Clinical trial NCT03578367
Conditions: CML Chronic Myelogenous Leukemia Leukemia, Myeloid Chronic Hematologic Diseases
Keywords: CML Chronic Myelogenous Leukemia leukemia, myeloid chronic Hematologic Diseases Asciminib ABL001 Imatinib Nilotinib deep molecular response DMR Ph+ CML chronic phase cancer of the white blood cells tyrosine kinase inhibitor leukemia, myeloid leukemia CML with Ph+
Sponsor: Novartis Pharmaceuticals
Start date: 2018-11-22; Completion date: 2025-02-28
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
To evaluate efficacy, safety and pharmacokinetic profile of asciminib 40mg+imatinib or asciminib 60mg+imatinib versus continued imatinib and versus nilotinib versus asciminib 80mg in pre-treated patients with Chronic Myeloid Leukemia in chronic phase (CML-CP)

Detailed description:
The study is a Phase 2, multi-center, open-label, randomized study of asciminib in two different doses (40 mg or 60 mg) in combination with imatinib 400 mg versus continued imatinib versus switch to nilotinib in Participants with chronic myeloid leukemia in chronic phase (CML-CP) who have been previously treated with imatinib first line therapy for at least one year and have not achieved deep molecular response (DMR). Eligible participants were randomized 1:1:1:1 to receive asciminib 60 mg once daily (QD) as add-on therapy to imatinib 400 mg QD, or 40 mg QD as add-on therapy to imatinib 400 mg QD, or to continue imatinib 400 mg QD, or to switch to nilotinib 300 mg twice a day (BID).

Participants on the imatinib continuation arm who had not achieved MR4.5 at 48 weeks were allowed to cross-over (CO) to receive the add-on treatment within 4 weeks after week 48 visit to receive the asciminib 60 mg combination add-on treatment, as this dose provided higher exposure. The cross-over is at the discretion of the investigator and the participant. Apart from a polymerase chain reaction (PCR) result of below MR4.5 at Week 48 visit, there are no other entry criteria for the cross-over part. Participants on nilotinib are not allowed to cross- over to receive the add-on treatment.

Participants on the study will continue on the allocated treatment until treatment failure, intolerability, or for up to 96 weeks (in arms 1 to 4) after the last participant received the first dose of treatment. After the last dose received, every participant will be followed up for safety for 30 days.

Arms: arm 1: Asciminib 60 mg taken once daily in combination with Imatinib 400 mg taken once daily arm 2: Asciminib 40 mg taken once daily in combination with Imatinib 400 mg taken once daily arm 3: Imatinib 400 mg taken once daily arm 4: Nilotinib 300 mg taken twice daily
Interventions: intervention 1: Asciminib add-on intervention 2: Imatinib intervention 3: Nilotinib
Intervention descriptions: intervention 1: Asciminib 60 mg or 40 mg taken orally once daily. intervention 2: Imatinib 400 mg taken orally once daily intervention 3: Nilotinib 300 mg taken orally twice daily (total daily dose of 600 mg)

Protocol documents:
Prot_000.pdf: 
 
 
 
Novartis Research and Development 
ABL001 
Clinical Trial Protocol CABL001E2201 
A phase 2, multi-center, open-label, randomized study of 
oral asciminib added to imatinib versus continued imatinib 
versus switch to nilotinib in patients with CML-CP who 
have been previously treated with imatinib and have not 
achieved deep molecular response  
Document type: 
Amended Protocol Version 
EUDRACT number: 
2018-001594-24 
Version number: 
04 (Clean) 
Clinical Trial Phase: 
II 
Release date: 
24-Aug-2023 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of NovartisClinical Trial Protocol Template version 8.0 dated 18-Jul-2023  


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 12 
Amendment 4 (24-Aug-2023) ........................................................................................... 14 
Amendment 3 (12-Jul-2022) ............................................................................................. 16 
Amendment 2 (10-Aug-2020) ........................................................................................... 21 
Local version Amendment 02-US.01 (10-Aug-2020) for USA ........................................ 23 
Amendment 1 (18-Jul-2019) ............................................................................................. 24 
Protocol summary .............................................................................................................. 30 
1 
Introduction ....................................................................................................................... 36 
1.1 
Background ............................................................................................................ 36 
1.1.1 
Introduction to investigational treatment(s) and other study 
treatment(s) ........................................................................................... 36 
1.2 
Purpose .................................................................................................................. 49 
2 
Objectives and endpoints ................................................................................................... 52 
3 
Study design ...................................................................................................................... 54 
4 
Rationale ............................................................................................................................ 56 
4.1 
Rationale for study design ..................................................................................... 56 
4.1.1 
Rationale for addition of asciminib single agent cohort ....................... 56 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 57 
4.3 
Rationale for choice of comparator and combination drugs .................................. 58 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 59 
4.5 
Risks and benefits .................................................................................................. 59 
4.6 
Rationale for public health emergency mitigation procedures .............................. 61 
5 
Population .......................................................................................................................... 61 
5.1 
Inclusion criteria .................................................................................................... 61 
5.2 
Exclusion criteria ................................................................................................... 62 
6 
Treatment ........................................................................................................................... 65 
6.1 
Study treatment ...................................................................................................... 65 
6.1.1 
Study drugs............................................................................................ 65 
6.1.2 
Additional study treatments .................................................................. 66 
6.1.3 
Treatment arms/group ........................................................................... 66 
6.1.4 
Guidelines for continuation of treatment .............................................. 66 


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6.1.5 
Treatment duration ................................................................................ 66 
6.2 
Other treatment(s) .................................................................................................. 67 
6.2.1 
Concomitant therapy ............................................................................. 67 
6.2.2 
Prohibited medication ........................................................................... 69 
6.3 
Subject numbering, treatment assignment, randomization .................................... 70 
6.3.1 
Subject numbering ................................................................................ 70 
6.3.2 
Treatment assignment, randomization .................................................. 71 
6.3.3 
Treatment assignment for asciminib single agent cohort ...................... 71 
6.4 
Treatment blinding ................................................................................................ 71 
6.5 
Dose escalation and dose modification.................................................................. 71 
6.5.1 
Dose modifications ................................................................................ 71 
6.5.2 
Follow-up for toxicities ......................................................................... 78 
6.6 
Additional treatment guidance ............................................................................... 79 
6.6.1 
Treatment compliance ........................................................................... 79 
6.6.2 
Emergency breaking of assigned treatment code .................................. 79 
6.7 
Preparation and dispensation ................................................................................. 79 
6.7.1 
Handling of study treatment and additional treatment .......................... 80 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 81 
6.7.3 
Asciminib single agent cohort - Instruction for prescribing and 
taking study treatment ........................................................................... 83 
7 
Informed consent procedures ............................................................................................ 84 
8 
Visit schedule and assessments ......................................................................................... 85 
8.1 
Screening ............................................................................................................... 96 
8.1.1 
Eligibility screening .............................................................................. 96 
8.1.2 
Information to be collected on screening failures ................................. 97 
8.2 
Subject demographics/other baseline characteristics............................................. 97 
8.3 
Efficacy .................................................................................................................. 97 
8.3.1 
Molecular response and BCR::ABL1 RT-qPCR .................................. 97 
8.3.2 
Bone marrow analysis and cytogenetics ............................................... 99 
8.3.3 
Appropriateness of efficacy assessments .............................................. 99 
8.4 
Safety and  tolerability ........................................................................................... 99 
8.4.1 
Laboratory evaluations ........................................................................ 100 
8.4.2 
Electrocardiogram (ECG) ................................................................... 102 
8.4.3 
Pregnancy and assessments of fertility ............................................... 105 
8.4.4 
Appropriateness of safety measurements ............................................ 106 
8.5 
Additional assessments ........................................................................................ 106 


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8.5.1 
Clinical Outcome Assessments (COAs) ............................................. 106 
8.5.2 
Pharmacokinetics ................................................................................ 108 
8.5.3 
Biomarkers .......................................................................................... 110 
9 
Study discontinuation and completion ............................................................................ 111 
9.1 
Discontinuation .................................................................................................... 111 
9.1.1 
Discontinuation of study treatment ..................................................... 111 
9.1.2 
Withdrawal of informed consent ......................................................... 113 
9.1.3 
Lost to follow-up ................................................................................. 113 
9.1.4 
Early study termination by the sponsor ............................................... 113 
9.2 
Study completion and post-study treatment ........................................................ 114 
10 Safety monitoring and reporting ...................................................................................... 114 
10.1 
Definition of adverse events and reporting requirements .................................... 114 
10.1.1 
Adverse events .................................................................................... 114 
10.1.2 
Serious adverse events ........................................................................ 116 
10.1.3 
SAE reporting...................................................................................... 117 
10.1.4 
Pregnancy reporting ............................................................................ 119 
10.1.5 
Reporting of study treatment errors including misuse/abuse .............. 119 
10.2 
Additional Safety Monitoring .............................................................................. 120 
10.2.1 
Liver safety monitoring ....................................................................... 120 
10.2.2 
Renal safety monitoring ...................................................................... 121 
10.2.3 
Steering Committee ............................................................................. 121 
11 Data Collection and Database management .................................................................... 121 
11.1 
Data collection ..................................................................................................... 121 
11.2 
Database management and quality control .......................................................... 122 
11.3 
Site monitoring .................................................................................................... 122 
12 Data analysis and statistical methods .............................................................................. 123 
12.1 
Analysis sets ........................................................................................................ 123 
12.2 
Subject demographics and other baseline characteristics .................................... 124 
12.3 
Treatments ........................................................................................................... 124 
12.4 
Analysis of the primary endpoint(s) .................................................................... 124 
12.4.1 
Definition of primary endpoint(s) ....................................................... 125 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 125 
12.4.3 
Handling of missing values/censoring/discontinuations ..................... 125 
12.4.4 
Supportive analyses ............................................................................. 125 
12.5 
Analysis of secondary endpoints ......................................................................... 126 


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12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................. 126 
12.5.2 
Safety endpoints .................................................................................. 128 
12.5.3 
Pharmacokinetics ................................................................................ 130 
12.6 
Analysis of exploratory endpoints ....................................................................... 131 
12.6.1 
Efficacy exploratory endpoints ........................................................... 131 
12.6.2 
Other exploratory endpoints ................................................................ 132 
12.6.3 
Biomarkers .......................................................................................... 132 
12.6.4 
Patient Reported Outcomes ................................................................. 132 
12.7 
Interim analyses ................................................................................................... 133 
12.8 
Sample size calculation........................................................................................ 133 
12.8.1 
Primary endpoint(s) ............................................................................. 133 
12.8.2 
Secondary endpoint(s) ......................................................................... 134 
13 Ethical considerations and administrative procedures .................................................... 135 
13.1 
Regulatory and ethical compliance ...................................................................... 135 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 135 
13.3 
Publication of study protocol and results............................................................. 136 
13.4 
Quality Control and Quality Assurance ............................................................... 136 
13.5 
Participant engagement ........................................................................................ 136 
14 Protocol adherence .......................................................................................................... 137 
14.1 
Protocol Amendments ......................................................................................... 137 
15 References ....................................................................................................................... 138 
16 Appendices ...................................................................................................................... 141 
16.1 
Appendix 1: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ....................................................................................................... 141 
16.2 
Appendix 2: Specific Renal Alert Criteria and Actions and Event Follow-up .... 143 
16.3 
Appendix 3: List of concomitant medications which are prohibited or to be 
used with caution ................................................................................................. 144 
16.3.1 
Concomitant medications to be used with caution for asciminib + 
imatinib arms ....................................................................................... 144 
16.3.2 
Prohibited comedications for asciminib + imatinib arms ................... 145 
16.3.3 
Concomitant medications to be used with caution for asciminib 
single agent cohort .............................................................................. 145 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 52 
Table 6-1 
Study drug ............................................................................................. 65 


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Table 6-2 
Criteria for dose reduction/interruption and re-initiation of 
asciminib + imatinib, or asciminib single agent treatment for 
adverse drug reactions ........................................................................... 72 
Table 6-3 
Dose reduction for asciminib and imatinib ........................................... 76 
Table 6-4 
Dose reduction for asciminib single agent cohort ................................. 77 
Table 6-5 
Dose and treatment schedule ................................................................. 81 
Table 8-1 
Assessment Schedule, randomized treatment arms 1 – 4 and 
asciminib single agent cohort ................................................................ 86 
Table 8-2 
Assessment Schedule, patients randomized to the continued 
imatinib arm who cross-over to receive asciminib 60 mg + imatinib ... 93 
Table 8-3 
Blood samples for PCR (primary and secondary efficacy 
endpoints) in all randomized treatment arms 1- 4, and asciminib 
single agent cohort ................................................................................ 98 
Table 8-4 
Blood samples for PCR in cross-over ................................................... 98 
Table 8-5 
Safety and tolerability assessments ....................................................... 99 
Table 8-6 
Laboratory  assessments ...................................................................... 101 
Table 8-7 
Central ECG collection plan in all randomized treatment arms 1- 4, 
and asciminib single agent cohort ....................................................... 103 
Table 8-8 
Central ECG collection plan in cross-over .......................................... 104 
Table 8-9 
Pharmacokinetic blood collection log ................................................. 109 
Table 8-10 
Biomarker sample collection plan ....................................................... 111 
Table 12-1 
Non-compartmental pharmacokinetic parameters .............................. 131 
Table 12-2 
90% Confidence intervals for 30% difference rate between the 
arms ..................................................................................................... 134 
Table 16-1 
Liver Event and Laboratory Trigger Definitions ................................ 141 
Table 16-2 
Follow Up Requirements for Liver Events and Laboratory Triggers . 141 
Table 16-3 
Specific Renal Alert Criteria and Actions ........................................... 143 
Table 16-4 
Concomitant medications to be used with caution for asciminib + 
imatinib arms ....................................................................................... 144 
Table 16-5 
Prohibited comedication for asciminib + imatinib arms ..................... 145 
Table 16-6 
Concomitant medications to be used with caution for asciminib 
single agent cohort .............................................................................. 145 
List of figures 
Figure 1-1 
Cumulative incidence of MR4.5 according to response level at 24 
months of imatinib treatment ................................................................ 51 
Figure 3-1 
Study design .......................................................................................... 55 
 


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List of abbreviations 
(e)CRF 
(Electronic) Case Report Form 
ABL 
Abelson proto-oncogene 
ADME 
Absorption, Distribution, Metabolism, and Excretion 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
Alb 
Albumin 
ALL 
Acute Lymphoblastic Leukemia 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AP 
Accelerated Phase  
AST 
Aspartate Aminotransferase 
ASAC 
Asciminib single agent cohort 
ATC 
Anatomical Therapeutic Chemical 
ATP 
Adenosine Triphosphate-binding  
AUC 
Area Under the Curve 
AUC0-12hours 
Area Under the plasma concentration-time Curve from time zero to 12 hours 
AUC0-24hours 
Area Under the plasma concentration-time Curve from time zero to 24 hours 
AUCinf 
Area Under the plasma drug concentration-time Curve from time zero to infinity 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (Tlast) (mass x 
time x volume-1) 
AUCR 
Area Under the Curve Ratio 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x 
volume-1) 
AV 
Atrioventricular 
BC 
Blast Crisis 
BCR 
Breakpoint Cluster Region 
BCR::ABL1 
BCR-ABL1 fusion protein 
BCR::ABL1 
BCR-ABL1 fusion gene  
BCRP 
Breast Cancer Resistant Protein 
BCS 
Biopharmaceutical Classification System 
BID 
Bis In Diem (twice a day) 
BLRM 
Bayesian Logistic Regression Model 
BP 
Blast Phase 
CABG 
Coronary Artery Bypass Graft 
CCA 
Clonal Chromosomal Abnormalities  
CCyR 
Complete Cytogenetic Response 
CDS 
Core Data Sheet (for marketed drugs) 
CFR 
Code of Federal Regulation 
CHR 
Complete Hematologic Response 
CI 
Confidence Interval 
Cmax 
The maximum (peak) observed plasma drug concentration after oral dose administration 
(mass x volume-1) 
Cmin 
Minimum drug plasma (serum/blood) concentration 
CML 
Chronic Myeloid Leukemia 


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CML-AP 
Chronic Myeloid Leukemia - Accelerated Phase 
CML-BC 
Chronic Myeloid Leukemia - Blast Crisis  
CML-CP 
Chronic Myeloid Leukemia - Chronic Phase 
CMO&PS 
Novartis Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CO 
Cross-Over 
COA(s) 
Clinical Outcome Assessments 
CRA 
Clinical Research Associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSF 
Clinical Service Form 
CSR 
Clinical Study Report 
CTC 
Common Toxicity Criteria 
CTIS 
Clinical Trial Information System 
CTR 
Clinical Trial Regulation 
Ctrough 
Minimal concentration before the next dose is administered 
CV 
Coefficient of Variation 
CYP 
Cytochrome P450 
DAR 
Dose Administration Record 
DDI 
Drug-Drug Interactions 
DHEA 
Dehydroepiandrosterone 
DILI 
Drug-Induced Liver Injury 
DLTs 
Dose Limiting Toxicities 
DMR 
Deep Molecular Response 
DS&E 
Oncology Novartis Drug Safety and Epidemiology Department 
DTI 
Direct Thrombin inhibitor 
EBV 
Epstein–Barr virus 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ELN 
European Leukemia Network 
EMA 
European Medicines Agency 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of Treatment 
eRT 
eResearchTechnology 
EU 
European Union 
EudraCT 
European Union Drug Regulatoring Authorities Clinical Trials 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIH 
First-In-Human 
FISH 
Fluorescent In-situ hybridization 
FMI 
Final Market Image 
FSH 
Follicle-stimulating hormone 


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GCP 
Good Clinical Practice 
GGT or γGT 
Gamma-glutamyl-transferase 
GP 
General Population 
GUSB 
Glucuronidase Beta 
HbA1c 
Hemoglobin A1c 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B  
HCV 
Hepatitis C 
hERG 
Human Ether-a-go-go-related Gene 
HIV 
Human Immunodeficiency Virus 
HSV 
Herpes simplex virus 
IB 
Investigator's Brochure 
IC50 
Inhibitory Concentration (IC50, the half maximal) 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
ID 
Identification Number 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRIS 
International Randomized Study of Interferon and STI571 
IRT 
Interactive Response Technology 
IS 
International Scale 
ITT 
Intent to treat 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
LC-MS/MS 
Liquid chromatography/tandem mass spectrometry  
LDL 
Low Density Lipoprotein 
LFT 
Liver function test 
LLN 
lower limit of normal 
LLOQ 
Lower limit of quantification 
LPLV 
Last Patient Last Visit 
LSC 
leukemic stem cell 
MCR or MCyR 
Major Cytogenetic Response 
MCV 
Mean corpuscular volume 
mCyR 
minor Cytogenetic Response 
MedDRA 
Medical dictionary for regulatory activities 
MI 
Myocardial Infarction 
MMR 
Major Molecular Response 
MNT 
Micronucleus test 
MR 
Molecular Response 
MRD 
Minimal Residual Disease 
MRI 
Magnetic Resonance Imaging 


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NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
 
 
nM 
nanoMolar 
NOAEL 
No observed adverse effect level  
NTCP 
sodium-dependent taurocholate co-transport protein 
OATP 
Organic anion-transporting polypeptide 
OCT 
Organic Cation Transporter 
OS 
Overall Survival 
P-gp 
Permeability glycoprotein 
PAS 
Pharmacokinetic analysis set 
PBPK 
Physiologically-Based Pharmacokinetic 
PCR 
Polymerase Chain Reaction 
PD 
pharmacodynamic(s) 
Ph+ 
Ph+ Philadelphia chromosome positive 
PK 
pharmacokinetic(s) 
PRO 
Patient Reported Outcome(s) 
PT 
Prothrombin Time 
QD 
Quaque Die (once daily) 
QLQ  
Quality of Life Questionnaire 
QMS 
Quality Management System 
QT 
QT interval 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected according to Fridericia's Formula 
RNA 
Ribonucleic acid 
RoW 
Rest of the World 
RP2D 
Recommended phase (Ph) II dose  
RT-qPCR 
real-time quantitative reverse transcriptase - Polymerase Chain Reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
statistical analysis system 
SC 
steering committee 
sCr 
serum creatinine 
SD 
standard deviation 
SOCs 
System Organ Classes 
SOP 
Standard Operating Procedure 
STAT5 
Signal transducer and activator of transcription 5 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBL 
total bilirubin 
TdP 
Torsade de Pointe 
TFR 
Treatment Free Remission 
TKI 
Tyrosine Kinase Inhibitor 
Tlast 
Time of last measurement (time) 
Tmax 
The time to reach maximum (Cmax) plasma drug concentration after oral dose administration 
(time) 
CCI
CCI


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TSQM 
Treatment Satisfaction Questionnaire for Medication 
UGT 
UDP-Glucuronosyltransferase  
ULN 
upper limit of normal 
ULQ 
upper limit of quantification 
US 
United States 
UV-LLNA 
Ultraviolet radiation - Local Lymph Node Assay 
WBC 
white blood cell(s) 
WHO 
World Health Organization 
ß-HCG 
Beta fraction of human chorionic gonadotropin  


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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), tissue, 
urine etc. taken from a study subject or patient 
Cycle 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g. q28 days) 
DMR 
Deep Molecular Response is considered as a response level of at least 
MR4.0 IS (either detectable disease ≤ 0.01% BCR::ABL1 IS or undetectable 
disease in cDNA with ≥ 10 000 ABL1 (log10 4.0) or ≥ 24 000 GUSB 
(glucuronidase beta) transcripts)  
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Enrollment 
Point/time of subject entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol). 
Investigational 
drug 
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product”. 
Investigational 
treatment 
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage. 
Medication 
number 
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system. 
Patient 
An individual with the condition of interest 
Period 
A minor subdivision of the study timeline; divides phases 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.  
Premature subject 
withdrawal 
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned. 
Randomization 
number 
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment 
Screen Failure 
A subject who is screened but is not treated or randomized 
Study completion 
Point/time at which the subject came in for a final evaluation visit or when 
study drug was discontinued whichever is later. 
Study drug 
discontinuation 
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal. 
Study 
drug/treatment 
Any drug (or combination of drugs) administered to the subject as part of the 
required study procedures; includes investigational drug, active drug run-ins or 
background therapy. 


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Study treatment 
discontinuation 
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date 
Subject 
An individual who has consented to participate in this study. 
Subject Number 
A unique identifying number assigned to each subject who enrolls in the study 
Sustained Minimal 
Residual Disease 
Sustained MRD (Minimal Residual Disease) is based on the last 5 quarterly 
performed PCR assessments, i.e (1) the first and the last assessments are 
MR4.5 (log10 4.5 reduction in transcripts), (2) no assessment is worse than 
MR4, and (3) no more than two assessments are between MR4 and MR4.5 
Treatment number 
A unique identifier assigned in non-randomized studies to each dosed subject, 
corresponding to a specific treatment arm  
Variable 
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified 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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Amendment 4 (24-Aug-2023) 
Amendment rationale 
The study is currently ongoing 84 patients in treatment arms 1– 4 have completed or 
discontinued the trial, and in the asciminib single agent cohort, 17 patients have been 
screened and 12/20 patients have been enrolled. 
This protocol amendment aims to update concomitant medications that should be used 
with caution. OATP1B and BCRP substrates have been added to this list. This is based 
on the results of a PBPK simulation study done as part of post-marketing requirements 
request per FDA (ABL001 IB Ed.10 – Section 1.4.2). 
Based on investigators feedback, the inclusion criterion 3 has been updated to allow 
enrollment of patients who were treated with imatinib at a dose of 300 mg QD or higher 
for at least one year and have not achieved DMR. The level of response for entering the 
trial remains unchanged, BCR::ABL1 levels > 0.01% IS and ≤ 1% IS at the time of 
randomization.) 
Imatinib 400 mg QD is the approved dose for newly diagnosed patients with CML. 
However, some patients require a lower dosage of imatinib to manage toxicity or impact 
on quality of life. For patients with BCR::ABL1 levels > 0.01% IS and ≤ 1% IS, stable 
on a 300 mg QD dose of imatinib, a switch to asciminib provides an opportunity to 
allow patients to remain on treatment at an optimal dose for longer in order to achieve 
deep responses. As the BCR::ABL1 levels required at the time of study entry are 
unchanged, no impact on the efficacy endpoints is expected with this change in the 
inclusion criteria. BCR::ABL1 levels required at the time of study entry are unchanged, 
no impact on the efficacy endpoints is expected with this change in the inclusion criteria. 
The exploratory biomarker assessments of 
 via 
 
 has been removed for patients entering the study in the asciminib single agent 
cohort. Sample collection and analysis will be completed for patients in treatment arms 
1-4 and discontinued there-after due to low number of samples meeting assay eligibility 
criteria(
 detected in 
samples analyzed to date. 
PK sample log specific for the asciminib single agent cohort is removed to harmonize it 
over all treatment arms (using the same for all arms). 
Updates based on Novartis template version implementation plan and guidance for 
protocols in the context of the upcoming transition for the European Clinical Trial 
Directive (EU CTD) 2011/C 172/01 to the European Union Clinical Trial Regulation 
(EU CTR) 536/2014   
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. 
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The following sections have been updated : 
• 
Section 1.1.1.1 Update for the CABL001A2301 is done to reflect current status of the 
trial along with ABL001 IB Ed. 10 updates. 
• 
Section 4.6 is updated to reflect changes in the protocol template.  
• 
Section 5.1 inclusion criteriona 3 is updated based on investigator’s feedback. The 
inclusion criterion number 3 is changed from 3a. to 3b. for reflecting the change in the 
protocol. 
• 
Section 6.1.1 Study drugs table is updated to reflect updated protocol template.  
• 
Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action :  
OATP1B, BCRP substrates added as permitted concomitant medication requiring 
caution. 
• 
Section 7 is updated to remove the optional phone call interview. 
• 
Table 8-1 Assessment Schedule, randomized treatment: asciminib single agent cohort 
added; subject interview removed; note added that sample collection for 
 
 is only for treatment arms 1-4. 
• 
Section 8.5.2.1 Table 8-10 PK sample log specific for the asciminib single agent 
cohort is removed to harmonize it over all treatment arms (using the same for all 
arms). 
• 
Section 8.5.3 and Table 8-11 (named as Table 8-10 in PA4): 
 
sample collection and exploratory biomarker analysis was limited to treatment arms 1-
4. 
• 
10.1.2 Serious adverse events and 10.1.3 SAE reporting sections are updated to reflect 
new protocol template. 
• 
10.1.5 is updated and Table 10-1 is removed to reflect new protocol template and EU-
CTR language. 
• 
13.3 is updated to reflect new protocol template and EU-CTR language. 
• 
16.3.3 Section Appendix 3 List of concomitant medications which are prohibited or to 
be used with caution: updated based on revisions in Section 6.2 and current 
knowledge. OATP1B and BCRP substrates updated as per ABL001 IB Ed.10. 
In addition, some minor changes including 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. 
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The changes here in 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. 
Amendment 3 (12-Jul-2022) 
Amendment rationale  
An interim analysis was performed to gain an early insight into the safety and efficacy of the 
asciminib add-on combination. The interim analysis was planned to be performed when at least 
40 (50%) patients have been randomized and have been followed for their 24 weeks visit 
assessment or have discontinued treatment. The interim analysis cut-off was on 22-July-2020. 
The results showed no excess of risk and/or reduced efficacy in the asciminib add-on arms. No 
change in study conduct were performed based on the benefit/risk balance. 
This amendment aims to add an asciminib single agent cohort to assess whether asciminib single 
agent at the recommended dose of 80 mg QD leads to similar efficacy and safety as observed 
in the add-on arms of asciminib and imatinib. This additional cohort will help to evaluate if the 
combination of asciminib with imatinib is needed to increase the likelihood of achieving DMR, 
or if this can be achieved by asciminib alone. The primary analysis cut-off was on 10-Jan-2022. 
Eighty-four patients have been randomized in the study. The primary analysis results show 
activity of asciminib as an add-on therapy to imatinib, assessed by MR4.5 rate at Week 48. The 
MR 4.5 rate at Week 48 was 19%, 28.6%, 0% and 4.8% in the asciminib 40 mg + imatinib, 
asciminib 60 mg + imatinib, continued imatinib and switch to nilotinib arm. Asciminib 40 mg 
QD or 60 mg QD added on to imatinib was well tolerated with no new or worsening events as 
compared to the known safety profile of single agent asciminib and imatinib.  
Data for molecular response with single agent asciminib is available from studies 
CABL001A2301 (called A2301 henceforth) and CABL001X2101 (called X2101 henceforth) 
that included heavily pre-treated CML-CP patients with prior treatment with at least 2 or more 
TKIs. The MR4.5 rate in study A2301, in the subgroup of patients treated with asciminib single 
agent with baseline BCR::ABL1 levels the same as that of patients enrolled in study 
CABL001E2201 (called E2201 henceforth) (i.e., > 0.01 ≤1%), was very similar (18.8%, 3 
responders among 16 patients) to that seen with the asciminib as add-on to imatinib in study 
E2201. 
The list of concomitant medications permitted to be used with caution and prohibited for the 
asciminib combination arms has been updated. Based on emerging data from pharmacokinetic 
studies [Asciminib Investigator Brochure], prohibition for strong CYP3A4/5 inhibitors has been 
removed and caution statement for asciminib combination arm are added. Additionally, 
instructions are added for strong CYP3A4 inducers to be used with caution for asciminib single 
agent and prohibited for the combination arms.  
Agents causing QT prolongation or with a "known", risk of Torsades de Pointes (TdP) are no 
longer prohibited but should be used with caution. Of note there is no need for caution or 
prohibition for drugs with “possible” or “conditional” risk of TdP and this statement is modified 
accordingly. Asciminib is not relevantly affected by UGT1A/2B inducers, or BCRP and P-gp 


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inhibitors, thus there is no longer a limitation to use of these agents for patients being treated 
with asciminib. No relevant interaction with sensitive substrates of CYP2C8 has been observed. 
Additionally, the amendment clarifies the exploratory biomarker objective studying the 
 and removes an exploratory objective based on subject qualitative 
interviews due to logistical issues to implement the process to complete these interviews. The 
interviews intended to describe concepts important to study patients not captured by standard 
PRO instruments that could inform future clinical trial designs were removed. 
As the TFR study has not been initiated and will not be available for patients completing the 
study E2201, the option for TFR study as a post-trial access mechanism for patients has been 
removed. 
The content of the local amendment for the USA Amendment 02-US.01 (10-Aug-2020) is 
superseded by this global amendment 03 as male contraception for the US patients on asciminib 
was removed based on the latest [Investigator’s Brochure] and approved US prescribing 
information (USPI), where no male contraception is required. 
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 following sections have been updated to include the asciminib single agent cohort: 
• Protocol Summary updated based on Protocol Amendment changes 
• Section 1.1.1 Introduction to investigational treatment(s) and other study treatment(s): 
updated for asciminib with current available information from non-clinical studies for 
phototoxicity and from ongoing clinical studies as reflected in the current [Asciminib 
Investigator’s Brochure] 
• Section 1.2 Purpose: added secondary objective to estimate the efficacy of asciminib single 
agent. Section 2 Objectives and related endpoints:  
• Duration of MR4.5 added to secondary objective (to assess additional parameters of the 
efficacy of asciminib 60 mg /40 mg added to imatinib vs continued imatinib or switch 
to nilotinib) to assess if patients in the add-on arms have a longer response to treatment  
• Secondary objectives and the corresponding endpoints added for asciminib single agent 
• Duration of MR4.5 added to exploratory objective (to describe the efficacy and safety of 
asciminib 60 mg + imatinib in patients randomized to continued imatinib who 
cross-over to receive asciminib 60 mg + imatinib) to assess if patients in the add-on 
arms have a longer response to treatment 
• Exploratory biomarker objective was reworded to add clarity, no changes to 
assessments 
• Exploratory objective to describe concepts not captured by standard PRO instruments 
to inform future clinical trial designs was removed due to unavailability of vendor 
contract 
• Section 3 Study design:  
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• Asciminib single agent cohort added 
• Four randomized treatment arms were labeled treatment arm 1-4 for clarity 
• End of treatment period added for asciminib single agent cohort 
• End of Study Treatment period added for asciminib single agent cohort, and reworded 
for clarity 
• Post trial access options were updated to align with clinical development strategy 
• Figure 1-1 was updated to reflect the addition of the asciminib single agent cohort 
• Section 4.1.1 Rationale for addition of asciminib single agent cohort section added 
• Section 4.2 Rationale for dose/regimen and duration of treatment: asciminib single agent 
cohort added 
• Section 4.5 Risks and benefits: risk-benefit evaluation updated based on new available data 
• Section 4.6 Rationale for public health emergency mitigation procedures: section added 
based on new standard procedures in the event of a public health emergency 
• Section 5: Population: asciminib single agent cohort added 
• Section 5.2 Exclusion criterion #15: Contraception duration revised to align with USPI; text 
updated for clarity  
• Criterion from local amendment 02-US.01: male contraception for patients on 
asciminib removed based on Novartis assessment of the risk for male-mediated 
embryo/fetal harm through semen transmission according to [Investigator’s Brochure] 
• Section 6.1.3 Treatment arm/group: asciminib single agent cohort added 
• Section 6.1.5 Treatment duration: asciminib single agent cohort added 
• Section 6.2 Concomitant therapy and prohibited medications updated to align with the latest 
Investigator Brochure Section 6.3.3 Treatment assignment for asciminib single agent cohort 
section added 
• Table 6-2: Criteria for dose reduction/interruption and re-initiation of asciminib + imatinib: 
asciminib single agent cohort added. Table updated, the rationale for the change is due to 
updates to internal NVS guidance on management of LFT derangements and clarification 
of guidance applicable to patients in the trial 
• Table 6-4 Dose reduction guidance for asciminib single agent cohort table added 
• Section 6.6.1 Treatment compliance: asciminib single agent cohort added 
• Section 6.7.1.1 Handling of study treatment: Reference to public health emergency 
mitigation procedures added 
• Section 6.7.3 Asciminib single agent cohort - Instruction for prescribing and taking study 
treatment section added 
• Section 7 Informed consent procedures text updated for clarity 
• Section 8 Visit schedule and assessments: Reference to public health emergency mitigation 
procedures added 
• Table 8-1 Assessment Schedule, randomized treatment: asciminib single agent cohort 
added; subject interview removed 


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• Section 8.1.2 Information to be collected on screening failures: asciminib single agent 
cohort added 
• Table 8-3 Blood samples for PCR: asciminib single agent cohort added 
• Section 8.4 Safety and Tolerability: Reference to public health emergency mitigation 
procedures added 
• Section 8.4.1 Laboratory evaluations: Reference to public health emergency mitigation 
procedures added 
• Table 8-7 Central ECG collection plan: asciminib single agent cohort added 
• Section 8.4.3 Pregnancy and assessments of fertility: Reference to public health 
emergency mitigation procedures added. Definition of post-menopausal and child-
bearing potential reworded to add more clarity 
• Section 8.5.1.4 Subject interview: section removed as exploratory objective was 
removed 
• Section 8.5.2.1 Pharmacokinetic blood collection and handling: asciminib single agent 
cohort added 
• Section 9.2 Study completion and post-study treatment: Section updated to clarify end 
of study, Week 96, and final analysis 
• Section 10.1.3 SAE reporting: reporting instructions reworded to cover requirements 
from authorities 
• Section 12.1 Analysis sets: asciminib single agent cohort added. The analysis of the 
duration of MR4.5 was added to the MR4.5 Responder set 
• Section 12.2 Subject demographics and other baseline characteristics: asciminib single 
agent cohort added 
• Section 12.3 Treatments: asciminib single agent cohort added 
• Section 12.5 Analysis of secondary endpoints: secondary endpoint analysis added to align 
with the objectives. Asciminib single agent secondary endpoint analysis added 
• Section 12.5.1 Efficacy and/or Pharmacodynamic endpoint(s): asciminib single agent 
added, text updated for clarity 
• Section 12.5.1.1 Rate of MR4.5 at 48 weeks: asciminib single agent added, text updated 
for clarity 
• Section 12.5.1.2 Rate of sustained MR4.5 at 96 weeks and section 12.5.1.3. Rate of MR4.5 
at 96 weeks and section 12.5.1.4 Rate of MR4.5 by 48 and 96 weeks: text updated for 
clarity 
• Section 12.5.1.6 Duration of MR4.5: Newly added section to describe the analysis of the 
duration of MR4.5 
• Section 12.5.2 text updated for clarity 
• Section 12.5.3 Pharmacokinetics: asciminib single agent cohort added 
• Table 12-1 Non-compartmental pharmacokinetic parameters: The Ctrough was removed 
from the list of pharmacokinetic parameters coming from non-compartmental analysis 


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as it will be derived from the descriptive stats of the different pre-dose (trough) 
assessments 
• Section 12.7 Interim analyses: clarified that primary analysis was performed in 
treatment arms 1-4 
• Section 12.8 Sample size calculation: updated for asciminib single agent cohort 
• Section 13.5 Subject engagement: section added per new protocol template  
• Section 15 References: newly cited references added 
• Section 16.3 Appendix 3 List of concomitant medications which are prohibited or to be 
used with caution: updated based on revisions in Section 6.2 and current knowledge.  
 
