
loss of CHR by adding the 
requirement that loss of CCyR 
(Ph+ bone marrow cells to > 
0%) must have led to treatment 
discontinuation because of 
lack of efficacy. 
Section 2.5.5 
 
 
 
 
 
 
 
Section 2.2.1 
 
 
 
Section 2.4.1 
 
Section 5.3 
 
 
 
Section 5.4.2 
14-
Oct-
2020 
Post 
DB 
lock 
for 
primary 
analysis 
Creation 
of 
addendum 1.0 
to include post-
hoc 
analyses 
added after FIR 
results review 
Added that protocol deviations 
during the treatment switch 
period 
will 
be 
reported 
separately and clarified . 
Clarified how to identify 
prohibited concomitant 
medications. 
Added an analysis of time to 
MMR considering 
Section 
2.3.1 
 
 
 
Section 
2.4.2 
 
 
Sections 
2.7.2 
and 
5.6.3 


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discontinuation from 
treatment due to any reason, 
without prior achievement of 
MMR as a competing risk. 
Added an analysis of the 
MMR rate using the number of 
subjects with adequate follow-
up as the denominator, i.e. for 
each time point (week x), only 
patients randomized at least x 
weeks prior to the cut-off date 
will be considered. 
Added that post-hoc 
exploration of the treatment 
effect in different subgroups 
and assessment of the 
possible effect of differences 
in distribution of baseline 
characteristics were 
conducted (e.g. distribution of 
reasons for discontinuation of 
last prior TKI by gender and 
treatment, distribution of 
MCyR status at baseline by 
reasons for discontinuation of 
last prior TKI, distribution of 
mutation status at Week 1 
Day 1 by reasons for 
discontinuation of last prior 
TKI). 
 
 
 
 
 
 
 
 
 
 
 
 
Section 2.14 
 


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