In addition, some minor changes including 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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Amendment 2 (10-Aug-2020) 
Amendment rationale 
As of 22-Jul-2020, 91 patients have been screened and 62 patients have been randomized in the 
study. The study is currently ongoing and no analysis has been conducted so far. 
Primary purpose of the amendment is: 
To allow for modification of study conduct based on interim analysis results in case of 
observation of an imbalance in the benefit risk profile of one of the investigational arms 
(asciminib add-on treatment arms), specifically findings related to excessive toxicity without 
added benefit. The interim analysis is planned to provide early insights into the safety and 
efficacy parameters to inform the benefit risk assessment of asciminib as an add-on therapy to 
imatinib. If excessive toxicity without added benefit is observed in one of the investigational 
arms, discontinuation of that treatment arm will be considered. The decision of discontinuation 
of an investigational arm in the study will be taken based on the risk benefit balance of the two 
investigational arms, and in context of the other two treatment options available for the patients 
in the study, namely, continue on imatinib with no potential improvement of efficacy, or switch 
to nilotinib with a potential to improve efficacy however with a relatively adverse safety profile 
as compared to imatinib. The interim analysis is planned to be performed when at least 40 (50%) 
patients have been randomized and have been followed for their 24 weeks visit assessment or 
have discontinued treatment. 
In addition, dose modification requirements have been updated to further clarify the dose 
modifications for recurrent Grade 3/4 cytopenias.  
• If, after a 1st event of Grade 1/2 cytopenia, recurrent cytopenia of any grade occurs, it is 
recommended that the study treatment be held until there is resolution to ≤ Grade 2, and 
thereafter current dose level can be maintained.  
• After a 1st event of Grade 3/4 cytopenia, if there is recurrence of Grade 3/4 cytopenia, the 
dose level should be maintained only if it resolves to ≤ Grade 2 in ≤ 14 days.  
• In case of recurrent Grade 3/4 cytopenias of duration >14 days asciminib and imatinib doses 
are recommended to be reduced by 1 dose level.  
Information for CYP3A substrates and inhibitors in the Appendix 3 has been updated in order 
to reflect updates introduced with protocol amendment 01 based on a most updated PBPK 
modeling. 
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.  
1. Protocol Summary: Study design and Data analysis sections updated in order to match with 
the updates made in the respective protocol sections.  
2. Section 1.1.1.1- Overview of asciminib: Narrow therapeutic index specified for substrates 
of CYP3A4/5, CYP2C8 and CYP2C9. 


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3. Section 2- Objectives and endpoints: Update of the endpoint for exploratory objective 
 
 was removed. 
4. Section 3- Study Design: Updated for possibility of modification of cross-over arm if 
signals of toxicity are seen in one or more treatment arms, at the time of interim analysis. If 
a decision is taken to discontinue asciminib 60 mg + imatinib treatment arm at interim 
analysis or upon emerging data, cross-over may be changed to asciminib 40 mg + imatinib 
treatment arm. Figure 3-1 subheading has been amended to match the updates in Section 3.  
5. Section 4.4- Purpose and timing of interim analyses/design adaptations: Update to 
allow possibility of modification of study conduct if excessive toxicity without added 
benefit is observed in one or more treatment arms, at the time of interim analysis. 
6. Section 6.5.1- Dose modification: Table 6-2 has been updated to clarify recommendations 
for recurrent cytopenias. 
7. Section 8- Visit schedule and assessments: Update for 
 
 
 was removed.  
8. Section 12.5.2- Safety endpoints: Updated for possibility of change of cross-over treatment 
based on results of the interim analysis. 
9. Section 12.6.2- Other exploratory endpoints: Updated for possibility of change of 
cross-over treatment based on results of the interim analysis. 
10. Section 12.7- Interim Analyses: Update to allow possibility of study modification if signals 
of toxicity are seen in one or more treatment arms, at the time of interim analysis. 
11. Section 16.3.3- Concomitant medications to be used with caution for asciminib + 
imatinib arms: Information in Appendix 3, Table 16-6 for CYP3A substrates and inhibitors 
updated in line with information in Section 6.2. 
The assessment of the Benefit/Risk concluded the absence of additional risks related to COVID-
19. 
In addition some minor changes including inconsistencies (discrepancies between sections, 
typos) have been corrected. 
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Local version Amendment 02-US.01 (10-Aug-2020) for USA 
Additional changes only applicable for the USA: 
Amendment rationale 
Based on FDA request, requirement for male contraception has been reintroduced in the study. 
Changes to the protocol 
Section 5.2 Exclusion criterion #15: Male contraception requirements added in exclusion 
criteria 15. Criteria numbering revised to 15b. 
Section 8.4.3 Pregnancy and assessments of fertility: added female partners of male to be 
recorded on Clinical trial pregnancy form and to include guidance for sexually active male. 
Additionally added, 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 in this period. 
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 1 (18-Jul-2019) 
Amendment rationale 
As of 18-Jul-2019, 32 patients were screened and 23 patients were randomized in the study. 
The study is currently ongoing. 
Primary purpose of the amendment is: 
Modification of the inclusion criteria #3 regarding imatinib pretreatment duration, from “at 
least 24 months” to “at least 12 months” in patients with BCR::ABL1 level between > 0.01% 
IS and ≤ 1% IS to frontline imatinib. The rationale of this change is based on evolving treatment 
goals in Chronic Myeloid Leukemia (CML) towards the achievement of faster deep molecular 
response (DMR) to enable treatment free remission (NCCN 2018, Rea and Cayuela 2017, 
Mahon 2016). A sustained DMR for at least 2 years is recognized as an essential requirement 
to attempt discontinuation of Tyrosine Kinase Inhibitor (TKI) therapy in Ph+ CML 
(NCCN 2018, Baccarani et al 2013, Hochhaus et al 2017). In addition, DMR is associated with 
improved survival rates and avoidance of disease progression (Cortes 2018, Dulucq and Mahon 
2016, Branford 2016, Yeung et al 2015, Hehlmann et al 2014; Etienne et al 2014; 
Falchi et al 2013). In CML Study IV with frontline imatinib, patients with MR4.5 at 4 years had 
a higher probability of survival at 8 years versus patients with BCR::ABL1 IS of 0.1-1% and 
no patient who achieved MR4.5 had experienced progression to accelerated phase/blast crisis by 
the data cutoff (Hehlmann et al 2014). A retrospective analysis of patients treated with frontline 
imatinib found that patients with confirmed MR4.5 at any time had a higher event-free survival 
rate (95.2%) compared to those with Major Molecular Response (MMR), but not MR4.5 (64.7%), 
and those who achieved Complete Cytogenetic Response (CCyR), but not MMR (27.7%) 
(Etienne et al 2014). Another retrospective study found a lower risk of losing CCyR, 
progression to Accelerated Phase (AP) or Blast Phase (BP), or death in patients achieving 
deeper MR (Falchi et al 2013). For patients with BCR::ABL1 level between >0.01% IS and ≤1% 
IS but no DMR on frontline imatinib for at least 12 months, an early treatment switch provides 
an opportunity to achieve a faster DMR with a better disease control. This is in line with current 
treatment guidelines. 
The European Leukemia Network (ELN) criteria suggest that (Baccarani et al 2013), patients 
with BCR::ABL1 levels > 0.1-1% at 12 months are considered to be at a warning level requiring 
more frequent monitoring. Based on ELN guidelines patients at a warning level may be treated 
with alternative treatments to improve the level of response (Baccarani et al 2013). Similarly, 
the ESMO treatment guidelines for CML also consider BCR levels between 0.1-1% at 12 
months and beyond to be warning levels and recommend that patients with warning levels may 
be eligible for potentially better treatments. Additionally, the NCCN CML treatment guidelines 
recommend a switch of TKI treatment at ≥ 12 months for patients with BCR::ABL1 levels 
between 0.1-1% and similarly emphasizes that the achievement of response milestones by 
specific month must be interpreted within the context of clinical and treatment goals 
(NCCN 2018). 
With this change in inclusion criterion, patients with optimal response (BCR::ABL levels > 
0.01 and ≤ 0.1% IS) pretreated with at least 12 months on front line imatinib will have the 


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opportunity to achieve a deeper response and will either continue to receive imatinib, or receive 
nilotinib, an approved treatment in frontline, or receive asciminib as an add-on to the backbone 
imatinib treatment. 
In view of the evolving understanding of the treatment landscape and to gain an early insight 
into the safety and efficacy of the asciminib combination, the statistical analysis for the primary 
objective has been updated to estimate the efficacy of asciminib 40 mg once daily (QD) + 
imatinib 400 mg QD or asciminib 60 mg QD + imatinib 400 mg QD as against continued 
imatinib. No formal comparisons between the treatment arms will be performed. Consequently, 
based on this update in the statistical analysis of the primary objective, the sample size was 
reassessed using the estimation-precision framework. The sample size of the study has been 
adjusted from 120 (30 patients per arm) to ~80 (20 patients per arm) patients based on the 
evaluation of the operating characteristics for the estimation of the efficacy in an exploratory 
framework while considering clinically relevant effect sizes and emerging clinical data. A 
sample size of ~80 patients will provide desired precision based on the expected true effect size. 
With 20 patients enrolled per arm, the lower bound of the two-sided 90% confidence interval 
of the difference between each asciminib + imatinib arms and the continued imatinib arm will 
exclude 0 assuming a true 30% difference in the MR4.5 rate at 48 weeks. 
Further, an interim analysis will be performed in order to gain an early insight into the safety 
and efficacy of the asciminib add-on combination which will help in planning the future 
development of the asciminib combination. The interim analysis will be performed when at 
least 40 (50%) patients have been randomized and have been followed for their 24 weeks visit 
assessment or have discontinued treatment. The enrollment will continue during this 24 weeks 
follow-up. The interim analysis will include all randomized patients until the date of data cut-
off, and include both efficacy (e.g. BCR::ABL1 assessment overtime, MR4 and MR4.5 rate at 
different time-points) and safety (e.g. Adverse Events and laboratory values) summaries, which 
will be detailed in the Statistical Analysis Plan for the interim analysis. There will be no change 
in the study conduct based on this interim analysis and the study will continue as planned after 
the interim analysis. It is not planned to write an interim CSR based on this interim analysis.  
Additionally, the below changes to inclusion and exclusion criteria of the study have been made 
based on emerging pre-clinical data and feedback received from investigators screening patients 
for this study: 
• Change in prior deep molecular response criteria (inclusion criteria #4) from “must not have 
achieved deep molecular response (MR4 IS) at any time during prior imatinib treatment" to 
" must not have achieved deep molecular response (MR4 IS) confirmed by 2 consecutive 
tests at any time during prior imatinib treatment. An isolated, single test result with 
BCR::ABL1 levels < 0.01 % (MR4 IS) is allowed, however, it should not have been 
observed within the 9 months prior to randomization". Additionally, an exclusion criteria 
(#16) to reinforce this criteria has been added to exclude any patient with “a deep molecular 
response (MR4 IS) confirmed by 2 consecutive tests at any time during prior imatinib 
treatment”. These changes have been made to ensure that patients with unconfirmed, 
isolated BCR::ABL1 levels of <0.01% are not excluded from the study. 


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• Patients with history of acute pancreatitis within 1 year prior to randomization or medical 
history of chronic pancreatitis are already excluded from the study as per exclusion criteria 
#6. In addition to that, serum lipase requirement for inclusion criteria #5, as a further detail 
for this criteria, were added. Serum lipase is the preferred test for pancreatitis 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 ≤ 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 and Ratnam 2015), therefore the requirement of amylase test at screening is not 
added. 
• The requirement for electrolyte levels prior to randomization have been modified (inclusion 
criteria #6). Increase in potassium of up to 6.0 mmol/L (grade 2) is acceptable at study entry 
if associated with creatinine clearance within normal limits. Patients with CML often 
present with hyperkalemia. The release of potassium from platelets is a well-known reason 
for pseudohyperkalemia in thrombocythemic states including myeloproliferative disorders. 
(Kim et al 1990). Thus, 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. In 
addition, total calcium (corrected for serum albumin) increase of up to 12.5 mg/dl or 3.1 
mmol/L (grade 2) is acceptable prior to randomization if associated with creatinine 
clearance within normal limits. Grade 1 increase of magnesium is acceptable in case of 
normal creatinine clearance as this is not considered to be a risk factor for QTc prolongation. 
• Based on most updated PBPK modeling predicting a negligible risk for sensitive CYP3A4/5, 
CYP2C8, or CYP2C9 substrates is predicted. Thus, the prohibition of narrow therapeutic 
index CYP3A4/5 substrates at study entry has been removed and is no longer an exclusion 
criterion for the study (exclusion criteria #11 modified). The in vivo potential of asciminib 
to interact with sensitive CYP3A4/5, CYP2C8 and CYP2C9 substrates is being evaluated. 
Preliminary results confirm the PBPK predictions with no or weak drug-drug interaction. 
• Based on emerging non-clinical data (Asciminib Investigator Brochure edition 6), the 
exclusion criteria #15 for sexually active males has been updated to remove the requirement 
of male contraception. 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 embryofetal 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 200mg BID 


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(Cmax 6985ng/ml) and the Cmax at the no observed adverse effect level (NOAEL) in the 
rat and rabbit embryofetal development studies. Hence the safety margins were 482- and 
561-fold in rats and rabbits, respectively. In conclusion, for asciminib, as outlined above, 
the safety margins are well above 25 and therefore no embryo- and feto-toxicity effects can 
be anticipated via seminal fluid. 
In addition some minor inconsistencies (discrepancies between sections, typos) have been 
corrected. 
Changes to the protocol 
1. Section 1: Introduction: Updates to clinical experience of asciminib based on edition 6 of 
the Investigator's Brochure (IB) have been made. Section modified to update use of Narrow 
therapeutic Index CYP3A4/5 substrates, NTI CYP3A4/5 to be used with caution and 
embryofetal development update. Purpose of study updated to reflect change in requirement 
of prior imatinib treatment from 24 months to 12 months. 
2. Section 3: Study design: Updated to reflect change in inclusion criteria and sample size. 
Figure 1-1 has been replaced. 
3. Section 4.1: Rationale for study design: Updated statistical details for primary analysis. 
4. Section 4.2: Rationale for Dose/Regimen: Data error corrected in reporting of DLTs. 
5. Section 4.4: Purpose and timing of interim analyses/design adaptations: Inclusion of 
the rationale for the interim analysis. 
6. Section: 4.5: Risk and Benefit: “Sexually active males” removed. 
7. Section 5: Population: Number of patients updated to eighty (80) from 120. 
8. Section 5.1- Inclusion Criterion #3: Duration of prior imatinib treatment changed from 24 
months to 12 months. 
9. Section 5.1- Inclusion Criterion #4: prior DMR changed from “no DMR at any time” 
to “no DMR achieved confirmed by 2 consecutive tests at any time during prior imatinib 
treatment. An isolated, single test result with BCR::ABL1 levels < 0.01 % (MR4 IS) is 
allowed, however it should not have been observed within the 9 months prior randomization. 
10. Section 5.1- Inclusion Criterion #5: laboratory criteria for Serum lipase before 
randomization added. 
11. Section 5.1- Inclusion Criterion #6: Criteria modified to define laboratory reference range 
for electrolytes: 
• Potassium increase of up to 6.0 mmol/L is accepted if associated with normal creatinine 
clearance 
• Total calcium (corrected for serum albumin) increase of up to 12.5 mg/dl or 3.1 mmol/L 
is acceptable if associated with creatinine clearance within normal limits 
• Magnesium increase up to 3.0 mg/dL or 1.23 mmol/L is acceptable if associated with 
creatinine clearance within normal limits 
• Criteria for phosphorus were removed 
12. Section 5.2- Exclusion criterion #1: Footnote to define “confirmed loss of MMR” as in 
the ELN criteria added 


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13. Section 5.2- Exclusion Criterion #7: reworded to clarify ongoing acute liver disease. 
14. Section 5.2- Exclusion Criterion #9: Hepatitis screen requirement clarified with additional 
tests (anti-HBs and HBV-DNA) that can be done if needed. 
15. Section 5.2- Exclusion criterion #11: Removal of substrates of CYP3A4/5 with narrow 
therapeutic index as an exclusion, based on most updated PBPK modeling predicting a 
negligible risk for sensitive CYP3A4/5 substrates. 
16. Section 5.2- Exclusion criterion #15: Male contraception requirements deleted on the 
basis of data available from embryofetal development studies. 
17. Section 5.2- Exclusion criterion #16: new criterion has been added to define DMR criteria 
on prior imatinib treatment. 
18. Section 6.2- Other treatment (Concomitant Medication and Prohibited Medication) 
section: Section on NTI substrates of CYP3A4/5 removed based on a most updated PBPK 
modeling predicting a negligible risk for sensitive CYP3A4/5 substrates and moved under 
requiring caution section. Other CYP3A4 substrates (sensitive and moderate CYP3A4 
substrates) have been removed from the caution list. 
19. Section 6.5.1- Dose modification: section has been updated based on Investigator Brochure 
version 6. 
20. Section 7- Informed Consent Procedure: update on male contraception. 
21. Section 8-Visit schedule and assessment: Visit schedule for patients on imatinib and 
nilotinib already present in Table 8‑1 as footnote, reiterated in text. 
22. Section 8.3.2- Bone Marrow analysis and cytogenetics: "cytogenetics" word has been 
added as clarification. 
23. Section 8.4.1- Laboratory evaluations: Local lab CRF and local lab test reporting 
requirements clarified. Clarification have been made in the table 8.6. 
24. Section 8.4.3- Pregnancy and assessments of fertility: Clarification added on Crossover 
treatment CO baseline assessment and update on male contraception. 
25. Section 8.5.1.1- EORTC QLQ-C30 and EORTC QLQ-CML 24: Clarification for sites 
where QLQ-CML24 not available due to missing language validation added. 
26. Section 8.5.2.1- Pharmacokinetic blood collection and handling: Table 8-9 updated with 
window periods for blood collection log. 
27. Section 9.1.1- Discontinuation of study treatment: clarification on criteria for treatment 
failure according to ELN 2013 guidelines. 
28. Section 10.2.1- Liver Safety monitoring: updated to delete liver CRF. Liver laboratory 
parameters will be reported on scheduled/unscheduled laboratory CRF. 
29. Section 12.4- Analysis of primary endpoint: Updated primary endpoint analysis. 
30. Section 12.5.1- Efficacy and/or Pharmacodynamic endpoint(s): Confidence interval of 
rate of MR4.5changed from 95 to 90%. 
31. Section 12.5.3- Pharmacokinetics section: Text updated for clarification. 
32. Section 12.7- Interim Analysis: Inclusion of interim analysis. 
33. Section 12.8- Sample size calculation: Updated based on updated primary endpoint 
analysis and addition of interim analysis. 
34. Section 15- References: Updated with newly added references in protocol. 


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35. Appendix 16.1 and Table 16.2: deleted liver CRF. Liver laboratory parameters will be 
reported on scheduled/unscheduled laboratory CRF. 
36. Appendix 16.3: Section on NTI substrates of CYP3A4/5 moved under requiring caution. 
IRB Section 
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 1.  


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Protocol summary 
Protocol 
number 
CABL001E2201 
Full Title 
A Phase 2, multi-center, open-label, randomized study of oral asciminib added to 
imatinib versus continued imatinib versus switch to nilotinib in patients with CML-
CP who have been previously treated with imatinib and have not achieved deep 
molecular response 
Brief title 
Study of efficacy and safety of asciminib in combination with imatinib in CML-CP 
patients 
Sponsor and 
Clinical Phase 
Novartis, Study Phase II 
Investigation 
type 
Drug 
Study type 
Interventional 
Purpose and 
rationale  
The trial is designed to assess the activity of 2 doses of asciminib + imatinib 
versus other two arms (continued imatinib arm and switch to nilotinib arm), 
assessed by the rate of Molecular Response (MR)4.5 at 48 weeks as well as 
additional efficacy parameters, pharmacokinetic (PK), biomarkers, patient 
reported outcomes (PROs) and safety and tolerability. Tyrosine kinase inhibitors 
(TKIs) have revolutionized the treatment of patients with chronic myeloid 
leukemia (CML), resulting in an overall survival (OS) that is close to that of the 
general population and therefore a near normal life expectancy. A new evolving 
treatment goal in CML treatment is treatment free remission, which requires 
patients to be in deep molecular response (DMR), considered as a response 
level of at least MR4.0 International Scale (IS). Currently, an option for patients 
who do not achieve the desired level of molecular response with continued 
imatinib treatment is to switch to a more potent second generation adenosine 
triphosphate (ATP)-binding site TKIs. However a high percentage of patients still 
do not achieve the desired level of response. Asciminib is an allosteric inhibitor 
of Breakpoint Cluster Region - Abelson proto-oncogene 1 (BCR::ABL1) and due 
to its distinct mode of action showed pre clinically an additive anti-tumor activity 
in combination with ATP-binding site TKIs. 
The addition of asciminib to imatinib is expected to result in more potent 
inhibition of the ABL kinase domain. It is hypothesized that the addition of 
asciminib in patients who have not achieved DMR with single agent imatinib will 
increase their likelihood of achieving this response over time and subsequently 
allow for consideration of TKI discontinuation. The purpose of this trial is to 
evaluate the efficacy and safety of the combination of asciminib + imatinib 
treatment in comparison to continued imatinib in patients who have not achieved 
MR4 after at least one year of imatinib first-line treatment. As a secondary 
endpoint, the difference in efficacy between the combination and nilotinib, a 
second generation TKI, will be estimated. 
Results from single agent studies in patients with CML-CP who have been 
treated with at least 2 prior TKIs have shown activity of single agent asciminib for 
achievement of DMR in this heavily pretreated population. In study A2301, MR4 
and MR4.5 rates of 10.8% and 7.6%, respectively were observed at Week 48 
(Mauro et al, 2021). In the subgroup of patients with baseline BCR::ABL1 levels 
(> 0.01% and ≤1%), the MR4.5 rate (18.8%, 3 responders among 16 patients) 
was similar to that observed in E2201 with asciminib as add-on to imatinib at the 
primary analysis. 


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Primary 
Objective(s)  
The primary objective of this study is to assess whether asciminib 40 mg once 
daily (QD) + imatinib 400 mg QD or asciminib 60 mg QD + imatinib 400 mg QD 
is more effective than continued imatinib by assessing the MR4.5 rates at 48 
weeks. 
Secondary 
Objectives 
Objective 1: to estimate efficacy of switch to nilotinib assessed by the MR4.5 rate 
at 48 weeks. 
Objective 2: to estimate difference in efficacy between asciminib 60 mg + 
imatinib and switch to nilotinib considering the difference in MR4.5 rate at 48 
weeks. 
Objective 3: to estimate difference in efficacy between asciminib 40 mg + 
imatinib and switch to nilotinib considering the difference in MR4.5 rate at 48 
weeks. 
Objective 4: to assess additional parameters of the efficacy of asciminib 60 mg 
or 40 mg added to imatinib versus continued imatinib or switch to nilotinib i.e. the 
rate of MR4.5 at 96 weeks, rate of MR4.5 by 48 and 96 weeks, sustained MR4.5 at 
96 weeks, time to MR4.5 and duration of MR4.5. 
Objective 5: to characterize the safety and tolerability profile of asciminib 60 mg 
or 40 mg + imatinib versus continued imatinib or switch to nilotinib by comparing 
the incidence and severity of adverse events (AEs), changes in laboratory 
values, clinically notable ECG abnormalities and vital signs. 
Objective 6: to assess the pharmacokinetic profile of asciminib 60 mg or 40 mg 
and imatinib when administered in combination. 
Objective 7: to estimate efficacy of asciminib 80 mg QD assessed by the MR4.5 
rate at 48 weeks, time to MR4.5 and duration of MR4.5. 
Objective 8: to characterize the safety and tolerability profile of asciminib 80 mg 
QD. 
Objective 9: to assess the pharmacokinetic profile of asciminib 80 mg QD. 
Study design 
The study is a Phase 2, multi-center, open-label, randomized study of asciminib 
in two different doses (40 mg or 60 mg) in combination with imatinib 400 mg 
versus continued imatinib versus switch to nilotinib in patients with chronic 
myeloid leukemia in chronic phase (CML-CP) who have been previously treated 
with imatinib first line therapy for at least one year and have not achieved deep 
molecular response (DMR). 
The eligible patients will be randomized 1:1:1:1 to receive asciminib 60 mg QD 
as add-on therapy to imatinib 400 mg QD, or 40 mg QD as add-on therapy to 
imatinib 400 mg QD, or to continue imatinib 400 mg QD, or to switch to nilotinib 
300 mg twice a day (BID). 
Patients on the study will continue on the allocated treatment until treatment 
failure, intolerability, or for up to 96 weeks after the last randomized subject 
received the first dose of treatment. After the last dose received, every subject 
will be followed up for safety for 30 days. 
An interim analysis will be performed when at least 40 (50%) patients have been 
randomized and have been followed for their 24 weeks visit assessment or have 
discontinued treatment. At the time of the interim analysis, if excessive toxicity 
without added benefit is observed in one of the investigational arms, 
discontinuation of that treatment arm will be considered. The decision to 
discontinue an investigational arm in the study will be taken based on the risk 
benefit balance of the two investigational arms, and in context of the other two 
treatment options available for the patients in the study, namely: continue on 
imatinib with no potential improvement of efficacy; or switch to nilotinib with a 


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potential to improve efficacy however, with a relatively adverse safety profile as 
compared to imatinib. If a decision is taken to discontinue asciminib 60 mg + 
imatinib treatment arm at interim analysis, patients ongoing on that treatment 
arm will be provided an opportunity to continue on the study at a lower dose 
(asciminib 40 mg + imatinib) if the investigator considers that is in the best 
interest of the patient. 
Patients on the imatinib continuation arm who have not achieved MR4.5 at 48 
weeks may cross-over (CO) to receive the add-on treatment within 4 weeks after 
week 48 visit. It is planned that these patients cross-over to receive the 
asciminib 60 mg add-on treatment, as this dose provides higher exposure. 
Based on the results of the interim analysis or emerging data, cross-over may be 
changed to the asciminib 40 mg add-on treatment. The cross-over is at the 
discretion of the investigator and the patient. Apart from a polymerase chain 
reaction (PCR) result of below MR4.5 at Week 48 visit, there are no other entry 
criteria for the cross-over part. Patients on nilotinib are not allowed to cross-over 
to receive the add-on treatment. 
After the primary analysis, the decision was made to add an additional cohort to 
the study (upon IRB and Health Authority approval) to investigate the efficacy 
and safety of asciminib 80 mg QD as compared to the add-on and continue on 
imatinib arms. This cohort will have approximately the same sample size as in 
treatment arms 1-4 (n = 20). As enrollments are closed in the treatment arms 1-
4, all incoming patients will be included in this additional cohort.  
The patients enrolled in the asciminib single agent cohort will not be allowed to 
cross-over to another investigational combination arm if they fail to achieve 
MR4.5 at week 48. 
Population 
Approximately eighty eligible patients with CML-CP will be randomized 1:1:1:1, 
with a target of 20 patients in each arm (treatment arms 1-4).  
Approximately n = 20 patients will be included in asciminib 80 mg QD cohort.  
Male or female patients ≥ 18 years of age will be enrolled. 
Key Inclusion 
criteria 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Male or female patients ≥ 18 years of age with a confirmed diagnosis of CML-
CP 
3. b . Minimum of one year (12 calendar months) treatment with imatinib first 
line for CML-CP (patients have to be on imatinib 300 mg QD or higher ). 
4. a. BCR::ABL1 levels > 0.01% IS and ≤ 1% IS at the time of randomization as 
confirmed with a central assessment at screening; patients must not have 
achieved deep molecular response (MR4 IS) confirmed by 2 consecutive 
tests at any time during prior imatinib treatment. An isolated, single test 
result with BCR::ABL1 levels < 0.01 % (MR4 IS) is allowed, however, it 
should not have been observed within the 9 months prior to randomization. 
5. a. Patient must meet the following laboratory values before randomization: 
• Absolute Neutrophil Count ≥ 1.5 x 109 L 
• Platelets ≥ 75 x 109/L 
• Hemoglobin ≥ 9 g/dL 
• Serum creatinine (sCr) < 1.5 mg/dL 
• Total bilirubin (TBL) ≤ 1.5 x upper limit of normal (ULN) except for patients 
with Gilbert’s syndrome who may only be included with total bilirubin ≤ 3.0 x 
ULN 
• Aspartate aminotransaminase (AST) ≤ 3.0 x ULN 


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• Alanine aminotransaminase (ALT) ≤ 3.0 x ULN 
• Alkaline phosphatase (ALP) ≤ 2.5 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 
6. a. Patients must have the following laboratory values (≥ lower limit of normal 
(LLN)) or corrected to within normal limits with supplements prior to 
randomization: 
• Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated 
with 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 if associated with creatinine clearance* 
within normal limits) 
• Magnesium (magnesium increase up to 3.0 mg/dL or 1.23 mmol/L if 
associated with creatinine clearance* within normal limits. 
*Creatinine clearance as calculated using Cockcroft-Gault formula 
Key Exclusion 
criteria 
1. Treatment failure according to ELN 2013 criteria during imatinib treatment. 
2. Known second chronic phase of CML after previous progression to 
accelerated phase/blast crisis (AP/BC). 
3. Previous treatment with any TKIs other than imatinib 
4. History or current diagnosis of ECG abnormalities indicating significant risk or 
safety for patients participating in the study such as: 
• History of myocardial infarction (MI), angina pectoris, coronary artery bypass 
graft (CABG) within 6 months prior to randomization 
• Concomitant clinically significant arrhythmias, e.g. sustained ventricular 
tachycardia, and clinically significant second or third degree 
atrioventricular (AV) block without a pacemaker 
• Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) prior to 
randomization 
• 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 including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia 
• Concomitant medications with a "known" risk of Torsades de Pointes per 
crediblemeds.org that cannot be discontinued or replaced by safe alternative 
medication 
• inability to determine the QTcF interval 
5. Severe and/or uncontrolled concurrent medical disease that in the opinion of 
the investigator could cause unacceptable safety risks or compromise 
compliance with the protocol (e.g. uncontrolled diabetes, active or 
uncontrolled infection, uncontrolled clinically significant hyperlipidemia 
and high serum amylase). 
6. History of acute pancreatitis within 1 year prior to randomization or medical 
history of chronic pancreatitis; ongoing acute liver disease or history of 
chronic liver disease. 


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7. History of other active malignancy within 3 years prior to randomization with 
the exception of basal cell skin cancer, indolent prostate cancer and 
carcinoma in situ treated curatively 
Study 
treatment 
• Asciminib (ABL001) 80 mg, 60 mg, 40 mg QD 
• Imatinib (STI571) 400 mg QD 
• Nilotinib (AMN107) 300 mg BID 
Efficacy 
assessments 
• Peripheral blood for BCR::ABL1 real-time quantitative reverse transcriptase-
Polymerase Chain Reaction (RT-qPCR) 
Key safety 
assessments 
• Physical examination 
• Extramedullary involvement 
• Vital signs 
• Hematology and biochemistry (and pregnancy when applicable) 
• ECG 
• Adverse Events 
Other 
assessments  
• Patient Reported Outcomes: EORTC QLQ-C30, EORTC QLQ-CML24, FACIT 
GP5 and TSQM 
• PK sampling 
• Biomarker assessments (characterization of 
, 
 
) 
Data analysis 
The primary efficacy endpoint of the study is the rate of MR4.5 at 48 weeks (± 
assessment window), defined as the proportion of patients still treated with the 
randomized treatment at 48 weeks and are in MR4.5 (BCR::ABL1 ratio of ≤ 
0.0032%) at 48 weeks. It will be calculated based on the Full Analysis Set (FAS).  
The difference in rate of MR4.5 between 1) asciminib 60 mg + imatinib versus 
continued imatinib and 2) asciminib 40 mg + imatinib versus continued imatinib 
with its 2-sided 90% confidence interval will be provided using the Wald method. 
The rate of MR4.5 at 48 weeks and its 2-sided 90% confidence interval based on 
the Clopper-Pearson method will be presented by treatment arm.  
To estimate the efficacy of asciminib single agent, the rate of MR4.5 at 48 weeks 
and its 2 sided 90% confidence interval based on the Clopper-Pearson method 
will be presented. No formal comparison or estimate of the difference with the 
other treatment arms will be performed for this additional cohort. 
Interim Analysis: 
An interim analysis will be performed when at least 40 (50%) patients have been 
randomized and have been followed for their 24 weeks visit assessment or have 
discontinued treatment. The interim analysis will include all randomized patients 
until the date of data cut-off, and include both efficacy (e.g. BCR::ABL1 
assessment overtime, MR4 and MR4.5 rate at different time-points) and safety 
(e.g. Adverse Events and laboratory values) summaries, which will be detailed in 
the Statistical Analysis Plan for the interim analysis. Based on the results of the 
interim analysis a benefit risk balance will be assessed for the two add-on 
treatment arms. It is not planned to write an interim CSR based on this interim 
analysis. 
The primary analysis will be performed after all patients in all 4 randomized 
treatment arms have completed Week 48 or discontinued prior to Week 48. A 
week 96 analysis will be performed after all patients in all 4 randomized 
treatment arms have completed Week 96 and/or discontinued study prior to 
CCI
CCI


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Week 96. The final analysis will be performed with all available data from the 
asciminib single agent cohort at the End of the Study. 
Key Words  
Chronic Myeloid Leukemia in Chronic Phase (CML-CP), Tyrosine Kinase 
Inhibitor (TKI), Glivec® (imatinib), Tasigna® (nilotinib), asciminib, Molecular 
Response 


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1 
Introduction 
1.1 
Background 
CML is a clonal myeloproliferative disorder of transformed, primitive hematopoietic progenitor 
cells. The hallmark of CML is the Philadelphia (Ph) chromosome found in up to 95% of patients. 
It results from a reciprocal translocation t(9;22)(q34;q11) which adds a 3' segment of the ABL 
gene on chromosome 9 to the 5' part of the breakpoint cluster region (BCR) gene on 
chromosome 22. The resulting fusion gene encodes for a constitutively active tyrosine kinase, 
the BCR-Abelson (ABL) tyrosine kinase (Faderl et al 1999), which has activity that imparts 
growth advantage to leukemic cells, increases proliferation and cytokine-independent growth, 
inhibits 
apoptosis, 
and 
inhibits 
alternate 
adhesion 
pathways 
(Sawyers 1999, 
Deininger et al 2000, Van Etten 2004). 
With a constant incidence of 1.2-1.5/100 000 per year the prevalence of CML is steadily 
increasing (Hochhaus and La Rosée 2013). Clinically, CML progresses through three distinct 
phases of increasing refractoriness to therapy: chronic phase (CP), accelerated phase (AP), and 
blast crisis (BC) (Enright H and McGlave 2000). Most patients, however, present in the CP, 
characterized by splenomegaly and leukocytosis with generally few symptoms. 
The gold standard for the treatment of CML was the tyrosine kinase inhibitor (TKI) Glivec® 
(imatinib), which was introduced in 2001 and revolutionized the CML treatment. Other TKI 
agents, including nilotinib, dasatinib, ponatinib, bosutinib, are also meanwhile approved for the 
treatment of CML. Possible options for first-line treatment include imatinib, nilotinib, dasatinib 
and bosutinib, while imatinib is most widely used in this setting and regarded as standard of 
care. 
Current treatment guidelines recommend continuing therapy with TKI indefinitely in patients 
with optimal response (Baccarani et al 2013, NCCN 2018). However, in selected CML patients 
meeting certain criteria, e.g. sustained deep molecular response (sustained DMR), 
discontinuation of TKI therapy is possible (Hochhaus et al 2017, NCCN 2018, [Tasigna SmPC], 
[USPI]). 
1.1.1 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.1.1.1 
Overview of asciminib 
Asciminib (ABL001) is a potent, orally bioavailable specific BCR::ABL1 inhibitor with a novel 
mechanism of action. In contrast to inhibitors such as imatinib, nilotinib and dasatinib that bind 
within the Adenosine Triphosphate -binding (ATP) 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 is active against cells expressing clinically observed ATP-
binding TKI resistance mutations. A combination of asciminib with an ATP-site inhibitor, such 


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as imatinib, has the potential to prevent the emergence of resistance due to point mutation(s) 
being acquired in one of the binding sites. 
As of 30-Jun-2022, asciminib has been approved for treatment of CML pts with resistance or 
intolerance to previous therapy in Albania, Canada, Japan, Korea, Switzerland, UK, and US. 
1.1.1.1.1 Non-clinical experience 
In vitro and in vivo pharmacology data 
Asciminib is an ABL1 inhibitor that binds with high affinity to the allosteric myristate-binding 
pocket on the kinase SH1 domain and inhibits the ABL1 kinase activity of the BCR::ABL1 
fusion protein. Asciminib potently inhibits the proliferation of CML and acute lymphoblastic 
leukemia (ALL) cell lines that express BCR::ABL1, at doses >1000-fold potent than in cell 
lines that do not express BCR::ABL1. 
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-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 this BCR::ABL1 
dependent KCL-22 xenograft model correlated with complete inhibition of the downstream PD 
marker STAT5 (signal transducer and activator of transcription 5), and the minimal total plasma 
concentration required to achieve this level of PD suppression was observed to be around 50-
100nM. 
The KCL-22 xenograft model was also used to assess the activity of asciminib and ATP-site 
binding TKIs (nilotinib) as single agents and in combination (Wylie et al 2017). 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 68 days of treatment or for > 100 days following discontinuation of treatment. Note that in 
this KCL-22 model, the cells (derived from a blast crisis CML subject) were grown as a solid 
tumor rather than as disseminated disease. Also, this model is much more aggressive than 
chronic phase CML in patients. 
Please refer to the latest [Asciminib Investigator’s Brochure] for more details. 
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 (Central Nervous System), and the respiratory systems. The half maximal 
inhibitory concentration (IC50) for asciminib in the hERG (Human Ether-a-go-go-related Gene) 
patch clamp is 11.4 μM (4498 ng/mL). Despite hERG inhibition occurring in vitro at low 
concentration, this potential did not translate into cardiac rhythm disturbances or QTc (QT 


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interval corrected for heart rate) prolongation in vivo up to exposures 120-fold higher than in 
patients at the maximum recommended therapeutic dose of 40 mg BID (free drug Cmax 
comparisons). 
Asciminib does not show mutagenic, clastogenic, or aneugenic potential in the in vitro assays 
or the MNT (Micronucleus test) assessment in vivo; therefore, no potential risk for human is 
perceived. 
Preclinical studies suggested that asciminib might cause phototoxicity and photosensitization. 
Within the sunlight range (290 to 700 nm), asciminib showed absorption maxima at 312 nm. A 
photo-inhibition factor (PIF) assay value of 41 was determined in the 3T3 NRU phototoxicity 
assay. As determined by the results of the phototoxicity assessment (in vitro and in vivo), 
phototoxic potential was identified in the mouse UV-LLNA (Ultraviolet radiation - Local 
Lymph Node Assay) at 200 mg/kg/day. However, at the NOAEL in animal studies, exposure 
based on Cmax in plasma was 15-fold higher than the exposure in patients at the 40 mg BID. 
Given the updated data, adult patients enrolled in the single agent asciminib cohort will not 
need sunlight protection. 
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 embryofetal 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 200mg BID (Cmax 6985ng/ml) and the 
Cmax at NOAEL in the rat and rabbit embryofetal development studies. Hence the safety 
margins were 482 and 561-fold in rats and rabbits, respectively. In conclusion, for asciminib, 
as outlined above, the safety margins are well above 25 and therefore no embryo- and feto-
toxicity effects can be anticipated via seminal fluid. 
Repeat dose toxicity studies identified the pancreas, liver, hematopoietic system, adrenal and 
gastro-intestinal tract as potential target tissues. All findings so far have demonstrated a partial 
to complete reversibility during a 4-week recovery phase, and can be readily monitored in 
clinical settings. 
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. 


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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 with direct glucuronidation 
occurred most readily in human, to a lesser extent in dog and monkey, and was noticeably 
absent in rat. Nevertheless, the metabolic turnover of asciminib was low to moderate across 
species. No unique human metabolites were detected in this in vitro hepatocytes metabolism 
study across species. 
The metabolite profile of asciminib has also been examined in vivo in rats. Following 
intravenous and oral administration of [14C-ABL001] to intact rats, asciminib was found to be 
the predominant component of plasma, accounting for ~86%-91% of radioactivity from 0 - 8 
hours. 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. An absorption, 
distribution, metabolism, and excretion (ADME) Study was as well conducted in monkey 
[R1500815] and showed that asciminib is the predominant drug-related component in plasma. 
All metabolites detected in human plasma were also observed in the ADME monkey Study. 
To assess for potential drug-drug interactions (DDI), studies have been conducted with 
cytochrome P450 (CYP) enzymes and several transporters in vitro. 
Based upon the clinical human ADME data and alignment with the in vitro human hepatocyte 
clearance and enzyme reaction phenotyping studies, the relative contribution of CYP- and UDP-
Glucuronosyltransferase (UGT) -mediated asciminib clearance was estimated to be 36.6% and 
58.3%, respectively. Multiple enzymes (UGT1A3, UGT1A4, UGT2B7, UGT2B17, CYP3A4/5, 
CYP2C8, CYP2J2 and CYP2D6) are involved in the metabolism of asciminib. CYP3A4 was 
estimated to contribute 35% to the total clearance of asciminib in humans, with UGT2B7 
contributing 27.9%. The contribution of UGT2B17 and UGT1A3/UGT1A4 to asciminib total 
clearance was 16.3% and 14.1%, respectively. Other CYP enzymes: CYP2C8, CYP2D6 and 
CYP2J2 were estimated to contribute to a minor extent (less than 1%). The potential for clinical 
DDIs with co-medications that inhibit a single UGT enzyme is likely to be low. 
Strong inducers or inhibitors of CYP3A4/5 have the potential to alter asciminib concentrations. 
Transporter phenotyping studies have identified asciminib to be a substrate of Breast Cancer 
Resistant Protein (BCRP) (Km ≈ 4 µM) and Permeability glycoprotein (P-gp) (Km could not 
be estimated due to insufficient saturation of efflux activity). Inhibitors of BCRP and P-gp may 
increase asciminib concentration and are to be used with caution in this study. 
The in vivo potential of asciminib to interact with sensitive CYP3A4/5, CYP2C8 and CYP2C9 
substrates has been evaluated by PBPK modeling and would indicate a minimal or negligible 
risk. At the dose of asciminib 80 mg qd (Cmax,ss of ~1270 ng/mL), the PBPK model predicted 
a AUC ratio of 1.22, 1.11 and 1.08 for the sensitive substrate of CYP3A4 (midazolam), 
CYP2C8 (repaglinide) and CYP2C9 (S-warfarin), respectively (R1700912) 


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Therefore, substrates of CYP3A4/5, CYP2C8 and CYP2C9 with narrow therapeutic index 
should be used with caution. 
Based on PBPK asciminib is a weak inhibitor of intestinal P-gp at 40 mg b.i.d., 80 mg q.d. and 
200 mg b.i.d.  
Further, at doses of 40 mg b.i.d., 80 mg q.d., and 200 mg b.i.d. asciminib weak to moderate 
increases in OATP1B substrates (e.g., pitavastatin, pravastatin) and BCRP substrates (e.g., 
sulfasalazine) are expected when administered concomitantly (DMPK-R2270328). At doses of 
40 mg b.i.d. and 80 mg q.d. asciminib was predicted to be moderate inhibitor of the dual BCRP 
and OATP1B substrate rosuvastatin and a strong inhibitor at 200 mg b.i.d. 
Please refer to the latest [Asciminib Investigator's Brochure] version for more details. 
1.1.1.1.2 Clinical experience 
As of 15-Jan-2023, asciminib is being investigated in 11 ongoing Novartis sponsored studies in 
patients with CML- CP/ AP or CML-BC or Ph+ ALL.  
The approval of asciminib monotherapy in CML-CP patients with Ph+ CML in CP, previously 
treated with 2 or more TKIs was based on results from the ongoing first-in-human (FIH) Phase 
I clinical Study, Study [CABL001X2101] (called X2101 henceforth), and the Phase 3 pivotal 
Study in 3rd line CML-CP [CABL001A2301] (called A2301 henceforth) .  
Study CABL001A2301 
Study A2301 is an ongoing Phase III, multi-center, active-controlled, open-label, randomized 
study of oral asciminib versus bosutinib in patients with CML-CP, previously treated with at 
least 2 TKIs. Overall, 233 patients with CML-CP were enrolled in the study of which 157 were 
randomized to asciminib arm and 76 to bosutinib arm, 89 patients (56.7%) in the asciminib arm 
and 17 patients (22.4%) in the bosutinib arm are still ongoing on study treatment. 
The study met its primary endpoint. The MMR rate at 24 weeks was 25.5% in the asciminib 
arm compared to 13.2% in the bosutinib arm. The estimated difference in MMR rates of 
asciminib compared to bosutinib at 24 weeks was clinically meaningful and statistically 
significant 12.2% (95% CI: 2.19, 22.30, p value: 0.029). At the Week 96 cut-off, the clinical 
superiority of asciminib versus bosutinib increased compared to the primary analysis, the MMR 
rate in the asciminib arm 37.58% (95% CI: 29.99, 45.65) compared to 15.79 % (95% CI: 8.43, 
25.96) in the bosutinib arm. 
As of the Week 96 cut-off (06-Oct-2021), 99 of the 233 patients (42.5%) were continuing the 
study treatment with 84 patients (53.5%) and 15 patients (19.7%) still ongoing in the asciminib 
and bosutinib arms, respectively. Treatment discontinuations were reported for 45.9% of the 
patients in the asciminib arm and for 80.3% in the bosutinib arm. Lack of efficacy (defined 
according to the response milestones in ELN 2013 recommendations) (24.2% in the asciminib 
arm and 35.5% in the bosutinib arm) remained the most frequently reported reason for treatment 
discontinuation. The median duration of exposure to study treatment was 103.1 weeks in the 
asciminib arm and 30.5 weeks in the bosutinib arm (from start of treatment to last treatment as 
per data cut-off date). 


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The frequency of AEs was lower in patients on asciminib (91.0%) as compared to bosutinib 
(97.4%), despite the considerably longer exposure to treatment on asciminib vs bosutinib noted 
above. In addition, lower percentage of patients with   
• 
 
Grade ≥ 3 AEs (56.4% vs 68.4%)  
• 
AEs leading to treatment discontinuation (7.7% vs 26.3%)  
• 
AEs Suspected to be treatment-related: 32.7% vs. 52.6%  
• 
Serious AEs: 17.9% vs. 26.3%  
• 
SAEs Suspected to be treatment-related: 3.2% vs. 13.2%  
• 
AEs leading to dose adjustment and/or interruption: 42.3% vs. 64.5% 
were reported in the asciminib group as compared to bosutinib group. The most commonly 
reported AEs in the asciminib and bosutinib treatment arms (≥ 10% in either arm) included the 
following: thrombocytopenia (23.1% vs. 14.5%, headache (19.9% vs. 15.8%), neutropenia 
(19.2% vs. 17.1%), fatigue (14.7% vs. 9.2%), hypertension (13.5% vs. 5.3%), arthralgia (12.8% 
vs. 3.9%), diarrhea (12.8% vs. 72.4%), nausea (11.5% vs. 46.1%), and nasopharyngitis (10.9% 
vs. 3.9%), anemia (10.3% vs. 7.9%), abdominal pain (9.0% vs. 15.8%), rash (9.0% vs. 23.7%), 
vomiting (7.7% vs. 26.3%), aspartate aminotransferase increased (5.8% vs. 21.1%), and alanine 
aminotransferase increased (4.5% vs. 30.3%). 
 
Please refer to the latest [Asciminib Investigator's Brochure] for more details. 
Study CABL001X2101 
Study X2101 is an ongoing first in human (FIH) dose escalation study. At the time of the 
primary analysis (cut-off date on 02-Apr-2020) a total of 317 patients  with CML-CP/AP or 
Ph+ ALL have been treated with asciminib monotherapy with dose levels from 10 mg BID to 
280 mg BID and dose levels from 80 mg QD to 200 mg QD. or a combination of imatinib, 
nilotinib or dasatinib. 
Asciminib Single Agent 
Safety 
As of the cut-off date of 02-Apr-2020, 200 patients with CML-CP/AP have been treated with 
asciminib single agent with dose levels from 10 mg BID to 200 mg BID and dose levels from 
80 mg QD to 200 mg QD. Seventy-seven patients (38.5%) discontinued study treatment. The 
most frequent primary reason for discontinuation was physician’s decision (16.0%). Adverse 
events leading to treatment discontinuation were reported in 19 patients (9.5%). Overall 88% 
of the patients experienced at least one adverse event suspected to be study related, 44.5% with 
Grade 3/4 events. 9% of patients experienced at least one Serious Adverse Event (SAE) 
suspected to be study related. The three most common AEs reported as suspected to be related 
to asciminib monotherapy in 200 patients with CML-CP or CML-AP were lipase increased 
(19.5%), fatigue (17.5%) and thrombocytopenia (16.5%). The most common Grade 3/4 events 


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as suspected to be related to asciminib monotherapy were lipase increased (11%) 
thrombocytopenia (9.5%), and neutropenia (8%). 
No SAEs related to QT prolongation have been observed with asciminib single agent in CML-
CP or /AP. QTcF increase > 60 ms from baseline, and new QTcF > 500 ms, were observed in 
2/48 (4.2%) patients with CML-CP harboring the T315I mutation treated with single agent 
asciminib 200 mg BID. In addition, new QTcF > 500 ms was observed in a patient treated with 
single agent asciminib 80 mg QD.  
Efficacy 
As per [Asciminib Investigator's Brochure] preliminary data with a cut-off date of 02-Apr-2020, 
from the ongoing Phase I FIH Study [CABL001X2101] indicate that asciminib exhibits activity 
as single-agent in patients with CML who have failed at least two prior TKIs or are intolerant 
to TKIs as well as patients carrying T315I mutation who have failed at least one prior TKI. 
Reviewing the totality of the efficacy, safety, and pharmacokinetic data derived from the 
[CABL001X2101] Study, 40 mg BID single agent dose was recommended for clinical studies 
in patientswith CML-CP who do not carry T315I mutations and 200 mg BID dose in CML 
patients carrying T315I mutation. 
Asciminib in combination with imatinib, nilotinib or dasatinib 
Safety 
Twenty-five patients have been treated with a combination of imatinib 400 mg QD and different 
asciminib dose levels (40 mg BID/QD, 60 mg QD and 80 mg QD). Twelve patients (48.0%) 
discontinued study treatment. The most frequent primary reason for discontinuation was 
physician’s decision due to lack of efficacy (16.0%). Adverse events leading to treatment 
discontinuation were reported in 2 patients (8.0%).  
Nausea (48%), abdominal pain (36%) and diarrhea (32%) were the three most common AEs 
reported in patientswith CML in CP or AP treated with a combination of asciminib and imatinib 
(all cohorts) regardless of relationship to study drug. Four of 25 patients (16.0%) with CML-
CP/-AP treated with a combination of asciminib and imatinib experienced at least one SAE 
assessed by the investigator as suspected to be related to the study drug: pancreatitis, hepatitis, 
decreased neutrophil count and myopathy were reported in 1 patient each.  
Liver related AEs were seen in 7 of 25 patients (28%) treated with asciminib in combination 
with imatinib. G3 AST increased, G3 GGT increased and G4 and SAE hepatitis were seen in 1 
patient each (4%). 
ECG data shows no reported QT prolongation (increase > 60 msec or new > 500 msec) in any 
asciminib and imatinib combination groups. 
Asciminib has been studied in 26 patients with CML-CP/-AP at dose levels of 20 mg BID or 
40 mg BID in combination with nilotinib 300 mg QD. Eleven patients (42.3%) discontinued 
study treatment. The most frequent primary reason for discontinuation was physician’s decision 
(26.9%, mainly due to lack of efficacy). Only one patient (3.8%) discontinued study treatment 
due to adverse events. 


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Asciminib has been studied in 23 patients with CML-CP/-AP at dose levels of 40 mg BID, 80 
mg QD and 160 mg QD in combination with dasatinib 100 mg QD. Six patients (26.1%) 
discontinued study treatment, 3 (13%) patients each due to physician’s decision and adverse 
events respectively. 
Efficacy 
As per [Asciminib Investigator’s Brochure] preliminary data from the ongoing Phase I FIH 
Study [CABL001X2101] indicate that asciminib in combination with imatinib or nilotinib or 
dasatinib exhibits activity in patientswith CML who have failed at least two prior TKIs or are 
intolerant to TKIs. 
Based on totality of data, asciminib 40 mg and 60 mg QD dose has been recommended in 
combination with imatinib 400 mg QD in CML–CP or -AP patients without T315I mutation. 
Overall, based on the experience from the ongoing Phase 1 Study, [CABL001X2101], the safety 
profile of asciminib is acceptable for continued clinical development. 
Please refer to the latest [Asciminib Investigator's Brochure] for more details. 
Pharmacokinetics 
Asciminib, administered as a twice daily and once daily dosing regimen, was rapidly absorbed 
with a median time to reach maximum plasma concentration (Tmax) of 2 to 3 hours, independent 
of dose. Systemic exposure of asciminib, after oral administration of a single dose and multiple 
doses, as measured by Cmax and AUC, increased in an approximately dose proportional manner. 
Generally, the variability of exposure was low to moderate with inter-subject variability 
(Coefficient of Variation (CV) percentage) ranging from approximately 25% to 70% for both 
Cmax and AUClast. With the twice daily dosing regimen, plasma asciminib accumulated slightly 
with the accumulation ratios ranging from 1.3 to 2.5, while with the once daily dosing regimen 
there was almost no accumulation of asciminib (1.1 to 1.4). 
The data of the human ADME 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 AUC0-24 hours ≥ 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% (half-life is 14.2 hours). 
The effect of food on asciminib PK was characterized in a Phase I Study [CABL001A2101] in 
healthy volunteers using two former variants of the tablet formulation. Food was found to 
influence the pharmacokinetics of asciminib and exhibited a negative food effect with the two 
tablet variants. The overall exposure (AUC) decreased by approximately 30% and 65% when 
administered with a low-fat and high-fat meal, respectively for both tablet variants. 
Study [CABL001A2104] assessed the relative bioavailability between a new asciminib tablet 
formulation (Final Market Image (FMI) 2.2) intended to be used for commercial use and the 


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clinical service form (CSF) formulation (capsule). The geometric mean ratios and two-sided 90% 
confidence intervals of the primary PK parameters Area under the plasma drug concentration-
time curve from time zero to infinity (AUCinf ), AUClast and Cmax of asciminib for tablet versus 
capsule comparison were 1.00 (0.909, 1.10), 1.01 (0.911, 1.11) and 0.909 (0.805, 1.03), 
respectively. Therefore, the two formulations have shown similar bioavailability supporting the 
switch from capsule to tablet. The food effect on this new tablet formulation was assessed in 24 
patientsusing an open-label, randomized and cross-over design [CABL001E2101]. A negative 
food effect was observed following low and high fat meals. Low-fat and high-fat meals 
decreased the bioavailability of asciminib by ~30% and ~60%, respectively, 
Please refer to the latest [Asciminib Investigator’s Brochure] for more details. 
Exposure-efficacy relationship 
A population PKPD is under development. The preliminary pharmacokinetic model for 
asciminib single agent is described by a two-compartment model with a dual absorption process 
(zero order absorption process followed by a first order absorption process). 
Based on this population PK model, simulations were conducted and revealed that a dose of 40 
mg BID maintains Ctroughs above the threshold trough concentration required for 90% 
inhibition of pSTAT5 derived from a preclinical PK-PD KCL- 22 mouse xenograft model (IC90: 
30 to 121 ng/mL, after correction for protein binding) [Asciminib Investigator's Brochure]. 
Exposure-safety relationship 
The relationship between observed plasma asciminib and change from baseline QT interval 
corrected using Fridericia's correction (ΔQTcF) was assessed in Study [CABL001X2101] (cut-
off 15-Jul-2018) in 217 CML and ALL patients receiving monotherapy in range of doses (from 
10 mg to 280 mg BID and 80 mg to 200 mg QD). Using the PK-QTcF model, the estimated 
mean ∆QTcF at the geometric mean Cmax of the highest evaluated dose of 280 mg BID was 
5.30 ms (upper bound 90% CI: 7.10 ms), which is below the regulatory threshold of 10 msec. 
The relationship between observed plasma asciminib concentration and QTcF showed a 
small, concentration dependent increase in ∆QTcF, which is not clinically relevant up to the 
highest evaluated dose of 280 mg BID. No clinically significant effect on ΔQTcF is expected 
at asciminib dose of 60 mg QD being used in the current study.  
1.1.1.2 
Overview of imatinib 
Amongst other approved indications, imatinib (Glivec®/Gleevec®) is indicated for the treatment 
of adult and pediatric patients with newly diagnosed Philadelphia chromosome positive chronic 
myeloid leukemia (Ph+ CML) for whom bone marrow transplantation is not considered as the 
first line of treatment and for the treatment of adult and pediatric patientswith Ph+ CML in 
chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast 
crisis [please refer to the latest Glivec®/Gleevec® local approved product information]. 


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1.1.1.2.1 Non-clinical overview 
Imatinib is not genotoxic but it was found to be teratogenic (Glivec®/Gleevec® local approved 
product information). The fertility of male and female rats was not affected, although there was 
evidence of effects on spermatogenesis in rats and dogs. Imatinib was carcinogenic in the rat. 
In vitro, imatinib was found to be a substrate of CYP3A4/5 and to a smaller extent CYP2C8 
and an inhibitor of CYP3A4/5 and CYP2D6 with potential clinical relevance. In vivo, a single 
dose of the potent CYP3A4 inhibitor ketoconazole increased mean maximum concentration 
(Cmax) and AUC of imatinib by 26% and 40%, respectively. Co-administration with rifampin, 
an inducer of CYP3A4, reduced plasma imatinib AUC by approximately 70%. Imatinib 
increased the Cmax and AUC of simvastatin by 2- and 3.5-fold, respectively, indicating inhibition 
of CYP3A4. AUC of the CYP2D6 substrate metoprolol was increased between 17% and 24% 
by imatinib co-administration. 
1.1.1.2.2 Clinical overview 
In 2001, imatinib, a BCR::ABL1 tyrosine kinase inhibitor, was approved for the treatment of 
CML (Cohen et al 2002), and since then more than 100 000 patients received the drug with 
some 
patients 
now 
on 
treatment 
since 
more 
than 
15 
years 
(Gambacorti-Passerini and Piazza 2015). Results from the Phase 3 International Randomized 
Study of Interferon and STI571 (IRIS) showed that imatinib at a dose of 400 mg once daily was 
more active and was associated with fewer side effects than interferon-alfa plus cytarabine in 
patientswith newly diagnosed CML in chronic phase. At 18 months, the estimated rate of 
complete cytogenetic response (CCyR) was 76.2% in the imatinib group, as compared with 
14.5% in the group that received interferon-alfa plus cytarabine, and the estimated rate of 
freedom from progression to the accelerated phase or blast crisis of CML was 96.7% versus 
91.5% (O'Brien et al 2003). In 2017, the final analysis of IRIS Study was published, with a 
median follow up of 10.9 years. In the imatinib group, the cumulative rate of major cytogenetic 
response (MCyR) at the end of the trial was 82.8% and among 134patients with cytogenetic 
assessment at 10 years, 91.8% had CCyR. Among 204 patients who had molecular assessment 
that could be evaluated at 10 years, 93.1% had major molecular response (MMR) and 63.2% 
had MR4.5. Among the patientsin the imatinib group, the estimated overall survival rate at 10 
years was 83% (Hochhaus et al 2017). 
Adverse reactions reported by system organ class (>10%) are: 
• Blood and lymphatic system disorders: neutropenia, thrombocytopenia, anemia; 
• Nervous system disorders: headache; 
• Gastrointestinal disorders: nausea, diarrhea, vomiting, dyspepsia and abdominal pain; 
• Skin and subcutaneous tissue disorders: periorbital oedema, dermatitis/eczema/rash; 
• Musculoskeletal and connective tissue disorders: muscle spasms and cramps, myalgia, 
arthralgia, bone pain; 
• General disorders and administration site conditions: fluid retention and oedema, fatigue; 
• Investigations: weight increased. 


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For further details please refer to the latest Glivec®/Gleevec® local approved product 
information. 
Pharmacokinetics 
Imatinib is a biopharmaceutical classification system (BCS) class 1 compound with high 
absolute bioavailability (98%) that is unaffected by food (Peng et al 2005). Based on an average 
terminal half-life of 18 hours (range 14 to 25 hours), imatinib exposure is expected to reach 
steady-state after four continuous daily doses i.e. by day 5 with an accumulation ratio of 1.5- to 
2.5-fold at steady state. The rate of absorption of imatinib, when given with a high-fat meal, 
was minimally reduced (11% decrease in Cmax and prolongation of Tmax by 1.5 h), with a small 
reduction in AUC (7.4%) compared to fasting conditions latest Glivec®/Gleevec® local 
approved product information. In addition, bioavailability is unaffected by food 
(Peng et al 2005). The average terminal elimination half-life is approximately 18 hours. In vitro 
metabolism studies indicate that CYP3A4 and to a smaller extent CYP2C8 are the major human 
P450 enzymes catalyzing the biotransformation of imatinib. The N-desmethyl metabolite 
CGP74588 was the main metabolite identified in humans, is biologically active and contributes 
to some extent to the therapeutic effect of imatinib. 
In a clinical DDI Study, co-administration of rifampicin, a strong CYP3A4 inducer increased 
imatinib oral-dose clearance by 3.8-fold, which significantly (p < 0.05) decreased mean Cmax 
and AUC while co-administration of ketoconazole, a strong CYP3A4 inhibitor increased the 
average Cmax and AUC by 26% and 40%, respectively. 
Imatinib was also shown to be a competitive inhibitor of marker substrates for CYP2C9, 
CYP2D6 and CYP3A4/5, with Ki values in human liver microsomes being 27, 7.5 and 7.9 
μmol/L, respectively. In vivo, the mean exposure to metoprolol, a CYP2D6 substrate, was 
increased upon imatinib co-administration by 17% in intermediate CYP2D6 metabolizers and 
by 24% in extensive CYP2D6 metabolizers [CSTI571A2106]. Imatinib increased the Cmax of 
the CYP3A4 substrate simvastatin 2-fold and the AUC 3.5-fold as shown [CSTI571A2108]. In 
a Phase III trial in pulmonary arterial hypertension patients [CQTI571A2301], sildenafil 
concentrations, both a moderate CYP2C19 and sensitive CYP3A4 substrate were raised by 64% 
when co-administered with imatinib. Therefore, drugs which are substrates of CYP2C9, 
CYP2D6 and CYP3A4/5 could have their exposure affected by imatinib. 
1.1.1.3 
Overview of nilotinib 
Nilotinib (Tasigna®) is currently approved for the treatment of adult patients with Philadelphia 
chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) and 
accelerated phase (AP) resistant to or intolerant to at least one prior therapy including imatinib 
and for the treatment of adult patients with newly diagnosed Ph+ CML in CP. Discontinuation 
of treatment may be considered in eligible Philadelphia chromosome positive (Ph+) CML 
patients in chronic phase who have been treated with Tasigna at 300 mg twice daily for a 
minimum of 3 years if a deep molecular response is sustained for a minimum of one year 
immediately prior to discontinuation of therapy. 


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Nilotinib is an aminopyrimidine, available as an oral formulation that is an Adenosine 
triphosphate (ATP)-competitive inhibitor of the protein tyrosine kinase activity of BCR::ABL1, 
which prevents the activation of BCR::ABL1 dependent mitogenic and anti-apoptotic pathways 
(e.g. Phosphatidylinositol 3-kinases (PI-3 kinase) and signal transducer and activator of 
transcription 5 (STAT5)), leading to the death of the BCR::ABL1 phenotype. 
Please refer to the latest [Nilotinib Investigator’s Brochure] for more details. 
1.1.1.3.1 Non-clinical experience 
In vitro safety pharmacology studies revealed a preclinical signal of potential QT prolongation 
for nilotinib. Despite these findings no QT interval effects were seen in dogs or monkeys. 
The main target organ of toxicity was the liver in dogs and monkeys and to a minor degree in 
rats and mice. Additional target organs after long term treatment were uterus in rats and skin, 
growing teeth and thymus in mice. 
Nilotinib was embryolethal and produced fetotoxicity in embryo-fetal development studies in 
rats and rabbits at doses that also produced maternal toxicity. There were no signs of 
teratogenicity. Nilotinib is transferred into the milk in lactating rats. 
Nilotinib is not genotoxic and was not carcinogenic in a rat two year bioassay. In a 26-week 
Tg.rasH2 mouse model carcinogenicity study skin papillomas/carcinoma occurred at 300 
mg/kg/day representing approximately 30 to 40 times (based on AUC) the human exposure at 
the maximum approved dose 800 mg/day (administered as 400 mg twice a day) while no 
increase occurred at 100 mg/kg/day (approximately 10 to 20 times human exposure, based on 
AUC). 
In vitro human liver microsomes enzyme inhibition studies revealed that nilotinib could act as 
an inhibitor of CYP2C8, CYP2C9, CYP2D6, and CYP3A4/5 activity and possibly, but less 
likely, CYP2C19. Enzyme induction studies indicate that nilotinib can be considered to be an 
in vitro inducer of CYP2B6, CYP2C8, and CYP2C9 activities. Therefore, caution should be 
exercised when co-administering nilotinib with drugs with narrow therapeutic index that are 
substrates of these enzymes. Nilotinib is not an effective inhibitor of the human sodium-
dependent taurocholate co-transport protein (NTCP). Nilotinib was also found to be a substrate 
for the P-gp transporter as well as a possible inhibitor of P-gp in vitro. 
1.1.1.3.2 Clinical experience 
The Phase III ENESTnd [CAMN107A2303] - Study assessed the efficacy and safety of 
nilotinib versus imatinib in newly diagnosed Ph+ CML-CP Results showed statistically 
significant differences in the primary endpoint defined as rate of major molecular response 
(MMR) at 12 months as well as other secondary endpoints such as CCyR by 12 months and 
time-to-progression to AP/BC on treatment. These results were confirmed at 24, 36, 48, 60, 72 
and 84 months Follow-up, which support superior efficacy of nilotinib over imatinib [Nilotinib 
Investigator’s Brochure]. 
The most commonly reported (> 5%) all-grade non-hematologic adverse reactions in patients 
with CML were rash, headache, nausea, pruritus, alopecia, myalgia, dry skin, fatigue, arthralgia, 


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muscle spasms, vomiting, abdominal pain upper, diarrhea, constipation, peripheral edema, 
abdominal pain, erythema, dyspepsia and asthenia. Hematologic adverse drug reactions 
included myelosuppression: thrombocytopenia, neutropenia and anemia. Clinically relevant 
biochemical abnormalities include hyperglycemia, hyperbilirubinemia, hypophosphatemia, and 
increases in lipase, ALT, and AST. 
Elevations in total cholesterol and low density lipoprotein (LDL) cholesterol have been very 
commonly observed. 
Newly-diagnosed or worsened ischemic vascular or cardiovascular events have occurred in 
patientstreated with nilotinib. Cardiovascular risk factors should be monitored and managed 
during nilotinib therapy. 
Unchanged nilotinib represents the predominant circulating component in serum. Metabolites 
do not significantly contribute to the pharmacological activity. Strong inhibitors or inducers of 
CYP3A4 can significantly alter the pharmacokinetics and systemic exposure of nilotinib in 
humans, so these drugs should be avoided or nilotinib dose changes should be considered. 
Hepatic impairment has a modest effect on nilotinib pharmacokinetics; however, impaired renal 
function is not expected to influence nilotinib pharmacokinetics. 
The currently approved dose of nilotinib is 300 mg BID for newly diagnosed Ph+ CMLpatients. 
Please refer to the latest [Nilotinib Investigator’s Brochure] for more details. 
1.1.1.4 
Potential for drug interaction 
There is a potential for drug-drug interaction between imatinib and asciminib. 
Effect of imatinib on asciminib 
The preliminary clinical data from the first-in human Study [CABL001X2101] suggested an 
increase in asciminib exposure when co-administered with imatinib. Following administration 
of asciminib 40 mg BID with imatinib 400 mg QD, the geo mean of the area under the plasma 
concentration-time curve from time zero to 12 hours (AUC0-12hours) values (coefficient of 
variation CV percentage, n) of asciminib after first dose on days 1, 8 and 22, respectively were 
estimated to be 3766 ng.h/mL (16%, n = 5), 8721 ng.h/mL (24%, n = 4) and 8890 (10%, n = 2) 
compared to 2840 ng.h/mL (57%, n = 27), 5402 ng.h/mL (72%, n = 15) and 5171 ng.h/mL 
(80%, n = 24), respectively for asciminib alone (~1.3 fold and ~1.7 fold increase on days 1 and 
after repeated doses, respectively) [Asciminib Investigator's Brochure]. In Study 
[CABL001X2101], patients were instructed to take asciminib under light meal conditions (i.e. 
< 400 kcal and 20% fat) when combined with imatinib, and under fasted conditions when 
administered alone. Asciminib exhibited a negative food effect, with low-fat and high-fat meals 
decreasing the bioavailability of asciminib by ~30% and 65%, respectively [CABL001A2101]. 
Hence, the estimate of the DDI magnitude might be reduced in Study [CABL001X2101] as 
asciminib was to be taken under different food conditions when administered alone or in 
combination. As a result, taking into account an increase in AUC ratio of asciminib between 
1.3 to 1.7 under combination therapy after single and multiple doses, respectively and an 
additional factor of adjustment on the basis of same food conditions (further increase of around 
30%), the DDI might vary between 1.7 and 2.3-fold increase. When integrating the in vitro and 


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in vivo data in a preliminary PBPK model and for a dosing regimen of asciminib doses between 
20 and 80 mg QD, the model predictions suggested a 1.21 to 1.70-fold increase in asciminib 
exposure as measured by AUC under combination with imatinib 400 mg QD after single and 
multiple doses, respectively. Based on these initial predictions, a drug-drug interaction may be 
expected, with a weak to moderate increase in asciminib exposure when co-administered with 
imatinib. 
Study [CABL001E2101] confirmed the earlier findings. The study assessed the effect of 
multiple doses of imatinib on the pharmacokinetics of a single oral dose (low-fat meal) of 40 
mg asciminib in healthy patients. The analysis showed that the exposure of asciminib was 
higher when administered in combination with imatinib compared to when asciminib was 
administered alone. The asciminib exposure, AUCinf and AUClast was approximately 108% 
higher and Cmax was 59% higher when administered in combination with imatinib compared 
to when administered alone. The Tmax was not impacted by the co-administration of imatinib. 
The effect of imatinib on asciminib may result from the inhibition of several metabolism and 
transport pathways that are involved in the disposition of asciminib (imatinib is an inhibitor of 
CYP3A4, UGT and P-gp).  
Effect of asciminib on imatinib 
Although there is a potential risk for asciminib to alter imatinib pharmacokinetics based on in 
vitro metabolism studies where CYP3A4 appears to be the main enzyme responsible for 
metabolism of imatinib (Filppula et al 2012), this has not been shown to be of clinical 
significance based on integration of data from clinical and modeling studies. In healthy patients, 
ketoconazole, a potent CYP3A4 inhibitor, increased the mean of imatinib Cmax and AUC by 26% 
and 40%, respectively, in healthypatients, confirming that imatinib is a CYP3A4 substrate, yet 
not meeting the criteria of a sensitive substrate [CST5710119]. Asciminib inhibited established 
marker substrates of CYP3A4/5 in vitro in human liver microsomes with IC50 values of 1.5 
μM and unbound Ki of approximately 0.348 μM but did not exhibit apparent time-dependent 
inhibition of CYP3A4/5 at asciminib concentrations of up to 50 μM. The clinical relevance of 
such interaction is considered limited. The PBPK model predictions did not suggest any 
clinically relevant DDI for imatinib 400 mg QD when co-administered with BID doses of 
asciminib up to 40 mg. This is also supported by preliminary human data in Study 
[CABL001X2101] where there was no apparent change in imatinib steady-state concentration 
upon co-administration with repeated daily doses of asciminib 40 mg BID [CABL001X2101]. 
Therefore, the potential for asciminib to affect the pharmacokinetics of imatinib is considered 
low. 
1.2 
Purpose 
TKIs have revolutionized the treatment of patients with CML, resulting in an overall survival 
(OS) that is close to that of the general population and therefore a near normal life expectancy. 
This has consequently drawn emphasis towards the need to improve patient’s quality of life, in 
line with that of the general population. Current treatment guidelines are therefore moving 
towards discontinuation of treatment in the context of “treatment free remission” (TFR). DMR 
is a prerequisite for TFR and is therefore emerging as a new treatment goal for CML patients 


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in chronic phase (NCCN 2018, Rea and Cayuela 2017, Mahon 2016). A sustained DMR for at 
least 2 years is recognized as one of the essential requirements to attempt discontinuation of 
TKI therapy in Ph+ CML-CP (NCCN 2018, Baccarani et al 2013, Hochhaus et al 2017). In 
addition, DMR is associated with improved survival rates and avoidance of disease progression 
(Cortes 2018, 
Dulucq and Mahon 2016, 
Branford 2016, 
Yeung et al 2015, 
Hehlmann et al 2014; Etienne et al 2014; Falchi et al 2013). In CML Study IV with frontline 
imatinib, patients with MR4.5 at 4 years had a higher probability of survival at 8 years versus 
patients with BCR::ABL1 IS of 0.1–1% and no patient who achieved MR4.5 in that analysis 
progressed to accelerated phase/blast crisis by the data cutoff (Hehlmann et al 2014). In a 
retrospective analysis of patients treated with frontline imatinib, (Etienne et al 2014) reported 
that confirmed CMR (defined in that study as MR4.5) at any time had higher event-free survival 
(95.2%) versus those with MMR, but not CMR (64.7%), and those who achieved CCyR, but 
not MMR (27.7%). In another retrospective study by (Falchi et al 2013), a lower risk of losing 
CCyR, progression to AP or BP, or death in patients with deeper MR was reported. Furthermore, 
the timing of switch from first line to 2nd line treatment in CML in the context of achieving a 
faster and deeper molecular response, is also being explored across various studies. Study 
TIDEL-II studied the effect of early switching from imatinib to nilotinib. Of the 210 patients 
enrolled in the study, switch to nilotinib occurred in 55 patients for failing to achieve molecular 
response targets (19, 16 and 20 at 3, 6 and 12 months, respectively). Of the 153 patients in 
MMR at 24 months, 42 (27%) were reported to have achieved MMR after switch to nilotinib. 
Of the 71 patients in MR4.5 at 24 months, 22 (31%) achieved MR4.5 after switch to nilotinib. The 
study demonstrated improved outcomes when patients were switched from imatinib to nilotinib 
for non-achievement of BCR::ABL 1 level milestones as per the ELN criteria, at month 3, 6 
and 12 (Yeung et al 2015). 
The majority of newly diagnosed CML-CP patients is treated with imatinib, but only a 
proportion of these patients is able to achieve DMR with imatinib treatment. In ENESTnd 
[CAMN107A2303], the cumulative rates of MR4.5 were 23% after 4 years and 33% after 6 years 
of imatinib treatment (Larson et al 2014). Landmark analysis (Branford et al 2015) performed 
elsewhere have shown that patientswho have not reached BCR::ABL1 levels of MR4 following 
24 months of imatinib treatment have low likelihood of achieving DMR with continued 
treatment; thus these patients would possibly benefit from additional therapy (Figure 1-1). 


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Figure 1-1 
Cumulative incidence of MR4.5 according to response level at 24 
months of imatinib treatment 
 
Currently, an option for patients who do not achieve the desired level of molecular response 
with continued imatinib treatment is to switch to a more potent second generation TKI. Results 
from ENESTcmr [CAMN107A2405] show that, after switching from imatinib to nilotinib, 
nearly half of the patients without MR4.5 at baseline will still not achieve this level of response 
even after 4 years of switch. Furthermore, second generation TKIs harbor a distinct toxicity 
profiles as compared to imatinib, and therefore can pose tolerability concerns, especially for 
patients who have associated co-morbidities. Hence, there is an unmet need for active and safer 
regimens for the aforementioned patients (Branford et al 2015). 
Asciminib is an allosteric inhibitor of BCR::ABL1 which targets the autoregulatory myristoyl 
binding pocket compared to the catalytic TKIs. Due to its distinct pharmacological profile and 
as shown by preclinical pharmacological studies demonstrating an additive anti-tumor activity, 
a combination of asciminib and an ATP-binding site TKI has the potential to achieve a DMR 
in a higher proportion of CML patients as compared to single agent TKI therapy. Additionally, 
targeting the ABL kinase domain at two distinct locations through the combination can 
theoretically prevent the emergence of single point mutation-associated treatment resistance. 
The value of non-overlapping resistance profiles was evident in mouse models where durable 
treatment-free regressions were observed with upfront administration of a nilotinib-asciminib 
combination (Wylie et al 2017). Furthermore, a study conducted by Saunders et al. showed that 
in vitro kinase inhibition achieved with asciminib in combination with imatinib, nilotinib or 
dasatinib is greater than that achieved with TKIs alone, even at concentrations 1000-fold lower 
than the average peak plasma concentration on asciminib 40 mg BID (currently investigated 
monotherapy dose), suggesting that simultaneous targeting of the myristate and ATP binding 
pockets may be more effective than targeting either side alone. Especially, patients with high 
IC50, who would be predicted to respond poorly to imatinib, could have dramatically increased 
kinase inhibition with the addition of low doses of asciminib (Saunders 2016). 
The addition of asciminib to imatinib is expected to result in more potent inhibition of the ABL 
kinase domain enhancing clinical efficacy. It is hypothesized that the addition of asciminib in 
patients who have not achieved DMR with single agent imatinib will increase their likelihood 


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of achieving this response over time and may allow TKI discontinuation in the context of TFR. 
The purpose of this trial is to evaluate the efficacy and safety of asciminib added on to imatinib 
treatment in comparison to continued imatinib in patients who have not achieved MR4 after at 
least one year of imatinib first-line treatment. As a secondary endpoint, the difference in 
efficacy between the combination and nilotinib, a second generation TKI, will be estimated.  
This amendment aims to add an asciminib single agent cohort to assess whether asciminib single 
agent at the recommended dose of 80mg QD leads to similar efficacy and safety as observed in 
the add-on arms of asciminib and imatinib. This additional cohort will help to evaluate if the 
combination of asciminib with imatinib is needed to increase the likelihood of achieving DMR, 
or if this can be achieved by asciminib alone. The primary analysis results show activity of 
asciminib as an add-on therapy to imatinib, assessed by MR4.5 rate at Week 48. The MR 4.5 
rate at Week 48 was 19%, 28.6%, 0% and 4.8% in the asciminib 40 mg + imatinib, asciminib 
60 mg + imatinib, continued imatinib and switch to nilotinib arm (Mauro et al, 2021). Results 
from other single agent studies in patients with CML-CP who have been treated with at least 2 
prior TKIs have shown activity of single agent asciminib for achievement of DMR in this 
heavily pretreated population. In Study A2301, MR4 and MR4.5 rates of 10.8% and 7.6%, 
respectively were observed at Week 48. In the subgroup of patients with baseline BCR::ABL1 
levels (> 0.01% and ≤1%), the MR4.5 rate (18.8%, 3 responders among 16 patients) was similar 
to that observed in E2201 with the asciminib as add on to imatinib at the primary analysis (data 
on file).  
2 
Objectives and endpoints 
Objectives and related endpoints are described in Table 2-1. 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To assess whether asciminib 40 mg QD + imatinib or 
asciminib 60 mg QD + imatinib is more effective than 
continued imatinib 
• 
Molecular Response (MR)4.5 rate at 48 
weeks 
Secondary objective(s) 
Endpoint(s) for secondary 
objective(s) 
• 
- To estimate efficacy of switch to nilotinib 
- To estimate difference in efficacy between asciminib 60 
mg + imatinib and switch to nilotinib 
- To estimate difference in efficacy between asciminib 40 
mg + imatinib and switch to nilotinib 
• 
- Molecular Response (MR)4.5 rate at 48 
weeks 
- Difference in rate of MR4.5 at 48 weeks 
• 
To assess additional parameters of the efficacy of  
- asciminib 60 mg added to imatinib vs continued imatinib 
or switch to nilotinib 
- asciminib 40 mg added to imatinib vs continued imatinib 
or switch to nilotinib 
• 
- Rate of MR4.5 at 96 weeks 
- Rate of MR4.5 by 48 and 96 weeks 
- Sustained MR4.5 at 96 weeks 
- Time to MR4.5 
- Duration of MR4.5 
• 
To characterize the safety and tolerability profile of 
asciminib 60 mg or 40 mg + imatinib vs continued imatinib 
or switch to nilotinib 
• 
Incidence and severity of adverse 
events, changes in laboratory values, 
clinically notable ECG abnormalities and 
vital signs 


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Objective(s) 
Endpoint(s) 
• 
To assess the pharmacokinetic profile of asciminib 60 mg 
or 40 mg and imatinib when administered in combination  
 
• 
Plasma concentrations of asciminib and 
imatinib when administered in 
combination. PK parameters include but 
are not limited to Cmax, Tmax, Cmin, AUClast 
and AUCtau 
• 
To estimate efficacy of asciminib 80 mg QD 
 
• 
-Molecular Response (MR)4.5 rate at 48 
weeks 
-Time to MR4.5 
-Duration of MR4.5 
 
• 
To characterize the safety and tolerability profile of 
asciminib 80 mg QD  
• 
Incidence and severity of adverse 
events, changes in laboratory values, 
clinically notable ECG abnormalities and 
vital signs 
 
• 
To assess the pharmacokinetic profile of asciminib 80 mg 
QD. 
• 
Plasma concentrations of asciminib. PK 
parameters include but are not limited to 
Cmax, Tmax, Cmin, AUClast and AUCtau 
Exploratory objective(s) 
Endpoint(s) for exploratory 
objective(s) 
• 
To describe the efficacy and safety of asciminib 60 mg + 
imatinib in patients  randomized to continued imatinib who 
crossover to receive asciminib 60 mg + imatinib 
• 
- Efficacy endpoints such as time to 
MR4.5 and duration of MR4.5 
- Safety endpoints such as incidence 
and severity of adverse events, changes 
in laboratory values, clinically notable 
ECG abnormalities and vital signs 
• 
To assess the proportion of patients eligible for TFR at 
end of the study 
• 
Patients, with sustained MRD* (Minimal 
Residual Disease) at the end of the 
study (i.e. 96 weeks after the first dose of 
study drug of the last randomized 
subject) 
* Please refer to glossary for the MRD 
definition 
• 
To explore relevant
 
 
, as well as 
 
 
• 
Analysis of
 
 
• 
To explore 
 
 
• 
 
• 
To evaluate
 
 
• 
 
  
• 
To explore the impact of treatment on patient reported 
outcomes 
(PROs) 
including 
CML-specific 
symptom 
assessment 
(disease 
and 
treatment), 
treatment 
satisfaction and overall impact of side effects of treatment 
from baseline 
• 
Overall Scores and individual domains 
for EORTC QLQ-C30 plus CML24, 
FACIT GP5 and TSQM questionnaire 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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3 
Study design 
The study is a Phase 2, multi-center, open-label, randomized study of asciminib + imatinib 
versus continued imatinib versus switch to nilotinib in patients with CML-CP who have been 
previously treated with imatinib first line therapy for at least one year (12 calendar months) and 
have not achieved DMR. 
The trial is designed to assess the activity of 2 doses of asciminib + imatinib QD versus imatinib 
continuation, and to estimate the difference compared to switch to nilotinib, assessed by the rate 
of MR4.5 at 48 weeks as well as additional efficacy parameters, PK, biomarkers, PROs and 
safety and tolerability. Additionally, the study will estimate safety and efficacy of single agent 
asciminib. 
Approximately eighty eligible patients will be randomized in a 1:1:1:1 ratio to receive study 
treatment in the below arms: 
Treatment arm 1: asciminib 40 mg QD as add-on therapy to imatinib 400 mg QD, or  
Treatment arm 2: asciminib 60 mg QD as add-on therapy to imatinib 400 mg QD, or  
Treatment arm 3: to continue imatinib 400 mg QD, or  
Treatment arm 4: to switch to nilotinib 300 mg BID  
The asciminib single agent cohort will be conducted as an open label cohort. Approximately 20 
eligible patients will be enrolled to receive asciminib 80 mg QD. 
In Treatment arms 1-4, patients on the study will continue on the allocated treatment until 
treatment failure, intolerability, or for up to 96 weeks after the last randomized subject received 
the first dose of treatment . After the last dose received every subject will be followed up for 
safety for 30 days. 
For patients in the asciminib single agent cohort, patients will continue on asciminib treatment 
until treatment failure, intolerability, or for up to 48 weeks after the last enrolled subject in the 
cohort received the first dose of treatment. After the last dose received every subject will be 
followed up for safety for 30 days.  
Interim analysis An interim analysis will be performed when at least 40 (50%) patients have 
been randomized and have been followed for their 24 weeks visit assessment or have 
discontinued treatment. At the time of the interim analysis, if excessive toxicity without added 
benefit is observed in one of the investigational arms, discontinuation of that treatment arm will 
be considered. The decision to discontinue an investigational arm in the study will be taken 
based on the risk benefit balance of the two investigational arms, and in context of the other 
two treatment options available for the patients in the study, namely: continue on imatinib with 
no potential improvement of efficacy; or switch to nilotinib with a potential to improve efficacy 
however, with a relatively adverse safety profile as compared to imatinib. If a decision is taken 
to discontinue asciminib 60 mg + imatinib treatment arm at interim analysis, patients  ongoing 
on that treatment arm will be provided an opportunity to continue on the study at a lower dose 
(asciminib 40 mg + imatinib) if the investigator considers that is in the best interest of the 
patient. 


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Crossover for  patients in the imatinib arm 
Patients who were randomized to continue on imatinib single agent treatment but who have not 
achieved MR4.5 at 48 weeks may cross-over to receive the add-on within 4 weeks after week 48 
visit (Figure 3-1). It is planned that these patients cross-over to receive the asciminib 60 mg + 
imatinib, as this dose provides higher exposure see ( Section 4.2). If a decision is taken to 
discontinue asciminib 60 mg + imatinib treatment arm at interim analysis or upon emerging 
data, cross-over may be changed to asciminib 40 mg + imatinib treatment arm. The cross-over 
is at discretion of the investigator and the patient. Apart from a PCR result of below MR4.5 at 
Week 48 visit, there are no other entry criteria for the cross-over part. Patients on nilotinib are 
not allowed to cross-over to receive the add-on treatment. 
Figure 3-1 
Study design 
 
(*)Patients on the imatinib continuation arm who have not achieved MR4.5 at 48 weeks may cross-over 
to receive the asciminib 60 mg add-on treatment. Based on the results of the interim analysis or 
emerging data, cross-over may be changed to asciminib 40 mg + imatinib arm. 
Primary analysis 
For patients in treatment arms 1 – 4, the primary analysis for the study will be performed when 
all patientshave completed the Week 48 visit or have discontinued treatment early. 
End of Study Treatment period 
The end of study treatment period for patients in Treatment arms 1-4 will be at 96 weeks (plus 
30 days for the safety follow up) after the last randomized subject received the first dose of 
study treatment.  
The end of study treatment period for patients in the asciminib single agent cohort will be at 
48 weeks (plus 30 days for the safety follow up) after the last enrolled subject in that cohort 
received the first dose of study treatment. 


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Post-Trial Access 
For patients  who in the opinion of the investigator are continuing to benefit from the study 
drug(s), efforts will be made to continue providing the study treatment outside the study. 
Options include, but are not limited to, a post-trial access program or access to commercial 
supplies in applicable countries. 
4 
Rationale 
4.1 
Rationale for study design 
The development of asciminib presents an opportunity to evaluate the beneficial effects of a 
combined inhibition of BCR::ABL1 together with ATP-binding site TKIs (e.g. imatinib) for 
greater pharmacological control of BCR::ABL1 in the treatment of patients with CML. The 
proposed study design will allow an assessment of the efficacy, safety, tolerability and patients 
reported outcomes of asciminib + imatinib in a population of patients with continuing medical 
need of achieving DMR. To characterize the pharmacokinetics of asciminib in the proposed 
patient population and assess the potential for drug-drug-interaction with imatinib (compared 
to historical data), PK samples of asciminib will be collected. 
The study randomizes patients 1:1:1:1 in four arms to assess efficacy and safety of the 
combination of asciminib and imatinib versus imatinib, and to estimate the difference in 
efficacy and safety between nilotinib and the combination arms. For patients randomized to 
continue imatinib, a cross-over to receive asciminib + imatinib after 48 weeks is implemented 
should they not have achieved MR4.5 at the time of the primary endpoint. This will allow 
patients without MR4.5 after continuation of imatinib to potentially benefit from the combination 
treatment. 
This study is conducted as an open label study; the conditions for drug administration being 
distinct for the four treatment arms makes blinding very complex and would increase the 
likelihood of dosing errors. Additionally, the characteristic adverse event profile of each of the 
drugs further preclude effective blinding. 
4.1.1 
Rationale for addition of asciminib single agent cohort  
The primary analysis cut-off for the study was performed on 10-Jan-2022. The results of the 
primary analysis showed activity of asciminib as an add-on therapy to imatinib, assessed by 
deep molecular response (MR4.5) rate at 48 weeks. MR4.5 was achieved in higher number of 
patients in asciminib 60 mg + imatinib arm as compared to continued imatinib and switch to 
nilotinib arm. At Week 48, 6 (28.6%) patients in asciminib 60 mg + imatinib arm and 4 (19 %) 
patients in asciminib 40 mg + imatinib arm achieved MR4.5 and 1 patient (4.8%) in the nilotinib 
arm achieved MR4.5. No patients in the imatinib arm achieved MR4.5 by Week 48.  
In study A2301 in heavily pre-treated patients (≥3L CML-CP) treated with asciminib 40 mg 
BID, the MR 4.5 rate at week 48 was 7.6% in the asciminib arm. Of the patients with BCR::ABL1 
levels >0.1≤1% at baseline, MR4.5 response rate was 18.8% (3 responders among 16 patients) 
at Week 48. 


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Adding an asciminib single agent cohort to assess the efficacy and safety at the recommended 
dose of asciminib in >3L CML-CP of 80 mg QD will help to evaluate if the combination of 
asciminib with imatinib is needed to increase the likelihood of achieving DMR, or if this can 
be achieved by asciminib alone. 
At the primary analysis in E2201, asciminib as add-on to imatinib was well tolerated. Adverse 
events leading to discontinuation were reported for 4.8% patients in the asciminib 40 mg + 
imatinib arm, 14.3% patients in the asciminib 60 mg + imatinib, 23.8% patients in nilotinib arm 
and none in imatinib arm. Safety profile of asciminib add-on to imatinib was similar to that of 
asciminib single agent observed in the studies in heavily pretreated patients (Hughes et al 2019; 
Mauro 2021).  
The exposure (AUCtau) of asciminib obtained in this study with asciminib 60 mg QD + imatinib 
(in the fed state) was similar than the exposure in study X2101 obtained with single agent 
asciminib 80 mg QD (in the fasted state). The Cmax was approximately 60% higher in X2101 
at 80 mg QD compared to asciminib 60 mg QD + imatinib in this study. 
Single agent treatment, if able to deliver the same benefit to the patient would be preferable 
over treatment with two agents, with the potential to be safer and more tolerable for long term 
treatment needed by patients with CML-CP. Thus, the addition of the asciminib single agent 
cohort aims to investigate the efficacy and safety of single agent 80 mg QD asciminib in the 
current study. 
4.2 
Rationale for dose/regimen and duration of treatment 
Currently the majority of newly diagnosed CML-CP patients are treated with imatinib at the 
dose of 400 mg QD. Imatinib is administered with a light meal at the dose of 400 mg QD in this 
study. Therefore, it is desirable to follow the same conditions of administration for asciminib. 
The exposure resulting from the Recommended Phase 2 Dose (RP2D) in CML-CP (40 mg BID 
monotherapy) is expected to be altered by the combined effect of drug interaction and food 
effect and may require a dose adjustment to achieve comparable exposure to the established 
RP2D (refer to  Section 1.1.1.4 ). 
The two doses of 40 mg or 60 mg administered daily in combination with imatinib 400 mg QD 
provide pharmacologically active exposure with different PK profiles; the benefit/risk ratio of 
each dose level needs to be further established. Indeed, 60 mg asciminib QD in combination 
with imatinib with low fat meals leads to comparable exposure to the monotherapy R2PD as 
measured by AUC, and higher Cmax by approximately 1.6 to 1.9-fold, while AUC was lower 
with asciminib 40 mg QD (approximately 40%) but with Cmax close to RP2D. Based on PK/DDI 
data, safety and tolerability, both combination doses will be investigated in this study. 
The safety profile of asciminib QD doses (40mg, 60 mg and 80 mg) has been evaluated in 
combination with imatinib 400 mg QD. Dose Limiting Toxicities (DLTs) have been observed 
at all dose levels, 1 in 9 patients  in the asciminib 40 mg QD cohort (neutrophil count decreased 
G4), 2 in 6 patients in the asciminib 60 mg QD cohort (abdominal pain G3, nausea G3 ) and 2 
in 4 patients  in the asciminib 80 mg QD cohort ( pancreatitis G2, lipase increased G3). From 
clinical point of view and supported by the Bayesian Logistic Regression Model (BLRM), both 


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asciminib 40 mg QD and 60 mg QD seem to be appropriate in combination with imatinib 400 
mg QD. 
The duration of treatment will allow both for detection of early activity and tolerability of the 
combination versus continued imatinib or switch to nilotinib as well to confirm the results at 
later time points up to 96 weeks. 
The asciminib single agent cohort will evaluate asciminib at a dose of 80mg once-daily (QD) 
for 48 weeks.  
The asciminib dose of 80 mg QD is based on the clinical experience in patients with CML-CP 
in studies X2101 and A2301 and PK/PD modelling based exposure-response and exposure-
safety analyses (Please refer to the latest [Asciminib Investigator's Brochure] for more details). 
Asciminib 80 mg QD has been approved by the FDA for the treatment of adult patients with 
Ph+ CML in CP, previously treated with 2 or more TKIs. The ongoing study CABL001J12301 
investigating efficacy and safety of single agent asciminib in patients with newly diagnosed 
CML is assessing asciminib at a dose of 80 mg QD. The duration of treatment of 48 weeks will 
allow for detection of anti-leukemic activity and tolerability of single agent asciminib in the 
study.  
4.3 
Rationale for choice of comparator and combination drugs 
Preclinical evidence supporting the rationale for the combination of an ATP-binding site TKI 
and asciminib is described in previous sections (Section 1.1.1.1, Section 1.1.1.2 and 
Section 1.2). The majority of newly diagnosed CML-CP patients are treated with imatinib, 
which has a well-defined tolerability profile. For patients on imatinib, where the treatment goal 
is to achieve DMR, e.g. in the context of attempting TFR, the addition of asciminib could be an 
efficacious and safe treatment option. 
Both ELN (European Leukemia Network) and NCCN (National Comprehensive Cancer 
Network) guidelines recommend the use of imatinib as approved first line treatment for CML-
CP, as well as other approved agents, including nilotinib. Robust clinical evidence has been 
generated so far with imatinib as first line treatment and it has been selected as comparator arm 
for the primary study endpoint. Being the investigational arms asciminib in combination with 
imatinib, keeping imatinib as comparator will support the assessment of the asciminib single 
agent contribution in the investigational arm. Imatinib will be administered at 400 mg QD. 
The choice of nilotinib as comparator is supported by results from ENESTcmr 
[CAMN107A2405] Study which showed that patients with residual disease after at least two 
years of imatinib treatment can achieve higher rate of MR4.5 when treatment is switched to 
nilotinib as compared to continuation with imatinib. Together with results from the ongoing 
ENESTop [CAMN107A2408] Study this suggests that a higher proportion of patientsswitching 
to nilotinib will be eligible for TFR (Hughes et al 2016). Thus nilotinib constitutes a current 
treatment option for patients in the target population with the goal of a deep molecular response. 
The comparison to nilotinib will allow to estimate the difference in regards of efficacy and 
tolerability versus the combination therapy. 
Based on data from ENESTnd [CAMN107A2303], the safety profile of the nilotinib 300 mg 
BID dose is more favorable in terms of tolerability, AEs and laboratory evaluation than the 


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nilotinib 400 mg BID dose, while showing similar efficacy. Additionally, the frequency of AEs 
leading to discontinuation was lower in the 300 mg BID arm compared to the 400 mg BID arm. 
As CML-CPpatients who are in CCyR but less than MR4 are not considered to be treatment 
failure according to current treatment guidelines, the selection of 300 mg BID dose for the 
nilotinib treatment arm is considered appropriate. 
4.4 
Purpose and timing of interim analyses/design adaptations 
An interim analysis will be performed in order to gain an early insight into the safety and 
efficacy of the asciminib add-on combination which will help in planning the future 
development of the asciminib combination. The interim analysis will be performed when at 
least 40 (50%) patients have been randomized and have been followed for their 24 weeks visit 
assessment or have discontinued treatment. The enrollment will continue during this 24 weeks 
follow-up. The interim analysis will include all randomized patients until the date of data cut-
off, and include both efficacy (e.g. BCR::ABL1 assessment overtime, MR4 and MR4.5 rate at 
different time-points) and safety (e.g. Adverse Events and laboratory values) summaries, which 
will be detailed in the Statistical Analysis Plan for the interim analysis.  
The interim analysis is planned to provide early insights into the safety and efficacy parameters 
to inform the benefit risk assessment of asciminib as an add-on therapy to imatinib. If excessive 
toxicity without added benefit is observed in one of the investigational arms, discontinuation of 
that treatment arm will be considered. The decision of discontinuation of an investigational arm 
in the study will be taken based on the risk benefit balance of the two investigational arms, and 
in context of the other two treatment options available for the patients in the study, namely: 
continue on imatinib with no potential improvement of efficacy; or switch to nilotinib with a 
potential to improve efficacy however, with a relatively adverse safety profile as compared to 
imatinib. If a decision is taken to discontinue asciminib 60 mg + imatinib treatment arm at 
interim analysis, patients ongoing on that treatment arm will be provided an opportunity to 
continue on the study at a lower dose (asciminib 40 mg + imatinib) if the investigator considers 
that is in the best interest of the patient. Additionally, cross-over arm may be changed to 
asciminib 40 mg + imatinib treatment arm. It is not planned to write an interim CSR based on 
this interim analysis. 
4.5 
Risks and benefits 
The benefit-risk for asciminib remains positive for the treatment of Ph+ CML and Ph+ALL 
patients with or without mutations conferring resistance to ATP-competitive inhibitors, 
including the T315I mutation. 
The most frequent adverse reactions to asciminib administered in monotherapy (in >20% 
patients) include headache (23.6%), fatigue (22.8 %), thrombocytopenia (22.8%), arthralgia 
(21.3%) and nausea (20.2%). Thrombocytopenia (15.2%), neutropenia (11.8 %) and lipase 
increased (10.7%) were the most frequently reported (>10.0 %) Grade ≥3 events. 
The important identified risks of asciminib include pancreatic toxicity (amylase and lipase 
elevations), myelosuppression and QT prolongation. Important potential risks include, 
hepatotoxicity including hepatic transaminase and bilirubin elevations, reproductive toxicity 
and Hepatitis B viral reactivation. Important potential class risks include cardiac failure, edema 


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and fluid retention, hemorrhage and ischemic heart and CNS conditions. Of note the risks which 
have been demoted are gastrointestinal toxicity, hypersensitivity and phototoxicity.  
The most common adverse reactions to asciminib administered in combination with imatinib 
(in > 10% patients) include nausea (25%) and lipase increased (15%). 
The important identified risks of nilotinib, authorized for over 10 years, include QT 
prolongation, myelosuppression, cardiovascular events, significant bleeding, severe infections, 
hepatotoxicity, pancreatitis, lipase and amylase elevations, fluid retention, blood glucose 
increased, blood cholesterol increased, use in patients with hepatic impairment and interactions 
with strong CYP3A4 inhibitors, strong CYP3A4 inducers, sensitive CYP3A4 substrates and 
food. The important identified risks of nilotinib include sudden death, cardiac failure, 
reproductive toxicity, skin malignancy, and interactions with P-gp inhibitors, drugs eliminated 
by CYP2C8, CYP2C9, CYP2D6 or substrates of UGT1A1, and P-gp and OCT1 transporters 
and drugs that may prolong the QT interval. 
In this trial, the aforementioned risks are managed through detailed information provided in the 
IB and requirements delineated in the study protocol. The latter include exclusion criteria, 
which limit enrollment of patients at unacceptable safety risks, required assessments/monitoring 
and recommendations for the management of adverse events including dose reduction and 
interruption. There may be unforeseen risks with study treatment which could be serious.  
Refer to the latest [Asciminib Investigator’s Brochure] and the latest local product information 
for imatinib and nilotinib. 
Women of child bearing potential must be informed that taking the study treatment may involve 
risks to the fetus if pregnancy were to occur during the study, and agree that in order to 
participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the subject will not reliably comply, they should 
not be entered or continue in the study.  
Imatinib, on the other hand, already on the market for more than 15 years, has a well-known 
efficacy profile, with high molecular and cytogenetic response rates offering an efficacious 
treatment to CMLpatients, and very low rates of severe non-hematological adverse events, as 
well as an acceptable hematological toxicity. Only a minority of patients treated with imatinib 
first-line will have a high likelihood of achieving DMR, allowing patients to become eligible 
for TFR (Branford et al 2015). 
Preclinical studies demonstrated that the combination of asciminib and imatinib is potentiating 
the inhibition of the BCR::ABL1 kinase (Saunders 2016), especially for patients predicted to 
respond poorly to imatinib. Furthermore targeting the kinase at two distinct locations and the 
value of non-overlapping resistance profiles was evident in a xenograft model, with durable 
treatment free remission observed with the administration of asciminib and an ATP-binding site 
TKI (Wylie et al 2017). This additive anti-tumor activity suggests a higher proportion of 
patients achieving a DMR compared to imatinib mono-therapy, and subsequently allow for 
consideration of TKI discontinuation. 
In summary, the combination of imatinib and asciminib represents an oral therapy option with 
a potentially high benefit-risk ratio for the treatment of patients with CML. This is also 


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supported by data (albeit limited) from the ongoing combination cohort of [CABL001X2101] 
Study showing good tolerability and no new safety signals. 
A potential risk for patients enrolling in the combination arm of the study is that the addition of 
asciminib may lead to no improved efficacy in terms of depth of response while exposing the 
subject to additional toxicity. However, the preclinical evidence to date (see Section 1.1.1.1) 
supports the hypothesis of a potentiation of activity. Furthermore, the adverse event profile of 
asciminib is similar qualitatively to that observed with other TKIs targeting BCR::ABL1. The 
risk of asciminib in combination with imatinib not being effective is mitigated by observing 
patients closely for evidence of efficacy, based on molecular response data, which will permit 
rapid decision making, and discontinuation of therapy if necessary (see  Section 12  data 
analysis). 
4.6 
Rationale for public health emergency mitigation procedures 
During a public health emergency as declared by local or regional authorities e.g., pandemic, 
epidemic, or natural disaster, mitigation procedures to ensure participant safety and trial 
integrity may be implemented. Notification of the public health emergency as declared by local 
or regional authorities should be discussed among investigators and Novartis. All procedures 
adapted to the situation must be submitted, if required as per local regulations, through a 
protocol amendment for approval by local or regional Health Authorities and Ethics 
Committees prior to implementation of mitigation procedures. 
 
5 
Population 
Approximately eighty patients with CML-CP who have been previously treated with imatinib 
and have not achieved deep molecular response will be randomized in a 1:1:1:1 ratio to receive 
asciminib 60 mg as add-on therapy to imatinib, or asciminib 40 mg as add-on therapy to 
imatinib, or to continue imatinib, or to switch to nilotinib.  
Approximately twenty patients with CML-CP who have been previously treated with imatinib 
for at least 1 year and have not achieved deep molecular response will be enrolled in the 
asciminib single agent cohort to receive asciminib 80 mg QD. The definition of CML-CP will 
be according to European Leukemia Network criteria (Baccarani et al 2013). 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
5.1 
Inclusion criteria 
Patientseligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Male or female patients ≥ 18 years of age with a confirmed diagnosis of CML-CP defined as: 
• < 15% blasts in peripheral blood and bone marrow 
• < 30% blasts plus promyelocytes in peripheral blood and bone marrow 


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• < 20% basophils in the peripheral blood 
• ≥ 100 x 109/L (≥ 100 000/mm3) platelets 
• No evidence of extramedullary leukemic involvement, with the exception of 
hepatosplenomegaly 
3. b. Minimum of one year (12 calendar months) treatment with imatinib first line for CML-
CP (patients have to be on imatinib 300 mg QD or higher)). 
4. a. BCR::ABL1 levels > 0.01% IS and ≤ 1% IS at the time of randomization as confirmed 
with a central assessment at screening; patients must not have achieved deep molecular 
response (MR4 IS) confirmed by 2 consecutive tests at any time during prior imatinib 
treatment. An isolated, single test result with BCR::ABL1 levels < 0.01 % (MR4 IS) is 
allowed, however it should not have been observed within the 9 months prior to 
randomization 
5. a. Patient must meet the following laboratory values before randomization: 
• Absolute Neutrophil Count ≥ 1.5 x 109/L 
• Platelets ≥ 75 x 109/L 
• Hemoglobin (Hgb) ≥ 9 g/dL 
• Serum creatinine < 1.5 mg/dL 
• Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert’s syndrome who may only 
be included with total bilirubin ≤ 3.0 x ULN 
• Aspartate transaminase (AST) ≤ 3.0 x ULN 
• Alanine transaminase (ALT) ≤ 3.0 x ULN 
• Alkaline phosphatase ≤ 2.5 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 
6. a. Patients must have the following laboratory values (≥ LLN) or corrected to within normal 
limits with supplements prior to randomization:  
• Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with 
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 if associated with creatinine clearance* within normal limits) 
• Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with 
creatinine clearance* within normal limits) 
*Creatinine clearance as calculated using Cockcroft-Gault formula 
5.2 
Exclusion criteria 
Patients meeting any of the following criteria are not eligible for inclusion in this study. 
1. Treatment failure according to European Leukemia Network criteria (Baccarani et al 2013) 
during imatinib treatment. 


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• after 3 months of treatment no Complete Hematologic Response (CHR) and/or Ph+ > 
95% 
• after 6 months of treatment BCR::ABL1 > 10% and/or Ph+ > 35% 
• after 12 months of treatment BCR::ABL1 > 1% and/or Ph+ > 0 
• at any time loss of CHR, loss of CCyR, confirmed loss of MMR*, mutations, clonal 
chromosomal abnormalities in Ph+ cells (CCA/Ph+) 
*In 2 consecutive tests, of which one with a BCR::ABL level ≥1%. 
2. Known second chronic phase of CML after previous progression to AP/BC. 
3. Previous treatment with any TKIs other than imatinib. 
4. History or current diagnosis of ECG abnormalities indicating significant risk or safety for 
patients participating in the study such as: 
• History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft 
(CABG) within 6 months prior to randomization 
• Concomitant clinically significant arrhythmias, e.g. sustained ventricular tachycardia, 
and clinically significant second or third degree AV block without a pacemaker 
• Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) prior to randomization 
• 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 including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia 
• Concomitant medications with a "known" risk of Torsades de Pointes per 
crediblemeds.org that cannot be discontinued or replaced by safe alternative 
medication  
• inability to determine the QTcF interval 
5. Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator 
could cause unacceptable safety risks or compromise compliance with the protocol (e.g. 
uncontrolled diabetes, active or uncontrolled infection, uncontrolled clinically significant 
hyperlipidemia and high serum amylase). 
6. History of acute pancreatitis within 1 year prior to randomization or medical history of 
chronic pancreatitis. 
7. a. History of chronic liver disease or ongoing acute liver disease. 
8. History of other active malignancy within 3 years prior to randomization with the exception 
of basal cell skin cancer, indolent prostate cancer and carcinoma in situ treated curatively. 
9. a. Known history of Human Immunodeficiency Virus (HIV), chronic Hepatitis B (HBV), 
or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBsAg), 
and Hepatitis B core antibody (anti-HBc) will be performed at study entry. If HBsAg or 
anti-HBc is positive, Hepatitis B surface antibody (anti-HBs) and/or HBV-DNA 
measurement is recommended to confirm negative viral status. 


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10. 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).  
11. a. Treatment with strong inducers or inhibitors of CYP3A that cannot be discontinued or 
switched to a different medication at least one week prior to the start of treatment and for 
the duration of the study. 
12. 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. 
13. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes. 
14. Participation in a prior investigational study within 30 days prior to randomization or within 
5 half-lives of the investigational product, whichever is longer. 
15. c. (i) Pregnant or nursing (lactating) women. 
(ii) Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
while taking study treatment and for 14 days after stopping study medication in 
treatment arms 1- 4, or for 3 days after stopping asciminib single agent treatment. If 
local regulations or locally approved prescribing information are more stringent than 
the protocol required duration of contraception, the longer duration must be followed. 
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 bilateral tubal ligation, female sterilization (have had surgical bilateral 
oophorectomy with or without hysterectomy), or total hysterectomy, at least six 
weeks before taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment. 
• Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that subject. 
• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods 
of contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate < 1%), for example hormone vaginal ring or transdermal hormone 
contraception. 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor 
symptoms). Women are considered not of child bearing potential, if they are post-
menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), 


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total hysterectomy or bilateral tubal ligation at least six weeks prior to enrollment on study. 
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 to be not of child 
bearing potential. 
If local regulations are more stringent than the contraception methods listed above to 
prevent pregnancy, local regulations apply and will be described in the Informed Consent 
Form (ICF). 
16. Patients who have achieved deep molecular response (MR4 IS), confirmed by 2 consecutive 
tests at any time during prior imatinib treatment. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
6 
Treatment 
6.1 
Study treatment 
The study treatments are asciminib (60 mg QD), asciminib (40 mg QD), asciminib (80 mg QD), 
imatinib (400 mg QD) and nilotinib (300 mg BID). Novartis will supply all compounds to the 
investigational sites: asciminib as 40 mg and 20 mg tablets, imatinib as 400 mg and 100 mg 
tablets and nilotinib as 150 mg and 200 mg hard gelatin capsules.  
6.1.1 
Study drugs 
Table 6-1 
Study drug 
 
Treatment 
Title  
Asciminib 
(ABL001)   
20 mg  
Asciminib 
(ABL001)   
40 mg 
Glivec®/Gleevec® 
(STI571)             100
mga 
Glivec®/Gleevec® 
(STI571)         400 
mg 
Tasigna® 
(AMN107) 
150 mg 
Tasigna® 
(AMN107) 
200 mgb 
Treatment 
Description  
Dose and treatment schedule are described in the Table 6-5 and all the information about the 
administration of the study drug are described in the  Section 6.1.3. Dose reductions can be 
performed as described in Table 6-3   
Type   
Drug  
Drug 
Drug 
Drug 
Drug 
Drug 
Dose 
Formulation  
Tablet 
Tablet 
Tablet 
Tablet 
Hard gelatin
capsule 
Hard gelatin
capsule 
Unit Dose 
Strength(s)  
20 mg 
40 mg 
100 mg 
400 mg 
150 mg 
200 mg 
Dosage 
Level(s)  
Dose amount and frequency are mentioned in Section 6.7.2 
Route of 
Administration  Oral 
Oral 
Oral  
Oral 
Oral 
Oral 
Use  
Experimental Experimental Experimental 
Experimental 
ExperimentalExperimental
IMP  
Yes  
Yes  
Yes  
Yes 
Yes 
Yes 


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Sourcing  
Provided 
centrally 
by 
the sponsor  
Provided 
centrally by 
the sponsor 
Provided centrally 
by the sponsor 
Provided centrally 
by the sponsor 
Provided 
centrally by 
the sponsor 
Provided 
centrally by 
the sponsor 
Packaging and 
Labeling  
Study 
treatment will 
be provided in 
a bottle. Each 
bottle will be 
labeled 
as 
required 
per
country 
requirement.  
Study 
treatment 
will 
be 
provided in a 
bottle. Each 
bottle will be 
labeled 
as 
required per 
country 
requirement.  
Study treatment will
be provided in a 
bottle. Each bottle
will be labeled as
required per country
requirement.  
Study treatment will
be 
provided 
in 
HDPE bottle. Each 
HDPE bottle will be
labeled as required 
per 
country
requirement.  
Study 
treatment 
will 
be 
provided 
in
HDPE bottle. 
Each HDPE 
bottle will be 
labeled 
as 
required per 
country 
requirement.  
Study 
treatment 
will 
be 
provided 
in
HDPE bottle. 
Each HDPE 
bottle will be 
labeled 
as 
required per 
country 
requirement.  
6.1.2 
Additional study treatments 
No additional treatment beyond investigational drug and control drug are included in this trial. 
6.1.3 
Treatment arms/group 
At Baseline, patients will be randomized to one of the following 4 treatment arms: asciminib 
60 mg + imatinib, asciminib 40 mg + imatinib, imatinib, or nilotinib in a ratio of 1:1:1:1. 
Treatment arm 1: Asciminib 40 mg + imatinib arm: asciminib 40 mg and imatinib 400 mg will 
be administered orally daily on a continuous schedule (QD). 
Treatment arm 2: Asciminib 60 mg + imatinib arm: asciminib 60 mg and imatinib 400 mg will 
be administered orally daily on a continuous schedule (QD). 
Treatment arm 3: Imatinib arm: imatinib 400 mg will be administered orally daily on a 
continuous schedule (QD). 
Treatment arm 4: Nilotinib arm: nilotinib will be administered orally at 300 mg twice daily on 
a continuous schedule (BID). 
Asciminib single agent cohort: asciminib 80 mg will be administered orally once daily on a 
continuous schedule (QD). 
6.1.4 
Guidelines for continuation of treatment 
Please refer to Section 6.5.1. 
6.1.5 
Treatment duration 
Treatment arms 1-4 
All patients will be given the opportunity to receive study treatment until the date that 
corresponds to 96 weeks after the last randomized subject receives the first study treatment dose. 
Patients may be discontinued from treatment at any time due to unacceptable toxicity, disease 
progression and/or at the discretion of the investigator or the subject. 


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Asciminib single agent cohort 
All patients will be given the opportunity to receive study treatment until the date that 
corresponds to 48 weeks after the last enrolled subject in the asciminib single agent cohort 
receives the first study treatment dose. Patients may be discontinued from treatment at any time 
due to unacceptable toxicity, disease progression and/or at the discretion of the investigator or 
the subject.  
6.1.5.1 
Treatment beyond disease progression 
Should a disease progression occur during study, the subject must be discontinued and can be 
treated at investigator’s discretion outside of the study. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
In general, concomitant medications and therapies deemed necessary for the supportive care 
and safety of the subject are allowed, provided their use is documented in the subject records 
and on the appropriate electronic case report form (eCRF), 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. 
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
in the concomitant medications/significant non-drug therapies section of the eCRF. 
All prior antineoplastic surgery, chemotherapy, biologic, immunologic and radiation therapy 
must be recorded in the “Prior antineoplastic therapy” section of the eCRF. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact Novartis to determine if the subject should continue participation in the study. 
Hormonal contraceptives are allowed as contraception methods. Highly effective contraception 
should be maintained throughout the study and for 14 days after study treatment discontinuation. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
6.2.1.1.1 Permitted concomitant medication requiring caution for asciminib 
combinations and asciminib single agent cohort 
Based upon the clinical human ADME data and alignment with the in vitro human hepatocyte 
clearance and enzyme reaction phenotyping studies, the relative contribution of CYP- and 
UGT-mediated asciminib clearance was estimated to be 36.6 and 58.3%, respectively. 
Strong Inhibitors of CYP3A4 when given to patients being treated with asciminib in 
combination with imatinib have the potential to increase asciminib and imatinib concentrations. 


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Therefore, strong CYP3A4 inhibitors should be used with caution in patients being treated with 
asciminib in combination with imatinib. 
Inducers of CYP3A4 have the potential to decrease asciminib concentrations. Therefore, strong 
CYP3A4 inducers should be used with caution in patients being treated with asciminib single 
agent. Based on clinical data available, CYP3A4/5 and CYP2C9 substrates with narrow 
therapeutic index should be used with caution. 
Use of anti-emetics is allowed. Prophylactic anti-emetics should be started only once the subject 
experiences nausea or vomiting, at the discretion of the investigator. It is recommended that 
patients use drugs that do not cause QT prolongation.  
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 
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 in vivo potential of asciminib to interact with sensitive CYP3A4 and 
CYP2C9 substrates has been evaluated by PBPK modeling and indicates a minimal or 
negligible risk, patients using anti-platelet pro-drugs should still be carefully monitored. 
Substrates of OATP1B, BCRP or both transporters, including, but not limited to sulfasalazine, 
methotrexate, pravastatin, atorvastatin, pitavastatin, rosuvastatin and simvastatin should be used 
with caution. Refer to OATP1B and BCRP substrates’ dose reductions, as recommended in 
their prescribing information. As far as possible avoid co-administering rosuvastatin and 
consider alternative statins. If during the study co-administration of rosuvastatin is required, 
then the dose of rosuvastatin should be reduced, as recommended in its prescribing information. 
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. 
 
QT prolonging agents 
As far as possible avoid co-administration of drugs with a "known" risk of Torsades de Pointes 
(TdP) during the course of the study. 
If concomitant administration of drugs with a "known" risk of TdP is required based on the 
investigator assessment and clinical need, study treatment may be continued under close ECG 
monitoring to ensure subject’s safety. 


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A list of drugs associated with QT prolongation and/or TdP is available online at 
//crediblemeds.org/. 
Please refer to Section 16.3 for more details. 
6.2.1.1.2 Permitted concomitant medication requiring caution for imatinib continuation 
arm and nilotinib arm 
Nilotinib and imatinib should be administered according to the locally approved product 
information. 
6.2.2 
Prohibited medication 
The concomitant administration of other investigational drugs is not allowed. 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 study after consultation with Novartis. The administration of other tyrosine 
kinase inhibitors indicated for treatment of Ph+ CML is not allowed. 
Use of the treatments displayed in the below sections are not allowed after start of study 
treatment. 
Please refer to Section 16.1 for more details. 
6.2.2.1 
Prohibited medication for asciminib combination arms  
Strong CYP3A4/5 inducers  
Every effort should be made NOT to concomitantly administer strong CYP3A4/5 inducers 
(Section 16.3). CYP3A4/5 inducers have the potential to reduce asciminib and imatinib 
concentrations. If administration of a strong CYP3A4/5 inducer cannot be avoided in the 
combination arms during the study and cannot be switched to an alternative therapy, temporary 
discontinuation of study treatment is NOT needed.  
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. 
Grapefruit and grapefruit products are prohibited. 
6.2.2.2 
Prohibited concomitant medication for imatinib continuation arm 
Imatinib should be administered according to the locally approved product information. 
In addition, the following applies: 


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• Every effort should be made NOT to administer strong CYP3A4 inhibitors. If 
administration of a strong CYP3A4 inhibitor cannot be avoided during the study and cannot 
be switched to an alternative therapy, study treatment must be STOPPED. 
• Every effort should be made NOT to administer strong CYP3A4 inducers however, if 
administration of a CYP3A4 inducer cannot be avoided during the study, temporary 
discontinuation of study treatment is NOT required. 
6.2.2.3 
Prohibited concomitant medication for nilotinib treatment arm 
Nilotinib should be administered according to the locally approved product information. 
Furthermore, the following applies: 
Every effort should be made NOT to administer strong CYP3A4 inhibitors. If administration of 
a strong CYP3A4 inhibitor cannot be avoided during the study and cannot be switched to an 
alternative therapy, study treatment must be STOPPED. 
Every effort should be made NOT to administer strong CYP3A4 inducers however, if 
administration of a CYP3A4 inducer cannot be avoided during the study, temporary 
discontinuation of study treatment is NOT required. 
Whenever avoid co-administering drugs with a “Known”, “Possible” or “Conditional” risk of 
Torsades de Pointe (per crediblemeds.org) during the course of the study: 
• If concomitant administration of drugs with a “Known risk of Torsades de Pointe” 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 Pointe” is required, based on the investigator assessment 
and clinical need, study treatment may be continued under close ECG monitoring to ensure 
subject safety. 
A list of drugs associated with QT prolongation and/or Torsades de Pointe is available online 
at qtdrugs.org. 
If a medication listed in Section 16 appears on both the list of prohibited and the list of 
medications to be used with caution, the medication is prohibited. 
6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the subject is assigned to the next sequential Subject 
No. available.  
Once the subject number is assigned, it cannot be reused for any other subject. 


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6.3.2 
Treatment assignment, randomization 
Patients will be assigned to one of the 4 randomized treatment arms (Section 3) in a ratio of 
1:1:1:1.  
At visit “baseline”, all eligible patients will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms. The investigator or his/her delegate will contact the IRT 
after confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign 
a randomization number to the subject, which will be used to link the subject to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the subject. 
The randomization numbers will be generated using the following centralized procedure to 
ensure that treatment assignment is unbiased and concealed from patients and investigator staff. 
A subject randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of subject numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Drug Supply Management using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment. 
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Office. 
6.3.3 
Treatment assignment for asciminib single agent cohort 
Patients will be enrolled in asciminib single agent cohort without randomization. The IRT will 
assign a number to the subject, which will be used to link the subject to the treatment arm and 
will specify a unique medication number for the first package of study treatment to be dispensed 
to the subject. 
6.4 
Treatment blinding 
This is an open-label study. 
6.5 
Dose escalation and dose modification 
Dose escalation is not applicable. For dose re-escalation following dose reduction or 
interruption, please refer to Section 6.5.1. 
6.5.1 
Dose modifications 
6.5.1.1 
Criteria for dose reduction/interruption and re-initiation of study 
treatment for adverse drug reactions in asciminib + imatinib arm 
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 patients to continue 
the study treatment. 


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If a subject requires a dose interruption of > 28 days for a non-hematologic toxicity, then the 
subject must be discontinued from the study treatment, unless otherwise specified. 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. A subject must 
discontinue treatment if, after treatment is resumed at a lower dose, the toxicity recurs with the 
same or worse severity, except for recurrence of cytopenias (See Table 6-2).  
These dose modifications are summarized in Table 6-2. Deviations to mandatory dose 
interruptions and/or reductions are not allowed. Permanent treatment discontinuation is 
mandatory for specific events indicated as such in Table 6-2 . 
These dose changes must be recorded on the appropriate CRF. 
The following criteria apply to patients under asciminib + imatinib treatment. 
Table 6-2 
Criteria for dose reduction/interruption and re-initiation of asciminib + 
imatinib, or asciminib single agent treatment for adverse drug 
reactions 
Dose modifications for asciminib + imatinib and asciminib single agent 
Worst toxicity as per 
CTCAE version5a 
during treatment 
  
Investigations (Hematologic) 
Hematologic toxicities  
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. 
Grade 1 
Recommendation: maintain dose level 
Grade 2 
Recommendation: maintain dose level 
Grade 3 
Mandatory: Hold dose until resolved to ≤ Grade 2 (recheck CBC (Complete 
Blood Count) 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 
Mandatory: Hold dose until resolved to ≤ Grade 2 (recheck CBC 2x/week), 
then:  
If resolved in ≤ 14 days, then maintain dose level. 
If resolved in > 14 days, then reduce dose ↓ 1 dose level 
Recurrence of all 
cytopenias 
Recommendation: Hold dose until resolved to ≤ Grade 2, then maintain 
current dose level. 
For recurrent Grade 3-4 cytopenias: 
If resolved to ≤ Grade 2 in ≤ 14 days, then maintain dose level 
If resolved in > 14 days, then reduce dose ↓ 1 dose level 
Non-hematologic adverse reactions except where further specified in individual sections  
If a subject requires a dose interruption of > 28 days for a non-hematologic toxicity, then the subject 
must be discontinued from the study treatment, unless otherwise specified. 


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Grade 1 
Recommendation: Maintain dose level 
Grade 2 
Recommendation: Hold dose until resolved to ≤ Grade 1, then maintain 
dose level 
Grade 3 
Mandatory: Hold dose (max 28 days) until resolved to ≤ Grade 1 then 
resume at ↓ 1 dose level 
Grade 4 
Mandatory: Permanently discontinue subject from study drug treatment 
Investigations (Hepatic)  
Combinedc 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 
xULN] 
Mandatory: Permanently discontinue subject from 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 the Section 6.5.2 for 
additional follow-up evaluations as applicable. 
Isolated AST or ALT elevation 
> ULN - 3.0 x ULN 
Recommendation: Maintain dose level 
Repeat liver tests within 48- 72 hours, then monitor weekly until recovery to 
≤Grade 1 or to baseline 
> 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 
> 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 
> 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. 
> 20.0 x ULN 
Mandatory: Permanently discontinue 
Isolated total Bilirubin elevation 
> ULN – 1.5 x ULN 
Recommendation: Maintain dose level 


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> 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 
> 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 
> 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. 
Investigations (Renal) 
Serum creatinine 
Grade 1 (> ULN - 1.5 
x ULN) 
Recommendation: Maintain dose level 
Grade 2 (> 1.5 - 3.0 
x ULN) 
Recommendation: Hold dose until resolved to ≤ Grade 1 or baseline, then 
maintain dose level 
Grade 3 (> 3.0 - 6.0 
x ULN)  
Mandatory: Permanently discontinue patient from study drug treatment. 
Grade 4 (> 6.0 x 
ULN) 
Mandatory: Permanently discontinue patient from study drug treatment. 
Investigation (metabolic) 
Asymptomatic amylase and/or lipase elevation 
Grade 1 (> ULN - 1.5 
x ULN) 
Recommendation: Maintain dose level, measure 2x week 
Grade 2 (> 1.5 - 2.0 
x ULN) 
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). 
Grade 4 (> 5.0 x 
ULN) 
Mandatory: Permanently discontinue patient from study drug treatment. 
Obtain appropriate imaging (i.e., MRI, CT scan or ultrasound). 
Gastro intestinal 
Pancreatitis** 
Grade 2 (enzyme 
elevations with 
radiologic findings for 
pancreatitis as per 
CTCAE v5. For 
Mandatory: If radiologic findings, hold treatment until resolved to ≤ Grade 1 
or baseline.  
If treatment delay is ≤ 14 days, then reduce dose ↓ 1 dose level. 


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isolated increased 
enzymes please see 
table for 
asymptomatic 
amylase and/or 
lipase elevation) 
If treatment delay >14 days, discontinue treatment and appropriate imaging 
(i.e. MRI, CT scan or ultrasound) should be obtained. 
Grade ≥ 3 
Mandatory: Permanently discontinue subject from study drug treatment. 
Appropriate imaging (i.e. MRI, CT scan or ultrasound) should be obtained. 
Diarrhea*** 
Grade 1 
Recommendation: Maintain dose level but, initiate anti-diarrhea treatment 
Grade 2 
Recommendation: Hold dose until resolved to ≤ grade 1, then maintain 
dose level.  
If diarrhea returns as ≥ grade 2, then hold dose until resolved to ≤ grade 1, 
then reduce dose ↓ 1 dose level 
Grade 3 
Recommendation: Discontinue patient from study drug treatment 
Grade 4 
Mandatory: Permanently discontinue patient from study drug treatment 
Skin and subcutaneous tissue disorders 
Rash/photosensitivity 
Grade 1 
Recommendation: Maintain dose level.  
Consider to initiate appropriate skin toxicity therapy (such as antihistamines, 
topical corticosteroids and low-dose systemic corticosteroids) 
Grade 2 
Recommendation: Maintain dose level, but initiate/intensify appropriate 
skin toxicity therapy (such as antihistamines, topical corticosteroids and low-
dose systemic corticosteroids) 
Grade 3, despite skin 
toxicity therapy 
Recommendation: Hold dose until resolved to Grade ≤ 1, then: 
If resolved in ≤ 7 days, then reduce dose ↓ 1 dose level  
If resolved in > 7 days (despite appropriate skin toxicity therapy), then 
discontinue patient from study drug treatment 
Grade 4, despite skin 
toxicity therapy 
Mandatory: Permanently discontinue patient from study drug treatment. 
General disorders and administration site conditions 
Fatigue/ Asthenia 
Grade 1 or 2 
Recommendation: Maintain dose level 
Grade 3 
Recommendation: Hold dose until resolved to ≤ grade 1, then :  
If resolved in ≤ 7 days, then maintain dose level  
If resolved in > 7 days, then reduce dose ↓ 1 dose level 
All dose modifications should be based on the worst preceding toxicity. 
a Common Toxicity Criteria for Adverse Events (CTCAE Version 5) 
b Core Liver Function Tests (LFTs) consist of ALT, AST, GGT, 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 general non-hematologic toxicity and 
take a conservative action based on the degree of the elevations (e.g. discontinue treatment at the 
situation when omit dose is needed for one parameter and discontinue treatment is required for 


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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) 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 
Dose re-escalation for asciminib and imatinib 
Re-escalation to asciminib 60 mg QD or 40 mg QD, respectively, and imatinib 400 mg QD at 
the discretion of the investigator. Re-escalation will be allowed only once for any given subject 
on the asciminib + imatinib arms per protocol. 
Dose re-escalation for asciminib 80 mg QD single agent 
Re-escalation to asciminib 80 mg QD is permitted only once for any subject per protocol and 
only if there is a change in the subject's individual benefit/risk assessment at the lower dose 
level.  
Any dose changes must be recorded on the appropriate eCRF (Dosage Administration Record 
eCRF). 
Table 6-3 
Dose reduction for asciminib and imatinib 
Dose reduction* 
  
Starting dose level – 0 
Dose level – 1 
Asciminib (ABL001) 
60 mg (QD) 
40 mg (QD) 
Asciminib (ABL001) 
40 mg (QD) 
20 mg (QD)** 
* Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
** Dose reduction below 20 mg is not allowed. 
Dose reduction* 
  
Starting dose level – 0 
Dose level – 1 
Imatinib (STI571) 
400 mg (QD) 
300 mg (QD)** 
* Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
** Dose reduction below 300 mg is not allowed. 


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Table 6-4 
Dose reduction for asciminib single agent cohort  
Dose reduction* 
 
 
Asciminib (ABL001) 
Starting dose level – 0  
80 mg (QD) 
Dose level – 1  
40 mg (QD)** 
* Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
** Dose reduction below 40 mg (QD) is not allowed. 
6.5.1.2 
Criteria for dose reduction/interruption and re-initiation of imatinib for 
adverse drug reactions in imatinib continuation arm 
Dose reductions for imatinib should be done in accordance to locally approved product 
information for imatinib. 
6.5.1.3 
Criteria for dose reduction/interruption and re-initiation of nilotinib for 
adverse drug reactions 
Dose reductions for nilotinib should be done in accordance to locally approved product 
information for nilotinib. 
6.5.1.4 
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 prolongation. 
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. 
After confirming ECG reading at site, if QTcF > 500 msec 
1. Interrupt study treatment 
2. Repeat ECG and confirm ECG diagnosis by a cardiologist or central ECG lab 
3. If QTcF confirmed > 500 msec  
• Correct electrolytes, eliminate culprit concomitant medication, and identify clinical 
conditions that could potentially prolong the QT interval 
• Consult with a cardiologist (or qualified specialist) and increase cardiac monitoring as 
indicated, until QTcF returns ≤ 480 msec 
After resolution to ≤ 480 msec, consider reintroducing treatment at reduced dose, and increase 
ECG monitoring for the next treatment 


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1. If QTcF remains ≤ 500 msec after dose reduction, continue planned ECG monitoring during 
subsequent treatment 
2. If QTcF recurs > 500 msec after dose reduction, discontinue subject from trial 
Patients should be withdrawn from the study for any one of the following treatment-related, 
clinically significant safety findings, including, but not limited to: 
• Documented episode of ventricular tachycardia, or ventricular fibrillation 
• Complete heart block (Grade III AV block) or Second degree AV block Mobitz type II 
6.5.2 
Follow-up for toxicities 
Patients whose treatment is permanently discontinued due to a study drug related adverse event 
or clinically significant laboratory value should be followed up at least once a week for 4 weeks, 
until resolution or stabilization of the event, whichever comes first. Appropriate clinical experts 
such as ophthalmologist, endocrinologist, dermatologist, psychiatrists etc. should be consulted 
as deemed necessary. All patients must be followed up for adverse events and serious adverse 
events for 30 days following the last dose of study treatment. 
6.5.2.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Patients with transaminase increase combined with total bilirubin increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the subject’s baseline AST/ALT and total 
bilirubin value; patients meeting any of the following criteria will require further follow-up as 
outlined below: 
• For patients with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT > 3.0 x ULN combined with total bilirubin> 2.0 x ULN 
• For patients with elevated AST or ALT or total bilirubin value at baseline: [AST or ALT > 
2 x baseline AND > 3.0 x ULN] , combined with [total bilirubin > 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. 
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 
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, creatine kinase, total bilirubin, direct 
and 
indirect 
bilirubin, 
gamma-glutamyl-transferase 
(GGT), 
prothrombin 
time 
(PT)/International Normalized Ratio (INR) and alkaline phosphatase. 


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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 (for patients treated with asciminib + imatinib), as close as possible to 
last dose of study drug. 
5. Additional testing for other hepatotropic viral infection (CMV (Cytomegalovirus), EBV 
(Epstein–Barr virus) or HSV (Herpes simplex virus)), 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 and reported as SAE using the term “potential 
drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed. Compliance will be assessed 
by the investigator and/or study personnel at each visit using pill counts (if applicable at the 
visit) and information provided by the subject. This information should be captured in the 
source document at each visit. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log. Total daily dose of study treatment administered with start and 
end date will be collected on the dedicated eCRF page. 
Pharmacokinetic parameters (measures of treatment exposure) will be determined in the 20 
patients randomized to asciminib 60 mg QD as add-on therapy to imatinib 400 mg QD in the 
20 patients randomized to asciminib 40 mg QD as add-on therapy to imatinib 400 mg QD and 
in the 20 patients enrolled in the asciminib 80 mg QD single agent cohort, as detailed in 
pharmacokinetics section (Section 8.5.2). 
6.6.2 
Emergency breaking of assigned treatment code 
Not applicable. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. 
A unique medication number is printed on the study medication label. 


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Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). Responsible site personnel will identify the 
study treatment package(s) to dispense by the medication number(s) assigned by IRT to the 
subject. Site personnel will add the subject number on the label. If the label has 2 parts (base 
plus tear-off label), immediately before dispensing the package to the subject, site personnel 
will detach the outer part of the label from the package and affix it to the subject’s source 
document. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the imatinib and nilotinib labels and in the [Asciminib Investigator’s 
Brochure]. Clinical supplies are to be dispensed only in accordance with the protocol. Technical 
complaints are to be reported to the respective Novartis Country Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits and at the completion of the trial. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, and at the end of the study or at the 
time of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.  
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic, geopolitical situation or natural disaster, that limits or prevents on-site 
study visits, delivery of IMP directly to a subject's home may be permitted (if allowed by local 
or regional health authorities and ethics committees, as appropriate) in the event the Investigator 
has decided that an on-site visit by the subject is no longer appropriate or possible, and that it 
is in the interest of the subject's health to administer the study treatment even without 
performing an on-site visit. The dispatch of IMP from the site to the subject’s home remains 
under the accountability of the Investigator. Each shipment/provisioning will be for a maximum 
of 3 months supply. In this case, regular phone calls or virtual contacts (as needed) will occur 
between the site and the subject for instructional purposes, safety monitoring, investigation of 
any adverse events, ensuring patients continue to benefit from treatment, and discussion of the 
subject's health status until the patients can resume visits at the study site. 


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6.7.1.2 
Handling of additional treatment 
Not applicable. 
6.7.2 
Instruction for prescribing and taking study treatment 
Study treatment (asciminib, imatinib and nilotinib) 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 and a unique medication number (corresponding to study treatment and 
strength). 
Dose and treatment schedule are described in the Table 6-4 and all the information about the 
administration of the study drug are described in the  Section 6.1.3. Dose reductions can be 
performed as described in Table 6-3. 
Table 6-5 
Dose and treatment schedule 
Study Drug 
Dose 
Frequency 
Asciminib (ABL001) 
60 mg 
once daily 
Asciminib (ABL001) 
40 mg 
once daily 
Imatinib (STI571) 
400 mg 
once daily 
Nilotinib (AMN107) 
300 mg 
twice daily 
At baseline visit the patients will be randomized into one of the 4 arms, and the responsible site 
personnel will identify the study treatment package(s) to dispense by the medication number(s) 
assigned by IRT to the subject. 
Asciminib + Imatinib arms: asciminib 60 mg or 40 mg and imatinib 400 mg will be administered 
orally daily on a continuous schedule (QD). Asciminib and imatinib tablets should be ingested 
as follows: 
• Patients should take asciminib daily at approximately the same time each day in the morning, 
immediately followed by imatinib 400 mg administration. 
• On days that PK samples are obtained, the subject should take asciminib and imatinib during 
the clinic visit after the pre-dose PK samples, when instructed by the study staff. 
• Patients should take asciminib and imatinib with a low-fat meal and a large glass of water, 
approximately 240 mL (8 ounces) of water. A low-fat meal is defined as any meal with less 
than 20% fat and not more than 400 calories. 
• Patients should be instructed to swallow whole tablets and not to chew or to break them. 
• If vomiting occurs during the first hour after taking the drug, re-dosing is allowed before 
the next scheduled dose. 
• If the subject does not take asciminib and imatinib within 6 hours after the usual dosing 
time, that dose should be skipped and treatment should continue with the next daily dose at 
the prescribed level. 


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• Patients should 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. Consumption of the aforementioned fruits or juices containing the fruits may 
enhance and prolong the exposure of patients to the study treatment. 
• Patients should use sunblock when going out in the sun and avoid tanning beds. 
Imatinib arm: imatinib 400 mg tablets will be administered orally daily on a continuous 
schedule (QD). Imatinib tablets should be ingested as follows: 
• Patients should take imatinib daily at approximately the same time each day in the morning. 
• Patients should take imatinib with a low-fat meal and a large glass of water, approximately 
240 mL (8 ounces) of water. A low-fat meal is defined as any meal with less than 20% fat 
and not more than 400 calories. 
• Patients should be instructed to swallow whole tablets and not to chew or open them. 
• If vomiting occurs during the first hour after taking the drug, re-dosing is allowed before 
the next scheduled dose. 
• If the subject does not take imatinib within 6 hours after the usual dosing time, that dose 
should be skipped and treatment should continue with the next daily dose at the prescribed 
level. 
• Patients should 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. Consumption of the aforementioned fruits or juices containing the fruits may 
enhance and prolong the exposure of patients to the study treatment. 
• Patients must avoid concomitant intake of strong and moderate CYP3A4/5 inhibitors and 
inducers. 
• Patients should use sunblock when going out in the sun and avoid tanning beds. 
Nilotinib arm: nilotinib will be administered orally at 300 mg twice daily (BID). Nilotinib hard 
gelatin capsules for oral use should be ingested as follows: 
• Patients should take nilotinib daily at approximately the same time each day in the morning 
and in evening at approximately 12 hour intervals 
• Patients should take nilotinib on an empty stomach. No food should be consumed for two 
hours before and at least one hour after the dose is taken. Each dose may be taken with a 
glass of water, approximately 240 mL (8 ounces) of water. 
• Patients should be instructed to swallow whole capsules and not to chew or open them. 
• If vomiting occurs during the course of treatment, no re-dosing of the subject is allowed 
before the next scheduled dose. 
• If the subject does not take the drug within 6 hours after the usual dosing time, that dose 
should be skipped and treatment should continue with the next daily dose at the prescribed 
level. 
• Patients should 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 


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medications, due to potential CYP3A4 interaction with the study medications. Orange juice 
is allowed. Consumption of the aforementioned fruits or juices containing the fruits may 
enhance and prolong the exposure of patients to the study treatment. 
All dosages for all compounds prescribed and dispensed to the patients and all dose changes 
during the study must be recorded on the Dosage Administration Record eCRF. 
The patients randomized in the imatinib arm who have not achieved MR4.5 at 48 weeks may 
cross-over to receive the add-on treatment (asciminib 60 mg + imatinib) within 4 weeks after 
week 48 visit (Figure 3-1). 
Patients who choose to cross-over will have to perform the "CO baseline" visit; in the timeframe 
from week 48 to CO baseline visit, these patients will continue to take imatinib. At the CO 
baseline visit, they will be registered in the cross-over arm in the IRT system and will be 
dispensed the new medication number(s) of asciminib and imatinib. 
The patients who prefer to continue the imatinib treatment will continue to take imatinib until 
the end of treatment. 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
6.7.3 
Asciminib single agent cohort - Instruction for prescribing and taking 
study treatment 
Asciminib 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 and a unique medication number (corresponding to study treatment and 
strength). 
Asciminib single agent cohort: asciminib 80 mg will be administered orally daily on a 
continuous schedule (QD). Asciminib tablets should be ingested as follows: 
• Patients should take asciminib daily at approximately the same time each day in the morning. 
• On days that PK samples are obtained, the subject should take asciminib during the clinic 
visit after the pre-dose PK samples, when instructed by the study staff. 
• 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. 
• Subject should be instructed to swallow whole tablets and not to chew or to break them. 
• If vomiting occurs during the first hour after taking the drug, re-dosing is allowed before 
the next scheduled dose. 
• If the subject does not take asciminib within 12 hours after the usual dosing time, that dose 
should be skipped and treatment should continue with the next daily dose at the prescribed 
level.  


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All dosages for all compounds prescribed and dispensed to the patients and all dose changes 
during the study must be recorded on the Dosage Administration Record eCRF. All kits of study 
treatment assigned by the IRT will be recorded in the IRT system. 
7 
Informed consent procedures 
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-
approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Counsel for Harmonization Good Clinical Practice (ICH 
GCP) guidelines and regulatory requirements and is considered appropriate for this study. Any 
changes to the proposed consent form suggested by the investigator must be agreed by Novartis 
before submission to the IRB/IEC.  
Information about common side effects already known about the investigational drug can be 
found in the [Asciminib Investigator's Brochure] and/or the latest local approved product 
information for imatinib and nilotinib. This information will be included in the subject informed 
consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements while taking study 
treatment and for 14 days after stopping study medication in treatment arms 1 – 4, and for 3 
days after stopping asciminib single agent. If local regulations or locally approved prescribing 
information are more stringent than the protocol required duration of contraception, the longer 
duration must be followed. 
patientsAs per Section 4.6, during a public health emergency as declared by local or regional 
authorities i.e. pandemic, epidemic, geopolitical situation or natural disaster, that may challenge 
the ability to obtain a standard written informed consent due to limits that prevent an on-site 
visit, Investigator may conduct the informed consent discussion remotely (e.g. telephone, 
videoconference) if allowable by a local health authority. 


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Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial subject and person obtaining informed consent, etc.). 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
8 
Visit schedule and assessments 
Assessment schedule lists all of the assessments when they are performed. All data obtained 
from these assessments must be supported in the subject’s source documentation. 
Patients should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. 
Note: week 2, 4, 6, 8, and 10 visits are not mandatory for patients randomized to imatinib or 
nilotinib arms. 
For all visits, a ± 3 day visit window is allowed. 
Patients who prematurely discontinue the study for any reason should be scheduled for a visit 
as soon as possible, at which time all of the assessments listed for the final visit will be 
performed. At this final visit, all dispensed study drugs should be reconciled, and the adverse 
event and concomitant medications recorded on the CRF. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic, geopolitical situation or natural disaster that limits or prevents on-site 
study visits, alternative methods of providing continuing care may be implemented by the 
Investigator as the situation dictates. If allowable by a local health authority, national and local 
regulations and depending on operational capabilities, phone calls, virtual contacts (e.g. tele 
consultation) or visits by site staff/off-site healthcare professional(s) staff to the subject´s home, 
can replace certain protocol assessments, for the duration of the disruption until it is safe for the 
subject to visit the site again. If the Investigator delegates tasks to an off-site healthcare 
professional, the Investigator must ensure the individual(s) is/are qualified and appropriately 
trained to perform assigned duties. The Investigator must oversee their conduct and remain 
responsible for the evaluation of the data collected.


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Table 8-1 
Assessment Schedule, randomized treatment arms 1 – 4 and asciminib single agent cohort 
Period 
Screening 
Randomized Treatment 
End of 
Treatment 
Post-Treatment Follow-Up 
Visit Name 
Screening Baseline Week 
21 
Week 
41 
Week 
61 
Week 
81 
Week 
101 
Week 
12 
Week 
24 
Week 
36 
Week 
482 
Every 12 
weeks up 
to 96 / 48 
weeks after 
the first 
dose of the 
last 
randomized 
/ enrolled 
subject3 
End of 
Treatment4,5 
Safety Follow-
Up 
End of 
Study 
Visit4,5 
Days 
-21 to -1 
1 
14 
28 
42 
56 
70 
84 
168 
252 
336 
- 
Within last 
dose +14 
Last dose 
+30 days 
- 
Informed consent X 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
IWRS/IRT 
Registration 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
  
  
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
Inclusion / 
Exclusion criteria X 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
Medical 
history/current 
medical 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
  


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Period 
Screening 
Randomized Treatment 
End of 
Treatment 
Post-Treatment Follow-Up 
Visit Name 
Screening Baseline Week 
21 
Week 
41 
Week 
61 
Week 
81 
Week 
101 
Week 
12 
Week 
24 
Week 
36 
Week 
482 
Every 12 
weeks up 
to 96 / 48 
weeks after 
the first 
dose of the 
last 
randomized 
/ enrolled 
subject3 
End of 
Treatment4,5 
Safety Follow-
Up 
End of 
Study 
Visit4,5 
Days 
-21 to -1 
1 
14 
28 
42 
56 
70 
84 
168 
252 
336 
- 
Within last 
dose +14 
Last dose 
+30 days 
- 
Prior 
Antineoplastic 
Therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
Prior concomitant 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
Concomitant 
medications 
 
Ongoing basis 
  
Physical 
Examination 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
  
  
Extramedullary 
involvement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Body Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
Body Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  


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Period 
Screening 
Randomized Treatment 
End of 
Treatment 
Post-Treatment Follow-Up 
Visit Name 
Screening Baseline Week 
21 
Week 
41 
Week 
61 
Week 
81 
Week 
101 
Week 
12 
Week 
24 
Week 
36 
Week 
482 
Every 12 
weeks up 
to 96 / 48 
weeks after 
the first 
dose of the 
last 
randomized 
/ enrolled 
subject3 
End of 
Treatment4,5 
Safety Follow-
Up 
End of 
Study 
Visit4,5 
Days 
-21 to -1 
1 
14 
28 
42 
56 
70 
84 
168 
252 
336 
- 
Within last 
dose +14 
Last dose 
+30 days 
- 
Peripheral Blood 
BCR-ABL1 RT-
qPCR 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
  
  
Bone marrow 
assessment for 
cytogenetic 
assessment 
 
 
Upon Treatment Failure 
  
  
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Clinical Chemistry X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
HbA1c 
X 
 
 
 
 
 
 
X 
X 
 
X 
Week 72 
X 
  
  
Hepatitis screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
Pregnancy Test 
(serum) 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
  
  
Pregnancy Test 
(urine) 
 
 
S - Every 4 weeks if serum pregnancy test is not performed 
  
  


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Period 
Screening 
Randomized Treatment 
End of 
Treatment 
Post-Treatment Follow-Up 
Visit Name 
Screening Baseline Week 
21 
Week 
41 
Week 
61 
Week 
81 
Week 
101 
Week 
12 
Week 
24 
Week 
36 
Week 
482 
Every 12 
weeks up 
to 96 / 48 
weeks after 
the first 
dose of the 
last 
randomized 
/ enrolled 
subject3 
End of 
Treatment4,5 
Safety Follow-
Up 
End of 
Study 
Visit4,5 
Days 
-21 to -1 
1 
14 
28 
42 
56 
70 
84 
168 
252 
336 
- 
Within last 
dose +14 
Last dose 
+30 days 
- 
Electrocardiogram 
(ECG) 
X 
X 
X 
X 
 
 
 
X 
X 
 
X 
Every 48 
weeks up to 
96 weeks 
after the first 
dose of the 
last 
randomized 
/ enrolled 
subject 
X 
  
  
Adverse Events 
Ongoing basis 
  
Study drug 
dispensation 
  
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
  
  
Study drug 
administration 
  
Ongoing basis 
 
  
  
PK sampling 
(Asciminib + 
Imatinib arms and 
  
 
X 
X 
 
 
 
X 
X 
X 
 
Week 60 
and 96 
 
  
  


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Period 
Screening 
Randomized Treatment 
End of 
Treatment 
Post-Treatment Follow-Up 
Visit Name 
Screening Baseline Week 
21 
Week 
41 
Week 
61 
Week 
81 
Week 
101 
Week 
12 
Week 
24 
Week 
36 
Week 
482 
Every 12 
weeks up 
to 96 / 48 
weeks after 
the first 
dose of the 
last 
randomized 
/ enrolled 
subject3 
End of 
Treatment4,5 
Safety Follow-
Up 
End of 
Study 
Visit4,5 
Days 
-21 to -1 
1 
14 
28 
42 
56 
70 
84 
168 
252 
336 
- 
Within last 
dose +14 
Last dose 
+30 days 
- 
asciminib single 
agent cohort only) 
Whole blood for 
 
 by 
 
  
 
 
 
  
 
  
 
EORTC QLQ-C30 
plus CML24 
  
X 
 
X 
 
 
 
X 
X 
 
X 
Week 96 
 
  
  
TSQM  
  
X 
 
X 
 
 
 
X 
X 
 
X 
Week 96 
 
  
  
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Period 
Screening 
Randomized Treatment 
End of 
Treatment 
Post-Treatment Follow-Up 
Visit Name 
Screening Baseline Week 
21 
Week 
41 
Week 
61 
Week 
81 
Week 
101 
Week 
12 
Week 
24 
Week 
36 
Week 
482 
Every 12 
weeks up 
to 96 / 48 
weeks after 
the first 
dose of the 
last 
randomized 
/ enrolled 
subject3 
End of 
Treatment4,5 
Safety Follow-
Up 
End of 
Study 
Visit4,5 
Days 
-21 to -1 
1 
14 
28 
42 
56 
70 
84 
168 
252 
336 
- 
Within last 
dose +14 
Last dose 
+30 days 
- 
FACIT GP5 
  
X 
 
X 
 
 
 
X 
X 
 
X 
Week 96 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
  
  
  
  
  
  
  
  
  
  
  
  
 
X 
 
Disposition 
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Not mandatory visits for patients in imatinib and nilotinib arm 
2 Patients in imatinib continuation arm may cross-over to receive asciminib+imatinib after Week 48 visit 
3 Asciminib single agent cohort, every 12 weeks up to 48 weeks after the first dose of the last enrolled subject 
4 Treatment arms 1 – 4: the study treatment will end at 96 weeks (plus 30 days for the safety follow up) after the last randomized subject received the first dose 
of study treatment. 
5 Asciminib single agent cohort: the study treatment will end at 48 weeks (plus 30 days for the safety follow up) after the last enrolled subject received the first 
dose of study treatment 


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Period 
Screening 
Randomized Treatment 
End of 
Treatment 
Post-Treatment Follow-Up 
Visit Name 
Screening Baseline Week 
21 
Week 
41 
Week 
61 
Week 
81 
Week 
101 
Week 
12 
Week 
24 
Week 
36 
Week 
482 
Every 12 
weeks up 
to 96 / 48 
weeks after 
the first 
dose of the 
last 
randomized 
/ enrolled 
subject3 
End of 
Treatment4,5 
Safety Follow-
Up 
End of 
Study 
Visit4,5 
Days 
-21 to -1 
1 
14 
28 
42 
56 
70 
84 
168 
252 
336 
- 
Within last 
dose +14 
Last dose 
+30 days 
- 
6 Whole blood for 
 by 
 will NOT be collected in asciminib single agent cohort. 
 
CCI
CCI


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Table 8-2 
Assessment Schedule, patients randomized to the continued imatinib arm who cross-over to receive asciminib 
60 mg + imatinib 
Period 
Cross-Over 
Baseline 
Cross-Over Treatment 
End of 
Treatment 
Post-Treatment 
Follow-Up 
Visit Name 
CO Baseline1 
CO 
Week 2 
CO 
Week 4 
CO 
Week 6 
CO 
Week 8 
CO 
Week 
10 
Start from 12 weeks after 
cross-over, every 12 weeks up 
to 96 weeks after the first dose 
of the last randomized subject 
End of 
Treatment 
Safety 
Follow-Up 
End of 
Study 
Days 
1 
14 
28 
42 
56 
70 
- 
Within last 
dose +14 
Last dose 
+30 
- 
IWRS/IRT 
Registration 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
Concomitant 
medications 
Ongoing basis 
  
Physical 
Examination 
S 
S 
S 
S 
S 
S 
S 
S 
 
  
Extramedullary 
involvement 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
Body Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
Peripheral Blood 
BCR-ABL1 RT-
qPCR 
 
 
X 
 
X 
 
X 
X 
 
  
Bone marrow 
assessment for 
cytogenetic 
assessment 
Upon Treatment failure 
 
  
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
Clinical Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
 
  


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Period 
Cross-Over 
Baseline 
Cross-Over Treatment 
End of 
Treatment 
Post-Treatment 
Follow-Up 
Visit Name 
CO Baseline1 
CO 
Week 2 
CO 
Week 4 
CO 
Week 6 
CO 
Week 8 
CO 
Week 
10 
Start from 12 weeks after 
cross-over, every 12 weeks up 
to 96 weeks after the first dose 
of the last randomized subject 
End of 
Treatment 
Safety 
Follow-Up 
End of 
Study 
Days 
1 
14 
28 
42 
56 
70 
- 
Within last 
dose +14 
Last dose 
+30 
- 
HbA1c 
 
 
 
 
 
 
12, 24, 48 and 72 weeks after 
cross-over 
X 
 
  
Pregnancy Test 
(serum) 
X 
 
X 
 
X 
 
X 
X 
 
  
Pregnancy Test 
(urine) 
S - Every 4 weeks if serum pregnancy test is not performed 
 
  
Electrocardiogram 
(ECG) 
X 
X 
X 
 
 
 
12, 24, 48 weeks after 
cross-over and every 48 weeks 
up to 96 weeks after the first 
dose of the last randomized 
subject 
X 
 
 
Adverse Events 
Ongoing basis 
 
Study drug 
dispensation 
X 
 
 
 
 
 
X 
 
 
 
Study drug 
administration 
Ongoing basis 
 
 
 
EORTC QLQ-C30 
plus CML24 
 
 
 
 
 
 
CO week 48, CO Week 96 
 
 
 
TSQM  
 
 
 
 
 
 
CO Week 48, CO Week 96 
 
 
 
FACIT GP5 
 
 
 
 
 
 
CO Week 48, CO Week 96 
 
 
 
Antineoplastic 
therapies since 
 
 
 
 
 
 
 
 
X 
 


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Period 
Cross-Over 
Baseline 
Cross-Over Treatment 
End of 
Treatment 
Post-Treatment 
Follow-Up 
Visit Name 
CO Baseline1 
CO 
Week 2 
CO 
Week 4 
CO 
Week 6 
CO 
Week 8 
CO 
Week 
10 
Start from 12 weeks after 
cross-over, every 12 weeks up 
to 96 weeks after the first dose 
of the last randomized subject 
End of 
Treatment 
Safety 
Follow-Up 
End of 
Study 
Days 
1 
14 
28 
42 
56 
70 
- 
Within last 
dose +14 
Last dose 
+30 
- 
discontinuation of 
study treatment 
Disposition 
 
 
 
 
 
 
 
X 
 
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 If the cross-over treatment starts within 7 days from Week 48 visit, it is not required to perform again hematology, chemistry and serum pregnancy test 
as well as the ECG assessments at the CO Baseline visit. 


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8.1 
Screening 
Written informed consent must be obtained before any study specific medical procedures are 
performed. 
All screening/baseline assessments should occur within 21 days before randomization. 
Screening assessments include: physical examination, extramedullary involvement, vital signs, 
body height and weight, ECG, laboratory (hematology, biochemistry, hemoglobin A1c 
(HbA1c), Hepatitis screen, serum pregnancy test, peripheral blood collection for BCR-ABL1 
RT-qPCR), evaluation of all relevant medical history including cardiovascular risk factors, 
CML disease history, including prior TKI therapy, antineoplastic medication, prior and 
concomitant medication and must be performed prior to randomization. For details of 
assessments required during screening please refer to Table 8-1. 
During the screening visit, inclusion and exclusion criteria will be assessed. Screening 
assessments to confirm eligibility must be performed prior to randomization. 
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 randomization.  
The central reading of the screening ECGs as well as the results of the BCR-ABL1 RT-qPCR, 
hematology, chemistry and hepatitis screen must be available prior to randomization to evaluate 
eligibility. 
A subject who has a laboratory test (peripheral blood test) or ECG results that do not satisfy the 
entrance criteria may have the tests repeated. These tests may be repeated as soon as the 
investigator believes the re-test results are likely to be within the acceptable range to satisfy the 
entrance criteria, but should be completed within the 21 day screening period. In this case, the 
subject will not be required to sign another ICF, and the original subject identification (ID) 
number assigned by the investigator will be used. 
In the event that the laboratory tests cannot be performed within the screening visit window, or 
the re-tests do not meet the entrance criteria, or other eligibility criteria have changed and are 
not met anymore, the subject 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 subject after 
a subject has screen failed and the subject will be assigned a new subject ID number. All 
required screening activities must be performed when the subject is re-screened for participation 
in the study. An individual subject 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. 
8.1.1 
Eligibility screening 
Following registering in the IRT for screening, subject eligibility check will be embedded in 
the IRT system by an eligibility transaction. The eligibility will be confirmed in the IRT after 


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screening procedures and prior to randomization visit. Please refer and comply with detailed 
guidelines in the IRT manual. 
8.1.2 
Information to be collected on screening failures 
Patients who sign an informed consent and subsequently are found to be ineligible prior to 
randomization for treatment arms 1- 4, and prior to enrollment for asciminib single agent cohort 
will be considered a screen failure. 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 subject 
experienced a serious adverse event during the screening phase (see SAE section for reporting 
details). If the subject fails to be randomized or enrolled, the IRT must be notified within 2 days 
of the screen fail that the subject was not randomized or enrolled. 
8.2 
Subject demographics/other baseline characteristics 
Subject demographic and baseline characteristic data to be collected on all patients include: age, 
gender, race, ethnicity, height, weight, source of subject referral, relevant medical 
history/current medical condition present before signing informed consent where possible, 
CML disease history, and prior and concomitant medication including prior TKI therapy and 
antineoplastic medication. Diagnoses and not symptoms will be recorded. 
Baseline assessments include: physical examination, extramedullary involvement, vital signs, 
body weight, ECG, laboratory (hematology, biochemistry, serum pregnancy test, blood 
collection for BCR-ABL1 mutational analysis), biomarker assessments and PROs. 
If the baseline assessments will be performed within 7 days from screening, it is not required to 
perform again the hematology, chemistry and serum pregnancy test as well as the ECG 
assessments. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. Significant new findings that begin or worsen after informed consent must be 
recorded on the AE page of the subject’s eCRF. 
8.3 
Efficacy 
8.3.1 
Molecular response and BCR::ABL1 RT-qPCR 
Molecular response (MR) will be assessed in all patients randomized to each treatment arm. 
Levels of BCR::ABL1 transcripts will be determined by real-time quantitative PCR (RT-qPCR) 
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 (IS), will be calculated for each sample. 
Major molecular response and related variables are defined as the following: 
• MMR: BCR::ABL ≤ 0.1% (IS) 


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• MR4.0: BCR::ABL ≤ 0.01% (IS) 
• MR4.5: BCR::ABL ≤0.0032% (IS) 
Unconfirmed loss of MMR is defined as increase of BCR::ABL to > 0.1% by International 
Scale (IS) in association with 5-fold rise in the BCR::ABL from the lowest value achieved on 
study treatment and confirmed by a duplicate analysis of the same sample. Loss of MMR is 
confirmed by a subsequent analysis of a sample collected within 4-6 weeks unless the loss of 
MMR is associated with confirmed loss of CHR, loss of CCyR, progression to AP/BC, or CML-
related death. 
Upon confirmed loss of MMR by RT-qPCR, mutation analysis will be performed at a 
designated laboratory by Sanger sequencing using remnant RNA from sample already collected 
and tested for RT-qPCR. 
BCR::ABL1 RT-qPCR analysis will be performed at a designated laboratory at screening, 
Week 4 (if applicable), Week 8 (if applicable), Week 12, 24, 36, 48, every 12 weeks up to 96 
weeks after the first dose of the last randomized subject and at end of treatment; for the 
cross-over arm at CO Week 4, 8, start from 12 weeks after cross-over, every 12 weeks up to 96 
weeks after the first dose of the last randomized subject and at end of treatment. 
The blood samples will be taken as described in Table 8-3 and Table 8-4. 
Table 8-3 
Blood samples for PCR (primary and secondary efficacy endpoints) in 
all randomized treatment arms 1- 4, and asciminib single agent cohort  
Sample Type 
Volume 
Visit 
Time point 
Blood for BCR::ABL 
quantification by RT-
qPCR 
20 mL 
Screening 
Pre-dose 
20 mL 
Week 4* 
Pre-dose 
20 mL 
Week 8* 
Pre-dose 
20 mL 
Week 12 
Pre-dose 
20 mL 
Week 24 
Pre-dose 
20 mL 
Week 36 
Pre-dose 
20 mL 
Week 48 
Pre-dose 
20 mL 
Every 12 weeks up to 
96 / 48 weeks after the 
first dose of the last 
randomized / enrolled 
subject** 
Pre-dose 
20 mL 
End of Treatment 
Anytime 
*Not mandatory visits for patients in Imatinib and Nilotinib arm 
**Asciminib single agent cohort, every 12 weeks up to 48 weeks after the first dose of the last enrolled 
subject  
Table 8-4 
Blood samples for PCR in cross-over 
Sample Type 
Volume 
Visit 
Time point 
20 mL 
CO Week 4 
Pre-dose 
20 mL 
CO Week 8 
Pre-dose 


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Blood for BCR::ABL 
quantification by RT-
qPCR 
20 mL 
Start from 12 weeks 
after cross-over, every 
12 weeks up to 96 
weeks after the first 
dose of the last 
randomized subject 
Pre-dose 
20 mL 
End of Treatment 
Anytime 
8.3.2 
Bone marrow analysis and cytogenetics 
Bone marrow aspirate for cytogenetic analyses will be performed only upon treatment failure 
(for definition of treatment failure, see Section 9.1.1). 
Quantification of the number of metaphases assessed, number of metaphases positive for Ph 
chromosome, additional chromosomal abnormalities as well as data from microscopic analysis 
of percentage of blasts and promyelocytes will be recorded on the Bone Marrow and 
cytogenetics eCRF. These exams will be performed and analyzed locally. Fluorescent In-situ 
hybridization (FISH) analysis will not be accepted. 
8.3.3 
Appropriateness of efficacy assessments 
Assessing molecular response with RT-qPCR is considered as standard in CML therapy and 
recommended in treatment guidelines (Baccarani et al 2013, NCCN 2018). It is acknowledged 
that response can be assessed using only standardized results via International Scale (IS) as 
BCR::ABL%. Mutational analysis is required in case of treatment failure. Cytogenetic 
assessment is required in case of treatment failure (Baccarani et al 2013, Baccarani et al 2015). 
8.4 
Safety and  tolerability 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to AE section. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic, geopolitical situation or natural disaster, that limits or prevents on-site 
study visits, regular phone or virtual calls can occur (as needed) for safety monitoring and 
discussion of the subject´s health status until it is safe for the subject to visit the site again. 
Table 8-5 
Safety and tolerability assessments 
Assessment 
Specification 
Physical 
examination 
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, vascular, and neurological. 
Information for all physical examinations must be included in the source 
documentation at the study site as unique source data, this information will 
not be captured in the CRF. Clinically relevant findings that are present prior 
to signing informed consent must be included in the Medical History part of 
the CRF. Significant findings made after first administration of study drug 


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Assessment 
Specification 
which meet the definition of an Adverse Event must be recorded on the 
Adverse Event section of the CRF. 
Physical examination will be evaluated during each performed visit. 
Extramedullary 
involvement 
Presence of extramedullary leukemic involvement will be checked with each 
physical examination as outlined above. Findings on physical examination 
consistent with extra-medullary leukemic involvement will be recorded (e.g. 
any organ involvement). With regards to lymph nodes, only those palpable 
lymph nodes should be considered to be CML related if leukemic blast 
infiltration has been confirmed via biopsy/histology or by technically adequate 
aspiration cytology. When extramedullary involvement other than of the 
spleen or liver is the only evidence of blast crisis, this finding must be 
confirmed by technically adequate (not contaminated with peripheral blood) 
aspiration cytology and/or biopsy (especially for isolated lymph nodes) and 
data entered into the extramedullary involvement eCRF. 
Extramedullary involvement will be evaluated during each performed visit. 
Vital signs 
Vital signs include systolic and diastolic blood pressure (supine position 
preferred when ECG is collected), pulse rate measurement, and body 
temperature. 
Vital signs will be evaluated during each performed visit. 
Height and weight 
Height in inches or centimeters (cm) and body weight (in pounds or to the 
nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be 
measured. 
Body height will be evaluated only during screening visit. 
Body weight will be evaluated during each performed visit. 
8.4.1 
Laboratory evaluations 
Central laboratory will be used for analysis of hematology, biochemistry, serum pregnancy and 
hepatitis marker specimens collected (safety monitoring). Details on the collections, shipment 
of the samples and reporting of results by the central laboratory are provided to investigators in 
the [CABL001E2201 laboratory manual]. The time windows granted for laboratory evaluations 
are identical with the corresponding visit time windows for each visit (see Section 8). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 1) they induce clinical signs or symptoms, 2) they are considered 
clinically significant, or 3) they require concomitant therapy or procedures. Clinically 
significant abnormal laboratory values or test results should be identified through a review of 
values outside of normal ranges/clinically notable ranges, significant changes from screening 
or the previous visit. 
Unscheduled local laboratory assessments may be performed if medically indicated to assess a 
(potential) adverse event or when the treating physician cannot wait for central laboratory 
results for decision making (e.g. therapeutic intervention, interruption of study treatment). In 
this particular situation, if possible, the blood sample obtained at the same time point should 
be submitted to the central laboratory for analysis in parallel with local analysis. The results of 
the local laboratory will be recorded in the eCRF if any of the following criteria are met: 
• A treatment decision was made based on the local results, or 


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• Local lab results document an adverse event not reported by the central lab, or 
• Local lab results document an adverse event severity is worse than the one reported by the 
central lab, or 
• There are no concomitant central results available 
For assessment of patients’ eligibility to the study, only laboratory results from 
the central laboratory will be used. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities’ 
i.e. pandemic, epidemic, geopolitical situation or natural disaster, that limits or prevents on-site 
study visits, if patients cannot visit the site for protocol specified safety lab assessments during 
the trial, an alternative lab (local) collection site may be used. 
At any time during the study, abnormal laboratory parameters which are clinically relevant and 
require an action to be taken with study treatment (e.g., require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the AE 
eCRF page. Laboratory data will be summarized using the Common Terminology Criteria for 
Adverse events (CTCAE) version 5. Additional analyses are left to the discretion of the 
investigator. 
Novartis must be provided with a copy of the local laboratory’s certification (if applicable), and 
a tabulation of the normal ranges and units of each parameter collected in the CRF. Any changes 
regarding normal ranges and units for laboratory values assessed during the study must be 
reported via an updated tabulation indicating the date of revalidation. Additionally, if at any 
time a patient has laboratory parameters obtained from a different laboratory, Novartis must be 
provided with a copy of the certification and a tabulation of the normal ranges and units for this 
laboratory as well. The investigator is responsible for reviewing all laboratory reports for 
patients in the study and evaluating any abnormalities for clinical significance. 
Table 8-6 
Laboratory  assessments 
Test 
Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Mean Corpuscular Hemoglobin (MCH), Mean 
Corpuscular Hemoglobin Concentration (MCHC), Mean Corpuscular 
Volume (MCV), Platelets, Red blood cells, White blood cells, Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Blasts, 
Promyelocytes, Myelocytes, Metamyelocytes, Bands) 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Total Calcium, Magnesium, Phosphorus, Sodium, 
Potassium, Creatinine, Creatine kinase, Direct Bilirubin, Indirect Bilirubin, Total 
Bilirubin, Total Cholesterol, Low Density Lipoprotein (LDL), High Density 
Lipoprotein (HDL), Total Protein, Triglycerides, Blood Urea Nitrogen (BUN) or Urea, 
Uric Acid, Amylase, Lipase, Glucose (fasting), Hemoglobin A1c 
Hepatitis 
markers 
HBsAg, anti-HBc 


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Test 
Category 
Test Name 
Pregnancy 
Test* 
Serum beta fraction of human chorionic gonadotropin (ß-HCG) testing 
* For details on pregnancy testing, please refer to Section 8.4.3. 
8.4.1.1 
Hematology 
Hematology assessments have to be analyzed at each scheduled visit by a central laboratory, 
according to Table 8-1 and Table 8-2. For details of the Hematology panel refer to Table 8-6. 
8.4.1.2 
Clinical  chemistry 
Clinical chemistry assessments have to be analyzed by a central laboratory, according to  
Table 8-1 and Table 8-2. For details of the clinical chemistry panel refer to Table 8-6 . 
Clinical chemistry assessments have to be analyzed at each scheduled visit. 
HbA1c assessment has to be analyzed as reported below: 
• Randomized treatment: Screening, Week 12, 24, 48, 72 and End of Treatment. 
• Crossover treatment: CO Week 12, 24, 48, 72 and End of Treatment. 
The hepatitis markers are analyzed only at screening visit. 
8.4.2 
Electrocardiogram (ECG) 
ECGs should be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. The Fridericia QT correction formula (QTcF) 
should be used for clinical decisions. 
Three serial ECGs (triplicate) should be performed half an hour prior to dosing for pre-dose 
assessment and prior to any PK blood draws scheduled for the visit. The serial ECGs should be 
taken approximately 5 minutes apart. After the subject has rested approximately 10 minutes in 
a supine position, three sequential standard 12-lead ECGs (triplicate) must be obtained with a 
recommended minimal interval of 5 minutes between each ECG at the time points specified in 
Table 8-1, Table 8-2, for details please refer to Table 8-7 and Table 8-8. 
These three sequential 12-lead ECGs are to be collected with ECG machines supplied by the 
central laboratory (eRT) and all three ECGs for each time point should be sent to eRT. 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 
[CABL001E2201 ECG Manual]. 
For any ECG with subject safety concerns, two additional ECGs must be performed as soon as 
possible to confirm the safety finding. A monitoring or review process should be in place for 
clinically significant ECG findings throughout the study and especially at baseline before 
administration of study treatment. 


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Readings for QTc prolongation will be based on the average seen in the scans for each time 
point. The enrollment of patients has to be based on centrally assessed QTcF time. If one of the 
3 serial ECGs prior to dosing on day 1 shows a QTcF ≥ 450 msec (male) or ≥ 460 msec (female) 
by automated reading, an immediate manual central reading must be requested by calling eRT. 
The subject may not be dosed if the average of the manually read ECGs confirms a QTcF ≥ 450 
msec (male) or ≥ 460 msec (female). 
In the event that a clinically significant ECG abnormality is identified at the site (e.g. severe 
arrhythmia, conduction abnormality of QTcF > 500 msec), a copy of the assessment is sent to 
the core laboratory for expedited review if applicable, and the ECG is repeated to confirm the 
diagnosis. If the subject is hemodynamically compromised, the investigator or a medically 
qualified person must initiate appropriate safety procedures without delay (for example 
cardioversion). 
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate. 
A standard 12 lead ECG will be performed at the following time points. 
Randomized treatment arms 1 – 4, asciminib single agent cohort: 
• at screening and baseline 
• at Week 2, 4, 12, 24, 48, every 48 weeks until the end of treatment 
• at the end of treatment 
Cross-over treatment: 
• at CO baseline, CO Week 2, 4, 12, 24, 48, every 48 weeks until the end of treatment 
• at the end of treatment 
Table 8-7 
Central ECG collection plan in all randomized treatment arms 1- 4, and 
asciminib single agent cohort 
Week 
Day 
Time 
ECG Type 
Screening 
-21 to -1 
Anytime 
12 Lead, triplicate 
Baseline 
1 
Pre-dose, *Post-dose 
2 hours 
12 Lead, triplicate 
Week 2** 
14 
Pre-dose, *Post-dose 
2 hours, 3 hours, 4 
hours 
12 Lead, triplicate 
Week 4** 
28 
Pre-dose, *Post-dose 
2 hours, 3 hours, 4 
hours 
12 Lead, triplicate 
Week 12 
84 
Pre-dose 
12 Lead, triplicate 
Week 24 
168 
Pre-dose 
12 Lead, triplicate 
Week 48 
336 
Pre-dose 
12 Lead, triplicate 
Every 48 weeks up to 
96 weeks after the first 
dose of the last 
- 
Pre-dose 
12 Lead, triplicate 


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Week 
Day 
Time 
ECG Type 
randomized / enrolled 
subject 
EOT 
- 
Pre-dose 
12 Lead, triplicate 
Unscheduled ECG 
- 
Anytime 
12 Lead, triplicate 
*Post-dose ECGs for asciminib + imatinib arms, and asciminib single agent cohort only 
** Not mandatory visits for patients in imatinib and nilotinib arm 
Table 8-8 
Central ECG collection plan in cross-over 
Week 
Day 
Time 
ECG Type 
Baseline cross-over 
1 
Pre-dose, Post-dose 2 
hours 
12 Lead, triplicate 
2 weeks after 
cross-over 
14 
Pre-dose, Post-dose 2 
hours, 3 hours, 4 
hours 
12 Lead, triplicate 
4 weeks after 
cross-over 
28 
Pre-dose, Post-dose 2 
hours, 3 hours, 4 
hours 
12 Lead, triplicate 
12 weeks after 
cross-over 
84 
Pre-dose 
12 Lead, triplicate 
24 weeks after 
cross-over 
168 
Pre-dose 
12 Lead, triplicate 
48 weeks after 
cross-over 
336 
Pre-dose 
12 Lead, triplicate 
Every 48 weeks up to 
96 weeks after the first 
dose of the last 
randomized subject 
- 
Pre-dose 
12 Lead, triplicate 
EOT 
- 
Pre-dose 
12 Lead, triplicate 
Unscheduled ECG 
- 
Anytime 
12 Lead, triplicate 
In order to enable ECG evaluation by the central laboratory for eligibility assessment, ECGs 
should be submitted to the ECG core laboratory in adequate time prior to the planned 
randomization date. 
In the event that a QTcF value of > 500 msec is observed or if an unscheduled ECG is performed 
for safety reasons, it is recommended to collect a time-matched PK sample and record the time 
and date of the last study drug intake to determine the drug exposure. Dose adjustments in case 
of QT prolongation should be performed per  Section 6.5.1.4. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the investigator. 
All ECGs, including unscheduled triplicate safety ECGs with clinically relevant findings, 
collected during the study should be transmitted to the central core ECG laboratory for review. 


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The results of the centrally assessed ECGs are automatically transferred into the clinical 
database. 
8.4.3 
Pregnancy and assessments of fertility 
All women of childbearing potential have to complete a serum pregnancy test (Serum ß-HCG) 
as indicated in Table 8-1 and Table 8-2. 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.  
Serum pregnancy assessments have to be analyzed by a central laboratory, according to  
Table 8-1 and Table 8-2, during the following time points: 
• Randomized treatment: screening, baseline, Week 4 (if applicable), Week 8 (if applicable), 
and at each visit from Week 12 onwards until the end of treatment. 
• Crossover treatment: CO baseline (if the crossover treatment starts within 7 days from Week 
48 visit, it is not required to perform serum pregnancy test again), CO Week 4, CO Week 8 
and at each visit from CO Week 12 onwards until the end of treatment. 
Urine pregnancy tests have to be performed at home every 4 weeks if serum pregnancy test is 
not performed. Test results performed at home should be recorded onto a subject diary and 
brought to each scheduled visit for the site to review. Information for urine pregnancy test must 
be included in the source documentation at the study site as unique source data, this information 
will not be captured in the CRF. If a test result indicates a pregnancy, the subject must contact 
the investigator immediately. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities’ 
i.e. pandemic, epidemic, geopolitical situation or natural disaster, that limits or prevents on-site 
study visits, if participants cannot visit the site to have serum pregnancy tests, urine pregnancy 
test kits may be used. Relevant patients can perform the urine pregnancy test at home and report 
the result to the site. It is important that patients are instructed to perform the urine pregnancy 
test first and only if the test result is negative proceed with the administration of the study 
treatment. A communication process should be established with the subject so that the site is 
informed and can verify the pregnancy test results (e.g., following country specific measures). 
All pregnancies 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 5.2. 
A woman is considered of childbearing potential from menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Medical documentation of 
oophorectomy, hysterectomy, or bilateral tubal ligation must be retained as source documents. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile. 


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In absence of the medical documentation, confirming permanent sterilization, or if the post-
menopausal status is not clear, the investigator should use his medical judgment to appropriately 
evaluate the fertility state of the woman and document it in the source document.. 
8.4.4 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/subject population. 
8.5 
Additional assessments 
The following additional assessments will be performed on patients entered into this study: 
• Patient Reported Outcomes 
• Pharmacokinetics 
• Biomarker 
8.5.1 
Clinical Outcome Assessments (COAs) 
Patient Reported Outcomes (PRO) 
The following PROs will be used: 
• European organization for research and treatment of cancer - quality of life questionnaire 
(EORTC QLQ-C30 and EORTC QLQ-CML24) 
• Functional assessment of chronic illness therapy - general population 5 (FACIT GP5) 
• Treatment satisfaction questionnaire for medication (TSQM) 
These questionnaires will capture data on the patient-reported outcome measures of health-
related quality-of life, treatment satisfactions and treatment-related side effects per Section 8 . 
The TSQM Version 1.4 will be used to assess how satisfied the subject is with treatment overall 
and FACIT GP5 to assess treatment-related side effects. All tools require subject’s direct 
completion and will be administered utilizing a tablet provided by a third party vendor. Data 
transfers of cleaned data will be performed by the PRO vendor. 
All questionnaires should be administered in the language most familiar to the subject at the 
beginning of scheduled visit prior to any interaction with the study investigator including any 
tests, treatments or receipt of results from any tests to avoid biasing the subject’s perspective. 
At baseline, the questionnaire(s) will be applied prior to randomization. This is to avoid 
potentially biasing patients or their responses to study questionnaires. 
The subject 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. Attempts should be made to 
collect responses to all questionnaires for all patients, however, if patients refuse to complete 
all or any part of a questionnaire, this should be documented in the study data capture system 
and should not be captured as a protocol deviation. 
Completed questionnaire(s) 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 


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investigators should not encourage the subject to change responses reported in the completed 
questionnaires. 
Study 
investigators 
must 
follow 
reporting 
instructions 
outlined 
in  Section 10  (e.g. reference “Adverse Events” section) of the study protocol. 
PRO assessments have to be performed from all patients during the treatment period, but not 
from patients who discontinue from study treatment. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic, geopolitical situation or natural disaster, that limits or prevents on-site 
study visits, COA data may be collected remotely. 
For PRO time points, please refer to Table 8-1 and Table 8-2. 
The PRO measure(s) should be completed in the following order: EORTC QLQ-C30, EORTC 
QLQ-CML24, TSQM and FACIT GP5.  
8.5.1.1 
EORTC QLQ-C30 and EORTC QLQ-CML24 
The EORTC QLQ-C30 Version 3.0 is a questionnaire developed to assess the quality of life of 
cancer patients which has been translated and validated into 81 languages and has been used in 
more than 3000 studies worldwide. The EORTC contains 30 items and is composed of both 
multi-item scales and single-item measures. These include five functional scales (physical, role, 
emotional, cognitive and social functioning), three symptom scales (fatigue, nausea and 
vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea 
and financial impact) and a global health status and QoL scale (Aaronson et al 1993). The 
EORTC QLQ-CML24 (Efficace et al 2014) is used in conjunction with the EORTC QLQ-C30 
and provides information on an additional 24 items specifically related to chronic myeloid 
leukemia. The QLQ-CML24 incorporates four multi-item scales assessing symptom burden (13 
items), impact on worry/mood (4 items), impact on daily life (3 items), and satisfaction with 
care and information (2 items), as well as two single items assessing body image problems and 
satisfaction with social life. For countries where the EORTC QLQ-CML24 will not be available, 
because of missing language validation, it will not be completed by the patients. Those 
questionnaires will be locked within the application and will not be available for completion. 
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. Thus a high score for a functional scale represents a 
high/healthy level of functioning; a high score for the global health status/QoL represents a high 
QoL, but a high score for a symptom scale/item represents a high level of 
symptomatology/problems. All scoring will follow the scoring procedures defined by the 
EORTC Scoring Manual (Fayers 2001). 
8.5.1.2 
TSQM 
The 14-item Treatment Satisfaction Questionnaire for Medication (TSQM, Version 1.4) is a 
generic, multidimensional, self-administered measure of patient satisfaction with a medication. 
The instrument has 14 items measuring four domains: effectiveness, side effects, convenience, 
and global satisfaction. Domain scores range from 0 to 100, with a higher score indicating 
higher satisfaction (Atkinson et al 2004). 


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Responses to items are summed and transformed so that higher scores indicate greater 
satisfaction. Specifically, TSQM scale scores are computed by adding the items loading on each 
domain. The lowest possible score is subtracted from the composite score and divided by the 
greatest possible score range. This provides a transformed score between 0 and 1 that is then 
multiplied by 100. If more than one item is missing from a subscale of the TSQM for a particular 
patient, this subscale should be considered invalid for that respondent. 
8.5.1.3 
FACIT GP5 
The FACIT GP5 Version 04, which is a single question, will be used to assess the overall 
bothersomeness with treatment side effects. The GP5 has a seven-day recall period and uses a 
5-point rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a bit; and 4 = Very 
much) to assess how bothered the subject is by side effects of treatment rated on a 5-point Likert 
scale. 
8.5.2 
 Pharmacokinetics 
Plasma samples will be obtained to characterize the disposition of the study drugs (asciminib, 
imatinib) after oral administration. In addition to parent drug analyses, exploratory metabolite 
analyses on remaining plasma material may be performed using a non-validated, semi-
quantitative or qualitative liquid chromatography/tandem mass spectrometry (LC-MS/MS) 
method, if deemed appropriate. Plasma samples remaining from the analysis may be retained 
by Novartis for additional investigations (i.e. long term stability, reproducibility). 
8.5.2.1 
Pharmacokinetic blood collection and handling 
PK samples will be collected for both the combination arms asciminib 60 mg + imatinib and 
asciminib 40 mg + imatinib, as well as for the asciminib single agent cohort. Blood samples 
will be taken from the arm by either direct venipuncture or an indwelling catheter inserted in a 
forearm vein. At specified time points, 4 mL blood (see ) will be collected. 
The remaining aliquots, must be kept at the clinical site as backup samples, and should only be 
disposed of after approval by Novartis.  
The sample requisition form should be completed and the tubes labeled appropriately. On the 
requisition form, it is important to record the EXACT time the sample was drawn rather than 
being close to the scheduled sampling time. Any sampling problems (e.g. subject took study 
drug before a draw took place) must be noted in the patient records. PK sampling scheme may 
be modified to optimize the sampling time for the study treatment disposition as needed. The 
label in the PK kits (i.e. PK plasma sample) should be used and the actual collection date and 
time should be noted on the label and recorded in the eCRF. Labels will be provided by the site 
with all label information preprinted. Labels will have a barcode, along with the subject number 
and the sequential PK sample number as reported in the PK Sample Scheduling Table  
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Table 8-9 
Pharmacokinetic blood collection log  
Week 
Day 
Scheduled 
Time  
Point 
Asciminib 
Dose 
Reference 
ID 
Imatinib 
Dose 
Reference 
ID 
Asciminib 
PK 
Sample 
No 
Imatinib 
PK 
Sample 
No 
Sample  
Volume  
2 
14 
Pre-dose 
(0h) 
1 
201 
1 
101 
4 
2 
14 
1 h (± 10 
min) 
1 
201 
2 
102 
4 
2 
14 
2 h (± 10 
min) 
1 
201 
3 
103 
4 
2 
14 
3 h (± 15 
min) 
1 
201 
4 
104 
4 
2 
14 
4 h (± 15 
min) 
1 
201 
5 
105 
4 
2 
14 
8 h (± 60 
min) 
1 
201 
6 
106 
4 
2 
14 
24 h (± 60 
min)/ Pre-
dose 
1 
201 
7 
107 
4 
4 
28 
Pre-dose 
(0h) 
5 
205 
8 
108 
4 
4 
28 
2 h (± 10 
min) 
5 
205 
9 
109 
4 
4 
28 
3 h (± 15 
min) 
5 
205 
10 
110 
4 
4 
28 
4 h (± 15 
min) 
5 
205 
11 
111 
4 
12 
84 
Pre-dose 
(0h) 
6 
206 
12 
112 
4 
24 
168 
Pre-dose 
(0h) 
7 
207 
13 
113 
4 
36 
252 
Pre-dose 
(0h) 
8 
208 
14 
114 
4 
60 
420 
Pre-dose 
(0h) 
9 
209 
15 
115 
4 
96 
672 
Pre-dose 
(0h) 
10 
210 
16 
116 
4 
Unscheduled 
- 
  
  
  
1001+ 
2001+ 
4 
Total 
  
  
  
  
  
  
64 
8.5.2.2 
Analytical method 
Plasma concentrations of asciminib will be measured at the designated laboratory using a 
validated high-performance liquid chromatography/tandem mass spectrometry (LC-MS/MS) 
method with a lower limit of quantification (LLOQ) of 1.00 ng/mL. 


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Plasma concentrations of imatinib and its metabolite N-desmethyl imatinib (CGP74588) will 
be determined using a validated liquid chromatography-tandem mass spectrometry (LC-
MS/MS) assay with a lower limit of quantification (LLOQ) of 20.0 ng/mL. 
8.5.3 
Biomarkers 
Biomarker analyses will be used to 
 
 as well as to determine 
 
. In addition, potential predictive markers of 
 
 will also be explored. 
All assessments will be performed by a Novartis-designated laboratory. Instructions for 
collection, storage and shipment of all biomarker samples will be provided in the 
[CABL001E2201 laboratory manual]. Required sample collection information must be entered 
on the appropriate CRF pages and requisition forms. 
Biomarker assessments in blood samples 
Characterization of 
 
Approximately 10 mL of blood sample will be collected to assess 
 
 via 
 for patients in treatment arms 1-4. The analysis aims to 
 
 
 will be performed at a Novartis designated laboratory at 
, at 
 and at 
 in  treatment arms 1-4 only, a 
sample is not collected or analyzed for patients in the asciminib single agent cohort. 
 
Approximately 12 mL of blood will be collected for 
 at the visits as 
indicated in  Table 8-10 . The analysis aims to 
 
 
. 
  
Approximately 2.5 mL of blood will be collected for 
 
 at the visits indicated in  Table 8-10 . 
 samples may be used to 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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CCI
CCI
CCI
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CCI
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 Table 8-10 
Biomarker sample collection plan  
  
Volume 
Visit 
Time 
point 
Whole blood for 
 
 analysis by 
 
(treatment arms 1-4 only) 
10 mL 
 
Pre-dose 
10 mL 
 
Anytime 
10 mL 
 
Anytime 
 
12 mL 
 
Pre-dose 
12 mL 
 
Anytime 
12 mL 
 
Anytime 
12 mL 
 
Anytime 
  
2.5 mL 
 
Pre-dose 
2.5 mL 
 
Anytime 
2.5 mL 
 
Anytime 
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given subject if he/she believes that 
continuation would negatively impact the subject's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Subject/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per e prohibited treatment section 
• Any situation in which study participation might result in a safety risk to the subject 
• Treatment failure and disease progression 
• In the case of certain adverse events and re-occurrence of adverse events (see Section 6.5.1)  
Progression is defined by one of the following criteria: 
1. CML-related death as determined by investigator. 
2. Progression to 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, but < 
30% blast in peripheral blood or bone marrow aspirate 
CCI
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• ≥ 20% basophils in the peripheral blood 
• Thrombocytopenia (< 100 x 109/L) unrelated to therapy 
3. Progression to blast crisis (BC) defined by any of the following: 
• ≥ 30% blasts in peripheral blood or bone marrow aspirate 
• Appearance of extramedullary involvement other than hepato-/splenomegaly proven by 
biopsy (i.e. chloroma) 
Any value of AP or BC within the first 4 weeks of study treatment is not defined as progression 
to AP/BC within the study unless the subject discontinues study treatment due to progression 
or the treating physician determines there is unsatisfactory therapeutic effect within the first 8 
weeks. 
Treatment failure is defined according to ELN guidelines (Baccarani et al 2013) as no CHR 
and/or Ph+ > 95% after 3 months, BCR::ABL1 > 10% and/or Ph+ > 35% after 6 months, BCR-
ABL1 > 1% and/or Ph+ > 0 after 12 months of treatment initiation, or as loss of CHR, loss of 
CCyR, confirmed loss of MMR*, BCR::ABL mutations, and major route clonal chromosome 
abnormalities in Ph+ cells at any time.  
* In 2 consecutive tests, of which one with a BCR::ABL level ≥1%. 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information. 
Patients who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdrawal of informed consent, Section 9.1.2). Where possible, they 
should return as soon as possible for the assessments indicated for the end of treatment 
visit in the assessment schedule. If they fail to return for these assessments for unknown reasons, 
every effort (e.g. telephone, e-mail, letter) should be made to contact the subject/pre-designated 
contact as specified in the lost to follow-up section. This contact should preferably be done 
according to the study visit schedule. 
The following assessments, according to Table 8-1 and Table 8-2, will be performed during the 
end of treatment visit: physical examination, extramedullary involvement, vital signs, body 
weight, blood collection (for hematology, chemistry, BCR::ABL1 RT-qPCR, 
 
 analysis, biomarkers, serum pregnancy test), ECG, assessments of adverse events 
and concomitant medications. 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• new/concomitant treatments 
• adverse events/Serious Adverse Events 
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The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
9.1.2 
Withdrawal of informed consent 
Patients 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  
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 RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
9.1.3 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject's welfare and safety. Should early termination be 


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necessary, patients must be seen as soon as possible (provide instruction for contacting the 
subject, when the subject should stop taking drug, when the subject should come for a final visit) 
and treated as a prematurely withdrawn subject. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the subject’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
End of Study will be declared 96 weeks after the last randomized subject received the first dose 
of treatment (plus 30 days for the safety follow up) in arms 1 to 4, or 48 weeks after the last 
enrolled subject in the asciminib single agent cohort received the first dose of study treatment 
(plus 30 days for the safety follow up), whichever occurs later, or when all patients complete 
their end of study visit, and any repeat assessments associated with this visit have been 
documented and followed-up appropriately by the Investigator. In the event of an early study 
termination decision, soon after the date of that decision each subject will be required to 
complete the end of study visit in its entirety and thereafter no further study treatment will be 
made available to them. All randomized and/or treated patients should have a safety follow-up 
call conducted 30 days after last administration of study treatment. The information collected 
is kept as source documentation. All SAEs reported during this time period must be reported as 
described in Section 10.1.3. Documentation of attempts to contact the subject should be 
recorded in the source documentation. 
• The primary analysis for the study will be performed when all patients in randomized 
treatment arms 1 - 4 have completed the Week 48 visit or have discontinued early.  
• The Week 96 analysis will occur when all patients in randomized treatment arms 1 - 4 
have completed the end of the study visit. The results will be summarized in a week 96 
Clinical Study Report (CSR). 
• All available data from asciminib single agent cohort up to the End of Study will be 
analyzed and summarized in a final Clinical Study Report (CSR). 
At the time of the end of study visit , patients who ho in the opinion of the investigator are 
continuing to benefit from the study drug(s), efforts will be made to continue providing the 
study treatment outside the study. Options include, but are not limited to, a post-trial access 
program or access to commercial supplies in applicable countries. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 


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


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d. fatal; or unknown. 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. Continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, loss of response, progression to accelerated phase or blast crisis), should 
not be reported as a serious adverse event. 
Adverse events separate from the progression of malignancy will be reported as per usual 
guidelines used for such events with proper attribution regarding relatedness to the drug. 
Information about adverse drug reactions for the investigational drug can be found in the 
[Asciminib Investigator Brochure]. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
the underlying disease. 
 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 


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• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (e.g. loss of response, treatment failure, progression to 
AP/BC) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered medically significant. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. 
All malignant neoplasms will be assessed as serious medically significant if other seriousness 
criteria are not met and the malignant neoplasm is not a disease progression of the study 
indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after subject stopped the study treatment must be 
reported to Novartis safety immediately without undue delay, but under no circumstances later 
than within 24 hours of obtaining knowledge of the events (Note: if more stringent, local 
regulations regarding reporting timelines prevail). The Investigator must complete and submit 


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the SAE report form directly in the CRF. Detailed instructions regarding the submission process 
and requirements are to be found in the investigator folder provided to each site. 
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. 
The following SAE reporting timeframes apply: 
1. Screen Failures (e.g. a subject who is screened but is not treated or randomized): SAEs 
occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis. 
2. Randomized OR Treated Patients: SAEs collected between time subject signs ICF until 30 
days after the subject has discontinued or stopped study treatment 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
Investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01, EU Clinical Trial Regulation 536/2014 (once transfer is completed), or as per 
national regulatory requirements in participating countries. Any SAEs experienced after the 30 
day safety evaluation period should only be reported to Novartis Safety if the investigator 
suspects a causal relationship to study treatment. 
SAE Reporting via an Electronic Data Collection Tool 
The primary mechanism for reporting an SAE to Novartis will be the electronic data collection 
tool. 
If the electronic system is unavailable, then the site will use the paper SAE data collection tool 
(see next section) to report the event within 24 hours. 
The site will enter the SAE data into the electronic system as soon as it becomes available. 


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After the study is completed at a given site, the electronic data collection tool will be taken 
offline to prevent the entry of new data or changes to existing data. 
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken offline, then the 
site can report this information on a paper SAE form (see next section) or by telephone. 
SAE Reporting via Paper Data Collection Tool 
Facsimile transmission of the SAE paper data collection tool is the preferred method to transmit 
this information to Novartis. 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier service. 
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the SAE data collection tool within the designated reporting timeframes. 
 
10.1.4 
Pregnancy reporting 
Pregnancies 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment of any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
For all pregnancies with live birth and/or unknown outcome the newborn has to be followed up 
to obtain infant health status and development up to twelve months after delivery. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (definition from European Medicines Agency). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 


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Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and (until transition to EU CTR) reported to Safety only if associated with an SAE. 
Misuse or abuse (and upon transition to EU CTR, also study treatment errors and uses outside 
of what is foreseen in the protocol) will be collected and reported in the safety database 
irrespective of it being associated with an AE/SAE within 24 hours of Investigator’s awareness. 
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of a 
study drug, a standardized process for identification, monitoring and evaluation of liver events 
has to be followed. 
The following two categories of abnormalities/adverse events have to be considered during the 
course of the study (irrespective of whether classified/reported as AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring  
Please refer to Table 16-1 in Section 16.1 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver event defined in Table 16-1 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-2. Repeat liver chemistry tests (ALT, AST, TBL, 
PT/INR, ALP and GGT) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a local 
laboratory to monitor the safety of the subject. If a liver event is subsequently reported, any 
local liver chemistry tests previously conducted that are associated with this event should 
have results reported on the unplanned local laboratory CRF . 
• If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the study drug (refer to the Discontinuation of study treatment section), 
if appropriate 
• Hospitalization of the subject if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  
• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 


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detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. 
10.2.2 
Renal safety monitoring 
Every renal laboratory trigger or renal event as defined in Table 16-3 should be followed up by 
the investigator or designated personnel at the trial site as summarized in Section 16.2. 
10.2.3 
Steering Committee 
A steering committee (SC) will be established comprising of investigators participating in the 
trial, i.e. not being members of the Novartis/sponsor representatives from the Clinical Trial 
Team. Additionally, a patient advocate will be an active member of this committee. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the electronic data capture (EDC) system until they have been trained. 
Automatic validation programs check for data discrepancies in the eCRFs, allow modification 
and/or verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 
Data collected by third parties (hematology, biochemistry, PCR assessments, biomarkers, ECG, 
PK and PROs) will be sent electronically to Novartis. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 


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11.2 
Database management and quality control 
Novartis personnel (or designated Contract Research Organization (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. 
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. Any changes to 
the database after that time can only be made after written agreement by Novartis development 
management. 
After database lock, the investigator will receive copies of the subject data for archiving at the 
investigational site. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor/Clinical Research Associate (CRA) will visit the site to check the 
completeness of subject records, the accuracy of data capture/data entry, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis/delegated CRO/CRA 
organization. Additionally, a central analytics organization may analyze data & identify risks 
& trends for site operational parameters, and provide reports to Novartis clinical teams to assist 
with trial oversight. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 


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subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed. 
12 
Data analysis and statistical methods 
Primary safety and efficacy analysis will be conducted on all randomized subject data at the 
time all patients will have completed at least 48 weeks of study treatment or discontinued earlier. 
Any additional data for patients continuing to receive study treatment past this time, as allowed 
by the protocol, will be further summarized in a final study report once these patients complete 
the study. 
The data will be analyzed by Novartis. It is planned that all 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, biomarker measurements. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
by randomization. According to the intent to treat (ITT) principle, patients will be analyzed 
according to the treatment, they have been assigned to during the randomization procedure. 
The Safety Set includes all patients who received any study treatment (i.e. at least one dose of 
the investigational drug or control drug in case of monotherapy, or at least one dose of any 
component of the study treatment in case of a combination therapy). Patients will be analyzed 
according to the study treatment received, where treatment received is defined as the 
randomized treatment if the subject took at least one dose of that treatment or the first treatment 
received if the randomized treatment was never received.  
For the asciminib single agent cohort the treatment received is defined as the asciminib single 
agent if the subject took at least one dose of that. 
The Pharmacokinetic analysis set (PAS) includes all patients randomized to asciminib + 
imatinib arm or asciminib single agent cohort who received at least one dose of asciminib or 
imatinib and provide at least one evaluable PK concentration. 


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For a concentration to be evaluable, patients are required to: 
• Take a dose of asciminib or imatinib prior to sampling, 
• For post-dose samples, do not vomit within 4 hours after the dosing of asciminib or 
imatinib. 
• For pre-dose samples, have the sample collected before the next dose administration. 
The MR4.5 Responder set consists of the patients in the FAS who achieved MR4.5 by the 
corresponding cut-off date. It will be used for the time to MR4.5 and duration of MR4.5 analysis. 
The Cross-over set consists of the patients randomized to the continued imatinib arm who 
crossed over to receive asciminib add-on treatment after 48 weeks of study treatment. This will 
be used in the analyses of the data after cross-over. 
12.2 
Subject demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment arm for the FAS and Safety set. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, by treatment arm and for asciminib single 
agent cohort. 
12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure in days to asciminib, imatinib and nilotinib as well as the dose 
intensity (computed as the ratio of actual cumulative dose received and actual duration of 
exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned 
dose intensity) will be summarized by treatment arm and for asciminib single agent cohort by 
means of descriptive statistics using the safety set. The duration of exposure will also be 
presented for asciminib + imatinib. 
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 arm and for asciminib single agent cohort. 
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment arm and for asciminib single 
agent cohort and all dosing data will be listed. 
12.4 
Analysis of the primary endpoint(s) 
The primary objective of the study is: 


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• To assess whether asciminib 40 mg + imatinib or asciminib 60 mg + imatinib is more 
effective than continued imatinib in patients with CML-CP who have received imatinib 
for at least one year (12-calendar months) and have not achieved DMR 
12.4.1 
Definition of primary endpoint(s) 
The primary efficacy endpoint of the study is the rate of MR4.5 at 48 weeks, defined as the 
proportion of patients still treated with the randomized treatment at 48 weeks and are in MR4.5 
(BCR::ABL1 ratio of ≤ 0.0032%) at 48 weeks (± assessment window), among all patients 
randomized to the respective treatment arm. Patients who discontinue the randomized treatment 
for any reason prior to 48 weeks are included in the denominator and considered as non-
responders. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The rate of MR4.5 at 48 weeks will be calculated based on the FAS. 
The rate of MR4.5 at 48 weeks and its 2-sided 90% confidence interval based on the Clopper-
Pearson method will be presented by treatment arm (asciminib 60 mg + imatinib, asciminib 40 
mg + imatinib and continued imatinib). The difference in rate of MR4.5 between 1) asciminib 
60 
mg 
+ 
imatinib versus continued 
imatinib 
and 
2) 
asciminib 
40 
mg 
+ 
imatinib versus continued imatinib with its 2-sided 90% confidence interval will be provided 
using the Wald method. 
12.4.3 
Handling of missing values/censoring/discontinuations 
Only patients still treated with the randomized treatment at 48 weeks with MR4.5 at 48 weeks 
are considered responders. In other words, any subject who achieves MR4.5 before 48 weeks, 
but is no longer in MR4.5 at 48 weeks, will be considered as a non-responder for this endpoint. 
Patients discontinuing the randomized treatment prior to 48 weeks due to any reason will be 
considered as non-responders. One exception to the rule above is if the 48-week PCR evaluation 
is missing, but both a PCR evaluation at 36 weeks and a PCR evaluation at 60 weeks are 
available and indicate MR4.5, then the 48-week assessment is imputed as a ‘Response’. 
12.4.4 
Supportive analyses 
The following supportive analyses for the primary endpoint will be performed on the FAS. 
1) The rate of MR4.5 at 48 weeks and its 2 sides 90% confidence interval based on the Clopper-
Pearson method will be presented by treatment arm (asciminib 60 mg + imatinib, asciminib 40 
mg + imatinib and continued imatinib) for the following subgroups if, within each treatment 
arm, each subgroup includes at least 5 patients: 
• prior imatinib duration < 5 years versus ≥ 5 years 
• molecular response at screening (0.1% < BCR::ABL1 ≤ 1.0% versus 0.01% < 
BCR::ABL1 ≤ 0.1%) 


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2) A logistic regression of MR4.5 status at 48 weeks on treatment arm (asciminib 60 mg + 
imatinib, asciminib 40 mg + imatinib and continued imatinib), prior imatinib duration category 
and molecular response status at screening will be performed. 
12.5 
Analysis of secondary endpoints 
The secondary objectives are: 
• To estimate efficacy (Rate of MR4.5 at 48 weeks) of switch to nilotinib 
• To estimate the difference in efficacy (Rate of MR4.5 at 48 weeks) between asciminib 60 mg 
QD + imatinib and switch to nilotinib 
• To estimate the difference in efficacy between asciminib 40 mg QD + imatinib and switch 
to nilotinib 
• To assess additional parameters of the efficacy of asciminib 60 mg QD or 40 mg QD added 
to imatinib versus continued imatinib or switch to nilotinib 
• To characterize the safety and tolerability profile of asciminib 60 mg or 40 mg + imatinib 
vs continued imatinib or switch to nilotinib 
• To assess the pharmacokinetic profile of asciminib 60 mg or 40 mg and imatinib when 
administered in combination  
• To estimate efficacy (Rate of MR4.5 at 48 weeks) of asciminib 80 mg QD 
• To characterize the safety and tolerability profile of asciminib 80 mg QD  
• To assess the pharmacokinetic profile of asciminib 80 mg QD. 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
The secondary efficacy endpoints of this study are: 
• Rate of MR4.5 at 48 weeks for switch to nilotinib, for asciminib single agent and difference 
between asciminib + imatinib and nilotinib  
• Sustained rate of MR4.5 at 96 weeks (for all 4 randomized treatment arms) 
• Rate of MR4.5 at 96 weeks (for all 4 randomized treatment arms) 
• Rate of MR4.5 by 48 and 96 weeks (for all 4 randomized treatment arms)  
• Rate of MR4.5 by 48 weeks (for asciminib single agent cohort) 
• Time to MR4.5 (for all 4 randomized treatment arms and asciminib single agent cohort) 
• Duration of MR4.5 (for all 4 randomized treatment arms and asciminib single agent cohort) 
12.5.1.1 Rate of MR4.5 at 48 weeks 
To estimate the efficacy of switch to nilotinib, the rate of MR4.5 at 48 weeks and its 2 sided 90% 
confidence interval based on the Clopper-Pearson method will be presented for the switch to 
nilotinib arm using the FAS. 
In addition, the difference in efficacy will be estimated between: 
• asciminib 60 mg + imatinib and switch to nilotinib 
and between 


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• asciminib 40 mg + imatinib and switch to nilotinib 
To estimate the difference in efficacy between asciminib 60 mg + imatinib (or asciminib 40 mg 
+ imatinib) and switch to nilotinib, the difference in the rate of MR4.5 between asciminib 60 mg 
+ imatinib (or asciminib 40 mg + imatinib) and switch to nilotinib at 48 weeks and its 2 sided 
90% confidence interval will be provided using the Wald method. 
To estimate the efficacy of asciminib single agent, the rate of MR4.5 at 48 weeks and its 2 sided 
90% confidence interval based on the Clopper-Pearson method will be presented using the 
FAS–ASAC. No formal comparison or estimate of the difference with the other treatment arms 
will be performed for this additional cohort.  
12.5.1.2 Rate of sustained MR4.5 at 96 weeks 
The rate of sustained MR4.5 at 96 weeks is defined as the proportion of patients who are in MR4.5 
at both 48 and 96 weeks under randomized treatment and who have no loss of MR4.5 in between 
those two time points among all patients randomized to the respective treatment arm. Rate of 
sustained MR4.5 and its 2 sided 90% confidence interval based on the Clopper-Pearson method 
will be presented by treatment arm using the FAS. 
As the treatment duration for the asciminib single agent cohort is shorter, the rate of sustained 
MR4.5 at 96 weeks will not be presented for the asciminib single agent cohort.  
12.5.1.3 Rate of MR4.5 at 96 weeks 
The rate of MR4.5 at 96 weeks will be calculated based on the FAS. 
In this analysis “at” 96 weeks, only patients with MR4.5 under randomized treatment at 96 weeks 
are considered as responders. A subject who has achieved MR4.5 before 96 weeks, but who is 
no longer in MR4.5 at 96 weeks, will be considered as a non-responder at 96 weeks. Patients 
who discontinued the randomized treatment for any reason prior to 96 weeks will be considered 
as non-responders. 
Rate of MR4.5 and its 2 sided 90% confidence interval based on the Clopper-Pearson method 
will be presented by treatment arm. 
The rate of MR4.5 at 96 weeks will not be presented for the asciminib single agent cohort. 
12.5.1.4 Rate of MR4.5 by 48 and 96 weeks 
The rate of MR4.5 by 48 and 96 weeks for all 4 randomized treatment arms will be calculated 
based on the FAS. 
The rate of MR4.5 by 48 weeks for asciminib single agent cohort will be calculated based on the 
FAS - ASAC. 
In the analyses “by” a specific time point, patients who had achieved MR4.5 under randomized 
treatment at or before the time point will be displayed as responders, whether they lost the 
response/discontinued treatment or not. Therefore, this response rate represents the best 
observed rate of MR4.5 under randomized/ assigned treatment up to that specific time point. 


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Rate of MR4.5 and its 2 sided 90% confidence interval based on the Clopper-Pearson method 
will be presented by treatment arm and for asciminib single agent cohort. 
The cumulative incidence of MR4.5 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 (e.g. up to 50% if half of 
the patients in the analysis population are able to achieve response). 
12.5.1.5 
Time to MR4.5 
Time to MR4.5 is defined for patients in the MR4.5 Responder set at the corresponding cut-off 
as: date of first MR4.5 – date of randomization + 1. Descriptive statistics (range, median, 
quartiles, mean, SD) of time to MR4.5 will be provided for the 4 randomized treatment arms and 
for asciminib single agent cohort separately. 
12.5.1.6 
Duration of MR4.5 
Duration of MR4.5 is defined for patients in the MR4.5 Responder set as the time from first 
documented MR4.5 and the end date of MR4.5 i.e. the earliest date of loss of MR4.5 or CML-
related death. Loss of MR4.5 is defined as an increase of the BCR::ABL ratio to >0.0032% in a 
single blood sample, by International Scale. 
For patients for whom none of the events above are reported, the duration will be censored. The 
duration of MR4.5 (in weeks) is calculated as: (end date or censoring date of MR4.5 - date of first 
MR4.5 + 1)/7. 
The survival distribution of duration of MR4.5 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 MR4.5 at 24, 48, 72 
and 96 weeks and the associated 95% confidence intervals, will be presented for each treatment 
arm and for asciminib single agent cohort. 
An additional analysis of the duration of MR4.5 will be performed where the end date of MR4.5 
is defined as the earliest date of confirmed loss of MR4.5 or CML-related death. Confirmed 
loss of MR4.5 is defined as an increase of the BCR::ABL ratio to >0.0032% in two consecutive 
blood samples, by International Scale. The date of confirmed loss of MR4.5 is the date of the 
first one of the two blood sample assessments. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment arm. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 


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(treatment-emergent AEs). Data from the cross-over period will be summarized separately. 
Data from the asciminib single agent cohort (SS - ASAC) will be summarized separately. 
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the date of the last actual administration of any study treatment. 
The overall observation period will be divided into four mutually exclusive segments: 
1. pre-treatment period: from day of subject’s informed consent to the day before first dose of 
study medication, 
2. on-treatment period: from day of first dose of study medication to 30 days after last dose of 
study medication (for patients who will crossover to receive asciminib 60 mg + imatinib, 
the on-treatment period will be from day of first administration of study medication to the 
day before the first administration of asciminib), 
3. post-treatment period: starting at day 31 after last dose of study treatment (for patients who 
will crossover, the post-treatment period will start at day 31 after last dose of crossover 
study treatment), 
4. cross-over period (for patients who will crossover to receive asciminib add-on treatment), 
from day of first dose of asciminib add-on treatment to 30 days after last dose of crossover 
study treatment. 
Adverse Events 
All information obtained on adverse events will be displayed by treatment arm and subject. 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the 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- and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 
Vital signs 
All vital signs data will be listed by treatment arm, subject, and visit/time and if ranges are 
available, abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time. 


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12-lead ECG 
All ECG data will be listed by treatment arm, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time. 
PR, QRS, QT, QTcF, and RR 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 arm. 
Clinical laboratory evaluations 
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5. 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 version 5, results will be 
categorized as low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, and biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE version 
5 grades if applicable and the classifications relative to the laboratory normal ranges 
For laboratory tests where grades are defined by CTCAE version 5, 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE version 5 grades to compare baseline to the worst on-treatment 
value 
For laboratory tests where grades are not defined by CTCAE version 5, 
• Shift tables using the low/normal/high (low and high) classification to compare baseline to 
the worst on-treatment value. 
For total cholesterol, calculated LDL and HbA1c, additional analyses will be conducted to 
describe the number and percentage of patients developing values outside of defined thresholds. 
In addition to the above mentioned tables and listings, other exploratory analyses might be 
specified in the analysis plan. 
12.5.3 
Pharmacokinetics 
PAS will be used in all pharmacokinetic data analysis and PK summary statistics. Descriptive 
summary statistics will be provided by treatment and visit/sampling time point. Plasma 
concentration data will be listed by treatment, subject, and visit/sampling time point for patients 


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treated with asciminib + imatinib in the Safety set. Data from the asciminib single agent cohort 
(PAS - ASAC) will be summarized separately. 
Summary statistics will include mean (arithmetic and geometric), standard deviation (SD), CV 
(arithmetic and geometric), median, minimum and maximum. Concentrations below LLOQ will 
be treated as zero in summary statistics and for PK parameter calculations but will not be 
included in the geometric mean and CV calculation. The mean and individual plasma 
concentration by treatment and visit/sampling time point will be displayed graphically. 
Pharmacokinetic parameters will be determined by non-compartmental method(s) using the 
pharmacokinetic profile of asciminib and imatinib. Pharmacokinetic parameters listed in  
Table 12-1 will be derived and reported, when feasible. For imatinib metabolite (N-desmethyl 
imatinib [CGP74588]), only Cmax, Tmax, AUClast and the metabolite-to-parent AUC ratio will be 
calculated. 
Pharmacokinetic parameters will be listed by treatment and subject. Descriptive summary 
statistics will include mean (arithmetic and geometric), SD, and CV (arithmetic and geometric), 
median, minimum and maximum. An exception to this is Tmax where median, minimum and 
maximum will be presented. 
Table 12-1 
Non-compartmental pharmacokinetic parameters  
AUClast 
The AUC from time zero to the last measurable concentration sampling time (Tlast) 
(mass x time x volume-1) 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time 
x volume-1) 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time) 
Tlast 
Time of last measurement (time) 
 
 
If appropriate, the potential relationship between asciminib exposure and primary efficacy 
endpoint or most critical safety endpoints may be assessed by graphic exploration and/or 
statistical modeling as appropriate. Details of the analysis and results may be reported separately. 
12.6 
Analysis of exploratory endpoints 
12.6.1 
Efficacy exploratory endpoints 
One exploratory objective for this trial is to assess the proportion of patients eligible for TFR at 
end of the study. For the purpose of endpoint definition to meet the TFR criteria, patients have 
to be treated with randomized treatment up to the end of study (96 weeks after the first dose of 
study drug of the last randomized subject) and based on the last five quarterly performed PCR 
assessments: (1) both first and last assessments are MR4.5, (2) no assessment is worse than MR4, 
and (3) no more than two assessments are between MR4 and MR4.5, among all patients 
randomized to the respective treatment arm. 


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12.6.2 
Other exploratory endpoints 
For cross-over patients (see Section 12.1), the efficacy (e.g. the time from cross-over to MR4.5) 
and safety of cross-over treatment (asciminib add-on treatment) will be summarized. Additional 
analyses may be performed. The details will be further specified in the statistical analysis plan 
(SAP). 
12.6.3 
Biomarkers 
As a project standard, only biomarkers collected in the clinical database will be analyzed. Since 
this study is not adequately powered to assess specific biomarker related hypotheses, the 
statistical analyses of these data should be considered exploratory and hypotheses generating in 
nature. Analytical results from such analyses may be used to generate additional hypotheses 
that must then be verified with data derived from subsequent clinical trials. Furthermore, 
additional post hoc exploratory assessments may be performed. 
While the goal of the biomarker analyses is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a sample collection, or not perform 
or discontinue the analysis of blood due to either practical or strategic reasons (e.g. issues 
related to the quality and or quantity of samples, or issues related to the assay that preclude the 
analysis of samples). Under such circumstances, the number of samples may be inadequate to 
perform a rigorous data analysis and the available data will only be listed. 
The biomarker analyses may be reported in a separate biomarker report. 
The proposed data analysis aligned with the exploratory biomarker objectives as well as the 
relevant aspects of data handling will be addressed in a dedicated SAP. 
Unless otherwise specified, all patients with evaluable biomarker measurements in the FAS will 
be included in the biomarker data analysis. 
Additional exploratory biomarker analyses may be performed depending on the data. 
For all patients, the biomarker objectives are: 
• To explore mechanisms of resistance associated with asciminib and other TKI treatments 
via assessment of
 
 This analysis will be done for only treatment arms 1-4, a sample is not 
collected or analyzed for patients in the asciminib single agent cohort. 
• To explore relevant
 
 
 
• To evaluate 
. 
12.6.4 
Patient Reported Outcomes 
The EORTC QLQ-C30 questionnaire along with the disease-specific chronic myeloid leukemia 
module (EORTC QLQ-CML24), TSQM and FACIT GP5 will be used to collect data on the 
patient-reported outcome measures of health-related quality-of life, treatment satisfactions and 
treatment-related side effects from baseline to EOT by treatment arms. Scoring of raw QoL data 
CCI
CCI
CCI


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and methods for handling of missing items or missing assessments will be handled according 
to scoring manuals for each respective patient questionnaire (Fayers 2001). No imputation will 
be applied if the total or subscale scores are missing at a visit. The number of patients 
completing each patient questionnaire and the number of missing or incomplete assessments 
will be summarized by each treatment arm for each scheduled assessment time points. 
The FAS will be used for analyzing PRO data. No formal statistical tests will be performed of 
PRO data. 
Descriptive statistics will be used to summarize the scored scales for the EORTC, GP5 and 
TSQM questionnaires at each scheduled assessment time point by treatment arm. Additionally, 
change from baseline in the domain scores at the time of each assessment will be summarized. 
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.  
Additional analysis may be performed and details will be described in the analysis plan.  
12.7 
Interim analyses 
An interim analysis will be performed in order to gain an early insight into the safety and 
efficacy of the asciminib add-on combination which will help in planning the future 
development of the asciminib combination. The interim analysis will be performed when at 
least 40 (50%) patients have been randomized and have been followed for their 24 weeks visit 
assessment or have discontinued treatment. The enrollment will continue during this 24 weeks 
follow-up. The interim analysis will include all randomized patients until the date of data cut-
off, and include both efficacy (e.g. BCR::ABL1 assessment overtime, MR4 and MR4.5 rate at 
different time-points) and safety (e.g. Adverse Events and laboratory values) summaries, which 
will be detailed in the Statistical Analysis Plan for the interim analysis. It is not planned to write 
an interim CSR based on this interim analysis. Based on the results of the interim analysis a 
benefit risk balance will be assessed for the two add-on treatment arms.  
The primary analysis will be performed after all patients in the 4 randomized treatment arms 
have completed Week 48 or discontinued prior to Week 48. A Week 96 analysis will be 
performed after all patients in the 4 randomized treatment arms have completed Week 96 and/or 
discontinued study prior to Week 96. A final analysis will be performed with all available data 
from asciminib single agent cohort at the End of Study.  
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
Based on the subset data in ENESTcmr [CAMN107A2405] and ENESTnd [CAMN107A2303], 
it is assumed that the rate of MR4.5 at 48 weeks is ranging between 3% and 10% in the continued 
imatinib arm.  
With 20 patients per arm enrolled in the two asciminib + imatinib arms and the continued 
imatinib arm, the precision of the estimates of the difference between 1) asciminib 60 mg + 
imatinib versus continued imatinib and 2) asciminib 40 mg + imatinib versus continued 
imatinib for different scenarios is shown in Table 12-2. 


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Table 12-2 
90% Confidence intervals for 30% difference rate between the arms 
Continued imatinib 
MR4.5 rate 
Asciminib + imatinib 
MR4.5 rate 
Difference 
90% CI 
3% 
33% 
30% 
[12% - 48%] 
5% 
35% 
30% 
[11% - 49%] 
7% 
37% 
30% 
[10% - 50%] 
10% 
40% 
30% 
[9% - 51%] 
With 20 patients per arm, the width of the two-sided 90% confidence interval for the difference 
in MR4.5 rate at 48 weeks between each asciminib + imatinib and switch to nilotinib will not be 
larger than 0.520 (corresponding to the situation when the estimated MR4.5 rate is 0.5 in both 
arms (i.e. no difference)). Its lower bound will exclude 0 assuming a true 30% difference in the 
MR4.5 rate at 48 weeks. 
In addition, the two-sided 90% Clopper-Pearson confidence interval for the MR4.5 rate at 48 
weeks will have a width not larger than 0.396 (the worst case corresponding to the situation 
when the MR4.5 rate at 48 weeks is 0.5).  
An interim analysis will be performed when at least 40 (50%) patients have been randomized 
and have been followed for their 24 weeks visit assessment or have discontinued treatment. The 
interim analysis will include all randomized patients until the date of data cut-off, and include 
both efficacy (e.g. BCR::ABL1 assessment overtime, MR4 and MR4.5 rate at different time-
points) and safety (e.g. Adverse Events and laboratory values) summaries. There will however 
be no adjustment for multiplicity due to the interim analysis as there is no formal comparison 
to be performed between the treatment arms, and only the estimation of effect size is planned 
in the primary analyses. 
These calculations were made using the software package PASS 11. 
12.8.2 
Secondary endpoint(s) 
For the primary objective, 20 patients per arm will be enrolled in the two asciminib + imatinib 
arms and the continued imatinib arm. With the same number of patients, i.e. 20 patients, in the 
switching to nilotinib arm, the two-sided 90% Clopper-Pearson confidence interval for the 
MR4.5 rate at 48 weeks will have a width not larger than 0.396 (the worst case corresponding to 
the situation when the MR4.5 rate at 48 weeks is 0.5). 
In addition, the width of the two-sided 90% Wald confidence interval for the difference in MR4.5 
proportions rate at 48 weeks between each asciminib + imatinib and switch to nilotinib will not 
be larger than 0.520 (corresponding to the situation when the estimated MR4.5 rate is 0.5 in both 
arms (i.e. no difference)). 
For the 20 patients enrolled in the asciminib single agent cohort, the two-sided 90% Clopper-
Pearson confidence interval for the MR4.5 rate at 48 weeks will have a width not larger than 
0.396 (the maximum width corresponding to the situation when the MR4.5 rate at 48 weeks is 
0.5).  
These calculations were made using the software package PASS 11. 


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13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, EU Clinical Trial Regulation 
536/2014 once transfer is completed, US CFR 21), and with the ethical principles laid down in 
the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to participant patients. 
Any amendments to the protocol will require IRB/IEC and Health Authority approval before 
implementation of changes made to the study design, except for changes necessary to eliminate 
an 
immediate 
hazard 
to 
study 
participants. 
Protocols 
and 
any 
substantial 
amendments/modifications to the protocol will require health authority approval prior to 
initiation except for changes necessary to eliminate an immediate hazard to study participants.  
The investigator will be responsible for the following: 
• Signing a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in 
this protocol and to give access to all relevant data and records to Novartis monitors, 
auditors, Novartis Quality Assurance represantatives, designated agents of Novartis, 
IRBs/ IECs, and regulatory authorities as required. 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• Taking any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, 
Novartis must be notified of this action and the IRB/IEC at the study site must be 
informed according to local regulations. 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), European Medical Device Regulation 2017/745 for clinical 
device research (if applicable), and all other applicable local regulations. 
• Informing Novartis immediately if an inspection of the clinical site is requested by a 
regulatory authority.  


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13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in the European Union Drug Regulatoring Authorities Clinical Trials (EudraCT) or 
the Clinical Trials Information System (CTIS) public website. In addition, after study 
completion (defined as last patient last visit) and finalization of the study report the results of 
this trial will be submitted for publication and posted in a publicly accessible database of clinical 
trial results, such as the Novartis clinical trial results website and all required Health Authority 
websites (e.g. Clinicaltrials.gov, EudraCT or CTIS public website once transfer to EU Clinical 
Trial Regulation 536/2014 is completed , etc). 
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Participant Last Visit (LPLV) date, since multinational studies are locked and reported 
based upon the global LPLV. 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
Any data analysis carried out independently by the Investigator must be submitted 
to Novartis before publication or presentation. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures (SOPs) as well as applicable global/local GCP regulations and ICH 
Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
13.5 
Participant engagement 
The following subject engagement initiatives are included in this study and will be provided, as 
available, for distribution to study participants at the time points indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 
• Thank You letter 
• Plain language trial summary - after CSR publication 
• Individual study results – after CSR publication 


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14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
14.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
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Int. J. Hematol.. 
Saunders VA (2016) A Low Concentration of ABL001 Potentiates in vitro TKI-induced Bcr-
Abl Kinase Inhibition in CML Cells p. Abstract #1121. 
Sawyers CL (1999) Chronic myeloid leukemia. N. Engl. J. Med. p. 1330-40. 
Van Etten RA (2004) Mechanisms of transformation by the BCR-ABL oncogene: new 
perspectives in the post-imatinib era. p. 28 Suppl 1:S21-8. 
Wylie AA, Schoepfer J, Jahnke W, et al (2017) The allosteric inhibitor ABL001 enables dual 
targeting of BCR-ABL1. Nature p. 733-737. 
Yeung DT, Osborn MP, White DL, et al (2015) TIDEL-II: first-line use of imatinib in CML 
with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood p. 
915-23. 


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16 
Appendices 
16.1 
Appendix 1: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements 
Table 16-1 
Liver Event and Laboratory Trigger Definitions  
  
Definition/threshold 
LIVER LABORATORY 
TRIGGERS 
• 
3 x ULN < ALT/AST ≤ 5 x ULN 
• 
1.5 x ULN < TBL ≤ 2 x ULN 
LIVER EVENTS 
• 
ALT or AST > 5 × ULN 
  
• 
ALP > 2 × ULN (in the absence of known bone pathology) 
  
• 
TBL > 2 × ULN (in the absence of known Gilbert syndrome) 
  
• 
ALT or AST > 3 × ULN and INR > 1.5 
  
• 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBL > 2 × 
ULN [mainly conjugated fraction] without notable increase in ALP to > 2 × 
ULN) 
  
• 
Any clinical event of jaundice (or equivalent term) 
  
• 
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, abdominal 
pain, nausea, or vomiting, or rash with eosinophilia 
  
• 
Any adverse event potentially indicative of a liver toxicity* 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms TBL: total bilirubin; ULN: upper limit of normal 
Table 16-2 
Follow Up Requirements for Liver Events and Laboratory Triggers  
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law casea 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
ALT or AST 
> 8 × ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN and INR > 1.5 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 5 to ≤ 8 × ULN 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, continue 
follow-up monitoring 
• 
If elevation persists for more 
than 2 weeks, discontinue the 
study drug 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
• 
Establish causality 
> 3 × ULN accompanied by 
symptomsb 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 × ULN (patient is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, 
initiate close observation of 
the patient 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks 
ALP (isolated) 
  
  
> 2 × ULN (in the absence of 
known bone pathology) 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, establish 
causality 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
TBL (isolated) 
  
  
> 2 × ULN (in the absence of 
known Gilbert syndrome) 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, 
discontinue the study drug 
immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 2 × ULN (patient is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, 
initiate close observation of 
the patient 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
Jaundice 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the patient 
• 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
Any AE potentially indicative of 
a liver toxicity* 
• 
Consider study treatment 
interruption or discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
Investigator discretion 
a Elevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × 
ULN 
b (General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia  
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death. 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms TBL: total bilirubin; ULN: upper limit of normal 


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16.2 
Appendix 2: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Table 16-3 
Specific Renal Alert Criteria and Actions 
Serum Event 
Serum creatinine increase 25 – 49% compared 
to baseline 
Confirm 25% increase after 24-48h 
Follow up within 2-5 days 
Acute Kidney Injury: Serum creatinine increase ≥ 
50%+ compared to baseline 
Follow up within 24-48h if possible 
Consider study treatment interruption 
Consider patient hospitalization /specialized 
treatment 
Urine Event 
New dipstick proteinuria ≥ 1+ 
Albumin- or Protein-creatinine ratio increase ≥ 2-
fold 
Albumin-creatinine ratio (ACR) ≥ 30 mg/g or ≥ 3 
mg/mmol; 
Protein-creatinine ratio (PCR) ≥ 150 mg/g or >15 
mg/mmol 
Confirm value after 24-48h 
Perform urine microscopy 
Consider study treatment interruption or 
discontinuation 
New dipstick glycosuria ≥ 1+ not due to diabetes 
Blood glucose (fasting) 
Perform serum creatinine, ACR 
New dipstick hematuria ≥ 1+ not due to trauma 
Urine sediment microscopy 
Perform serum creatinine, ACR 
For all renal events: 
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed 
Monitor patient regularly (frequency at investigator’s discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or 
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months. 
+ Corresponds to KDIGO criteria for Acute Kidney Injury 


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16.3 
Appendix 3: List of concomitant medications which are 
prohibited or to be used with caution 
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited in Section 6.2. 
The following lists are based on the [Oncology Clinical Pharmacology Drug-Drug Interaction 
Database] (release date: April 2021), which was compiled from the Indiana University School 
of Medicine’s “Clinically Relevant” Table and supplemented with the Food and Drug 
Administration (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. 
16.3.1 
Concomitant medications to be used with caution for asciminib + 
imatinib arms  
Table 16-4 
Concomitant medications to be used with caution for asciminib + 
imatinib arms  
Category 
Drug Names 
Strong CYP3A4 inhibitors 
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak)3, 
indinavir/ritonavir3, tipranavir/ritonavir3, ritonavir, cobicistat, indinavir, 
ketoconazole, troleandomycin, telaprevir, danoprevir/ritonavir3, 
elvitegravir/ritonavir3, saquinavir/ritonavir3, lopinavir/ritonavir3, 
itraconazole, voriconazole, mibefradil, clarithromycin, posaconazole, 
telithromycin, grapefruit juice2, conivaptan, nefazodone, nelfinavir, 
idelalisib, boceprevir, atazanavir/ritonavir3, darunavir/ritonavir3 
Narrow Therapeutic index 
substrates of CYP2C9 
phenytoin, warfarin 
CYP3A4/5 substrates with 
narrow therapeutic index 
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
sirolimus, tacrolimus, terfenadine 
Torsade de pointe (TdP) 
TdP/QT risk: Known* 
amiodarone, anagrelide, arsenic trioxide, astemizole (off US market), 
azithromycin, bepridil (off US market), chloroquine, chlorpromazine, 
cilostazol, cisapride (off US market), citalopram, clarithromycin, 
cocaine, disopyramide, dofetilide, domperidone (not on US market), 
donepezil, dronedarone, droperidol, erythromycin, escitalopram, 
flecainide, fluconazole, grepafloxacin (off market worldwide), 
halofantrine, haloperidol, ibutilide, levofloxacin, levomethadyl (off 
market worldwide), mesoridazine (off market worldwide), methadone, 
moxifloxacin, ondansetron, oxaliplatin, papaverine hydrochloride, 
pentamidine, pimozide, probucol (off market worldwide), 
procainamide (oral off US market), propofol, quinidine, sevoflurane, 
sotalol, sparfloxacin (off US market), sulpiride (not on US market), 
terfenadine (off US market), thioridazine, vandetanib 
1 Herbal product 


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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 Combination ritonavir-boosted regimens are listed here as strong CYP3A inhibitors (to avoid potential 
confusion), even though some are considered moderate CYP3A inhibitors in the University of 
Washington's DDI Database 
 
16.3.2 
Prohibited comedications for asciminib + imatinib arms 
Table 16-5 
Prohibited comedication for asciminib + imatinib arms 
Category 
Drug Names 
Strong CYP3A4 inducers 
carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, 
rifabutin, rifampicin, mitotane, St. John’s wort (Hypericum perforatum) 
 
 
16.3.3 
Concomitant medications to be used with caution for asciminib single 
agent cohort 
Table 16-6 
Concomitant medications to be used with caution for asciminib single 
agent cohort 
Category 
Drug Names 
Strong CYP3A4 
inducers 
carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, 
rifabutin, rifampicin, mitotane, St. John’s wort (Hypericum perforatum) 
CYP3A4/5 
substrates with 
narrow therapeutic 
index 
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
sirolimus, terfenadine 
Narrow Therapeutic 
index substrates of 
CYP2C9 
phenytoin, warfarin  
OATP1B substrates 
aliskiren, ambrisentan, anacetrapib, atenolol, asunaprevir, atogepant, 
atorvastatin, bosentan, bromocriptine, caspofungin, celiprolol, danoprevir, 
digoxin, docetaxel, eliglustat, empangliflozin, ezetimibe, fimasartan, 
fexofenadine, fluvastatin, glyburide, ibrexafungerp, maraviroc, 
methotrexate, montelukast, nateglinide, olmesartan, paclitaxel, 
pirataprevir, pitavastatin, pravastatin, repaglinide, revefenacin, rifampicin, 
rosuvastatin, saquinavir, simvastatin, telmisartan, tezacaftor, ticlopidine, 
valsartan 
BCRP substrates 
alpelisib, atorvastatin, baricitinib, daunorubicin, dolutegravir, doxorubicin, 
hematoporphyrin, imatinib**, methotrexate, mitoxantrone, ozanimod, 
paritaprevir, pitavastatin, rimegepant, rosuvastatin, irinotecan, ethinyl 
estradiol, simvastatin, sofosbuvir, sulfasalazine, tenofovir, tezacaftor, 
topotecan, ubrogepant, venetoclax 


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Category 
Drug Names 
Torsade de pointe 
(TdP) TdP/QT risk: 
Known* 
amiodarone, anagrelide, arsenic trioxide, astemizole (off US market), 
azithromycin, bepridil (off US market), chloroquine, chlorpromazine, 
cilostazol, cisapride (off US market), citalopram, clarithromycin, cocaine, 
disopyramide, dofetilide, domperidone (not on US market), donepezil, 
dronedarone, droperidol, erythromycin, escitalopram, flecainide, 
fluconazole, grepafloxacin (off market worldwide), halofantrine, haloperidol, 
ibutilide, levofloxacin, levomethadyl (off market worldwide), mesoridazine 
(off market worldwide), methadone, moxifloxacin, ondansetron, oxaliplatin, 
papaverine hydrochloride, pentamidine, pimozide, probucol (off market 
worldwide), procainamide (oral off US market), propofol, quinidine, 
sevoflurane, sotalol, sparfloxacin (off US market), sulpiride (not on US 
market), terfenadine (off US market), thioridazine, vandetanib 
*Check crediblemeds.org/healthcare-providers/drug-list for the most updated list. 
**Imatinib must not be combined with ABL001 in asciminib single agent cohort. 
 

SAP_001.pdf: 


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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) 
9-Oct-
2018 
Prior 
to DB 
lock 
Creation of 
final version 
N/A - First version 
NA 
11-Dec- 
2019 
Prior 
to DB 
lock 
Protocol 
amendment 1 
Change in study design to reduce imatinib 
pretreatment duration, from at least 24 
months to at least 12 months 
Section 1.1 
 
 
 
 
 
 
 
 
Change in the study design to reduce the 
sample size from 120 to approximately 80 
Section 1.1 
Section 3.1 
Section 3.2 
 
 
 
 
 
 
 
 
Addition of intolerability as a reason to stop 
the treatment 
Section 1.1 
 
 
 
 
 
 
 
 
Addition of Interim Analysis (IA) to have 
early assessment of benefit (efficacy) and 
risk (safety) of treating patients with 
asciminib + imatinib arms vs continued 
imatinib arm and switch to the nilotinib arm. 
The IA will be will be performed when at 
least 40 (50%) patients have been 
randomized and have been followed for their 
24 weeks visit assessment or have 
discontinued treatment. 
Section 1.1 
Section 2.1 
Section 2.14 
 
 
 
 
 
 
 
 
Removal of the formal statistical hypothesis 
testing, replaced with a point estimate and a 
confidence interval 
Section 2.2.1 
Section 2.5.2 
Section 5.5.1 
 
 
 
 
 
 
 
 
Changing the estimation of the difference in 
rate of MR4.5 between asciminib + imatinib 
versus continued imatinib from a supportive 
analysis to a primary analysis 
Section 2.5.4 
 
 
 
 
 
 
 
 
Change of some non-compartmental 
pharmacokinetics parameters 
Section 2.9 
 
 
 
 
 
 
 
 
Update of the references 
Section 6 


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DILI Clinical 
Safety 
Guidance 
update 
Change in the summaries produced for Liver 
function parameters to be in accordance with 
DILI Clinical Safety Guidance update 
Section 2.8.3 
 
 
 
 
 
 
 
Data issue 
with serum 
Magnesium 
results from 
Roche 
Diagnostics 
Cobas 
analyzer in the 
UK laboratory 
Clarification about how invalid laboratory 
samples for magnesium will be handle 
Section 2.8.3 
27-Aug- 
2020 
Prior 
to DB 
lock 
Changes 
before Interim 
analysis 
Adding a 3-day window for the definition of 
the baseline for PRO. 
Adding a definition of the end of the efficacy 
assessment period. 
Section 2.1.1, 
Table 2-2, Table 
2-3 
 
 
 
 
 
 
 
 
Adding an imputation rule for dates with 
available day and missing month. 
Section 5.1 
 
 
 
 
 
 
 
 
Adding a definition of MR4 and derivation of 
MR4 and MR4.5 for not detectable transcripts. 
Section 5.4 
 
 
 
 
 
 
 
 
Adding a definition of effcacy sets for the 
interim analysis. 
Section 2.2, 
Table 2-4, 
Section 2.14 
24-11-
2021 
Prior 
to DB 
lock 
Changes 
before primay 
analysis 
Updating Phoenix WinNonlin® software 
version. Updating Table 2-6 to clarify which 
PK parameters will be provided for the 
different visits. 
Section 2.9, 
Table 2-6 
 
 
 
 
 
 
 
 
Specifying that exploratory biomarker 
objectives will reported in an independent 
report unless requested by HAs. 
Section 2.12 
 
 
 
 
 
 
 
 
Adding this section about analyses to assess 
the impact of COVID-19 on the study. 
Section 2.15 
 
 
 
 
 


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Clarifing how the dose adjustments and 
discontinuation of study treatment for the 
combination arms  
Section 2.4.1 
 
 
 
 
 
 
 
 
Specifying that the conversion factor for 
deriving PCR results has changed during the 
course of the study. It will be provided by the 
vendor rather than set at 1.1. 
Section 5.4 
 
 


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Table of contents 
Table of contents ................................................................................................................. 5 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design............................................................................................................. 8 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 16 
2.2.1 
Subgroup of interest .............................................................................. 17 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 18 
2.3.1 
Patient disposition ................................................................................. 18 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 20 
2.4.1 
Study treatment / compliance ................................................................ 20 
2.4.2 
Prior, concomitant and post therapies ................................................... 22 
2.5 
Analysis of the primary objective .......................................................................... 23 
2.5.1 
Primary endpoint ................................................................................... 23 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 23 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 23 
2.5.4 
Supportive analyses ............................................................................... 23 
2.6 
Analysis of the key secondary objective ............................................................... 24 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 24 
2.7.1 
Secondary endpoints ............................................................................. 24 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 25 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 26 
2.8 
Safety analyses ....................................................................................................... 26 
2.8.1 
Adverse events (AEs) ............................................................................ 26 
2.8.2 
Deaths .................................................................................................... 27 
2.8.3 
Laboratory data ..................................................................................... 27 
2.8.4 
Other safety data ................................................................................... 29 
2.9 
Pharmacokinetic endpoints .................................................................................... 30 
2.10 
PD and PK/PD analyses......................................................................................... 31 
2.11 
Patient-reported outcomes ..................................................................................... 31 
2.12 
Biomarkers ............................................................................................................. 31 
2.12.1 
Somatic mutation biomarker data handling and analysis ...................... 33 


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2.13 
Other Exploratory analyses .................................................................................... 33 
2.13.1 
Proportion of subjects eligible for TFR at end of study ........................ 33 
2.13.2 
Efficacy and safety evaluation after cross-over .................................... 33 
2.13.3 
Patient-reported outcomes ..................................................................... 34 
2.14 
Interim analysis ...................................................................................................... 35 
2.15 
COVID-19 related analysis.................................................................................... 36 
3 
Sample size calculation ..................................................................................................... 36 
3.1 
Primary objective ................................................................................................... 36 
3.2 
Secondary objective ............................................................................................... 37 
4 
Change to protocol specified analyses .............................................................................. 37 
5 
Appendix ........................................................................................................................... 37 
5.1 
Imputation rules ..................................................................................................... 37 
5.1.1 
Study drug ............................................................................................. 37 
5.1.2 
AE, ConMeds and safety assessment date imputation .......................... 37 
5.2 
AEs coding/grading ............................................................................................... 39 
5.3 
Laboratory parameters derivations ........................................................................ 39 
5.4 
Derivation of PCR results and loss of response ..................................................... 40 
5.5 
Statistical models ................................................................................................... 40 
5.5.1 
Primary analysis .................................................................................... 40 
5.5.2 
Key secondary analysis ......................................................................... 41 
5.6 
Scoring system for PROs ....................................................................................... 41 
5.6.1 
EORTC QLQ-C30 ................................................................................ 41 
5.6.2 
EORTC QLQ-CML24 .......................................................................... 42 
5.6.3 
FACIT-GP5 ........................................................................................... 42 
5.6.4 
TSQM .................................................................................................... 42 
6 
Reference ........................................................................................................................... 42 


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List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
bid 
bis in diem/twice a day 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee  
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
OS 
PCR 
Overall Survival 
Polymerase Chain Reaction 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
qd 
Qua’que di’e / once a day 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


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1 
Introduction 
This statistical analysis plan (SAP) describes all planned statistical analyses for the clinical 
study report(s) (CSR) of study CABL001E2201, a phase 2, multi-center, open-label, 
randomized study of oral ABL001 added to imatinib versus continued imatinib versus switch 
to nilotinib in patients with CML-CP who have been previously treated with imatinib and have 
not achieved deep molecular response. 
The content of this SAP is based on protocol CABL001E2201 version 01. All decisions 
regarding the planned analyses as defined in the SAP, have been made prior to database lock of 
study data for the specific CSR.  
Data will be analyzed according to the data analysis section 12 of the study protocol version 01. 
Important information is given in the following sections and details are provided, as applicable, 
in Appendix 16.1.9 of the corresponding CSR. 
1.1 
Study design 
The study is a phase 2, multi-center, open-label, randomized study of 2 doses of asciminib + 
imatinib versus continued imatinib versus switch to nilotinib in subjects with CML-CP who 
have been previously treated with imatinib first line therapy for at least one year (12 calendar 
months) and have not achieved deep molecular response.  Approximately eighty subjects will 
be randomized to one of the following arms in a 1:1:1:1 ratio: 
x Asciminib 60 mg QD + imatinib 400 mg QD 
x Asciminib 40 mg QD + imatinib 400 mg QD 
x Imatinib 400 mg QD 
x Nilotinib 300 mg BID 
Subjects will be treated for up to 96 weeks after the last randomized subject received the first 
dose of treatment (LPFT), if they do not discontinue study treatment earlier for treatment failure 
or intolerability. After the last dose received, every subject will be followed up for safety for 30 
days.  
Subjects randomized to continue on imatinib single treatment who will not achieve MR4.5 at 48 
weeks may cross over to receive the asciminib add-on treatment within 4 weeks after week 48 
visit. 


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Figure 1-1 
Study design
(*) Subjects on the imatinib continuation arm who have not achieved MR4.5 at 48 weeks may crossover 
to receive the asciminib add-on treatment.
The primary analysis for this study will be performed when all subjects have completed Week 
48 visit or have discontinued treatment early. The final analysis will be performed at the end of 
the study. 
An interim analysis will also be performed when at least 40 (50%) patients have been 
randomized and have been followed for their 24 weeks visit assessment or have discontinued 
treatment. This interim analysis will be performed on all randomized patients at that time point.
1.2 
Study objectives and endpoints 
Table 1-1 
Objectives and related endpoints
Objectives
Endpoints
Primary objective
Endpoint for primary objective
x
To assess whether asciminib 40 mg QD + imatinib 
or asciminib 60 mg QD + imatinib is more effective 
than continued imatinib
x
Molecular Response (MR)4.5 rate at 
48 weeks
Secondary objectives
Endpoints for secondary objectives
x
- To estimate efficacy of switch to nilotinib
- To estimate difference in efficacy between 
asciminib 60 mg + imatinib and switch to 
nilotinib
- To estimate difference in efficacy between 
asciminib 40 mg + imatinib and switch to 
nilotinib
x
- Molecular Response (MR)4.5 rate at 
48 weeks
- Difference in rate of MR4.5 at 48 
weeks
x
To assess additional parameters of the efficacy of 
x
- Rate of MR4.5 at 96 weeks
- Rate of MR4.5 by 48 and 96 weeks




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Objectives 
Endpoints 
x 
To describe any concepts important to study subjects 
not captured by standard PRO instruments that will 
inform future clinical trial designs 
x 
A summary report of concepts raised 
by subjects via qualitative interviews 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The planned analyses will be performed by Novartis and/or designated CRO. SAS version 9.4 
or later will be used to perform all data analyses and to generate tables, figures and listings. 
Data included in the analyses 
The analysis data cut-off dates for the planned analyses are:  
x Interim analysis: when at least 40 (50%) patients have been randomized and have been 
followed for their 24 weeks visit assessment or have discontinued treatment. 
x Primary analysis: after all randomized subjects have completed Week 48 visit or have 
discontinued earlier. 
x Final analysis: once the last ongoing patient has been followed up for safety for 30 days 
after last dose received. 
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 data cut-off date and end date after the 
respective data cut-off date will be reported as ongoing. The same rule will be applied to events 
starting before or on the respective data 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 subjects 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 subjects 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, 25th and 75th percentiles, 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 asciminib only whereas study treatment will refer to 
asciminib+imatinib, imatinib or nilotinib. 
Study treatment component will refer to asciminib, imatinib or nilotinib. 
Date of first administration of asciminib, imatinib or nilotinib respectively 
The date of first administration of asciminib, imatinib or nilotinib is defined as the first date 
when a nonzero dose of asciminib, imatinib or nilotinib is administered and recorded on the 
Study Treatment electronic case report form (eCRF), respectively. The date of first 
administration of asciminib, imatinib or nilotinib will also be referred as start of asciminib, 
imatinib or nilotinib respectively. 
Date of last administration of asciminib, imatinib or nilotinib respectively 
The date of last administration of asciminib, imatinib or nilotinib is defined as the last date when 
a nonzero dose of asciminib, imatinib or nilotinib is administered and recorded on the Study 
Treatment eCRF, respectively. The date of last administration of asciminib, imatinib or nilotinib 
will also be referred as end of asciminib, imatinib or nilotinib respectively. 
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 any component of study treatment was administered as per the Study Treatment eCRF. 
(Example: if 1st dose of asciminib is administered on 05-Jan-2015, and 1st dose of imatinib is 
administered on 03-Jan-2015, then the date of first administration of study treatment is on 03-
Jan-2015). The date of first administration of study treatment will be referred to as start of study 
treatment. 
Date of last administration of study treatment 
The date of last administration of study treatment is derived as the last date when a non-zero 
dose of any component of study treatment was administered as per Study Treatment eCRF. 
(Example: if the last asciminib dose is administered on 15-Apr-2014, and the last dose of 
imatinib is administered on 17-Apr-2014, then the date of last administration of study treatment 
is on 17-Apr-2014).  
For patients randomized to the continued imatinib arm, who cross over to receive asciminib 
+ imatinib, the date of last administration of imatinib is derived as the last date when a non-
zero dose of imatinib was administered before the first date when a non-zero dose of asciminib 
was administered as per the Study Treatment 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: 


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x The date of the event (visit date, onset date of an event, assessment date etc.) í reference 
start date + 1 if event is on or after the reference start date; 
x 7KHGDWHRIWKHHYHQWYLVLWGDWHRQVHWGDWHRIDQHYHQWDVVHVVPHQWGDWHHWFíUHIHUHQFH
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 (i.e., response assessment, and 
patient reported outcomes (PRO)) 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. 
For patients who cross over to receive asciminib + imatinib, the reference start date will be 
reset to the date of first administration of asciminib once they cross over. 
Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). 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. 
Baseline 
For efficacy and other non safety evaluations, the last non-missing assessment, including 
unscheduled assessments on or before the date of randomization is taken as “baseline” value or 
“baseline” assessment. For PROs the last non-missing assessment, including unscheduled 
assessments on or before the date of randomization + 3 days, but no later than the treatment 
start date, is taken as “baseline” value or “baseline” assessment.  
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken as ‘‘baseline” assessment.  
For patients who cross over to receive asciminib+imatinib, the last available assessment on or 
before the date of first administration of asciminib is taken as “baseline” value or “baseline” 
assessment for the cross over period. 
In case time of assessment and time of treatment start are  captured (e.g. 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 multiple values are from the same laboratory (local or 
central) then the value with the last sequence/repeat number should be considered as baseline. 
If subjects have no value as defined above, the baseline result will be missing. 


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On-treatment assessment/event and observation periods  
For adverse event reporting, the overall observation period will be divided into four mutually 
exclusive segments:  
x pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment, 
x 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) (For 
patients who cross over to receive asciminib+imatinib, the on-treatment period will be from 
the date of first administration of study treatment to the day before the first administration 
of asciminib), 
x cross-over period: (for subjects who cross over to receive the asciminib add-on treatment), 
from the date of first administration of asciminib to 30 days after last administration of 
asciminib or imatinib, whichever is the latest. 
x post-treatment period: starting at day 30+1 after last administration of study treatment (For 
patients who cross over to receive asciminib+imatinib, the post-treatment period will start 
31 days after last administration of asciminib or imatinib, whichever is the latest).  
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment, cross-over 
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 addition, a separate summary for death including on treatment and post 
treatment deaths will be provided.  In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). Data from the cross-over period will be summarized separately. 
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment, the cross-over and post-treatment period will be 
flagged. 
Efficacy summaries include data from baseline up to either the last assessment on or before the 
end of treatment visit or before or on treatment discontinuation, whichever is the earliest. 
Windows for multiple assessments  
In order to summarize molecular response, ECG, and PRO measures data collected over time 
(including unscheduled visits), the assessments will be time slotted. The following general rule 
will be applied in creating the assessment windows: If more than one assessment is done within 
the same time window, the assessment performed closest to the target date will be used. If 2 
assessments within a time 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 average case 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 
'D\# 


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Assessment 
Target day of assessment 
Time Interval 
Week 4* 
28 
Day 2 to day 38 
Week 8* 
56 
Day 39 to day 66 
Week 12 
84 
Day 67 to day 122 
Week k (k=24, 36, 48, …) 
7k 
From Day 7k-45 to Day 7k+38 
# Day 1 = Date of randomization 
* Not mandatory for subjects in imatinib and nilotinib arm  
 
Table 2-2 
Time windows for ECG assessments 
Assessment 
Target day of assessment 
Time Interval 
Baseline 
 1 (On or before Day 1) 
'D\# 
Week 2* 
14 
Day 2 to day 17 
Week 4* 
28 
Day 18 to day 52 
Week 12 
84 
Day 53 to day 122 
Week 24 
168 
Day 123 to day 248 
Week 48 
336 
Day 249 to day 500 
Week 96 
672 
Day 501 to day 836 
Week k (k=144, …) 
7k 
From Day 7k-171 to Day 7k+164 
# Day 1 = Date of start of study treatment 
* Not mandatory for subjects in imatinib and nilotinib arm  
 
Time windows for PRO assessments 
Time windows will be defined for descriptive summary of PRO data 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. Data obtained at the end of treatment will be classified as other assessment in 
the corresponding time window. The end of treatment assessment will be included if collected 
within 7 days of the last dose intake. 
Table 2-3 
Time windows for PRO assessments 
Assessment 
Target day of assessment 
Time Interval 
Baseline 
1 
'D\+3, no later than treatment 
start date # 
Week 4 
28 
Day 4 to day 52 
Week 12 
84 
Day 53 to day 122 
Week 24 
168 
Day 123 to day 248 
Week 48 
336 
Day 249 to day 500 
Week 96 
672 
Day 501 to day 700 
# Day 1 = Date of randomization 


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2.2 
Analysis sets 
Full analysis set 
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent to treat (ITT) principle, subjects will be analyzed 
according to the treatment they have been assigned to during the randomization procedure. 
Safety set 
The Safety Set includes all subjects who received any study treatment (i.e at least one dose of 
any component of the study treatment). Subjects will be analyzed according to the study 
treatment actually received. 
The actual treatment received corresponds to: 
x the randomized treatment if the subject took at least one dose of that treatment; 
x the first treatment received if the randomized treatment was never received. 
Pharmacokinetic Analysis Set 
The Pharmacokinetic analysis set (PAS) includes all subjects randomized to the asciminib + 
imatinib arm who received at least one dose of asciminib or imatinib and provide at least one 
evaluable PK concentration. For a concentration to be evaluable, subjects are required to: 
x Take a dose of asciminib or imatinib prior to sampling. 
x For post-dose samples, do not vomit within 4 hours after the dosing of asciminib or 
imatinib,  
x For pre-dose samples, have the sample collected before the next dose administration. 
Other analysis sets 
MR4.5 Responder set: this set consists of the subjects in the FAS who achieved MR4.5 under 
randomized treatment by the corresponding cut-off date. It will be used for the time to MR4.5 
analysis. 
Crossover set: this set consists of the subjects randomized to the continued imatinib arm who 
crossed over to receive the asciminib add-on treatment after 48 weeks of study treatment. This 
will be used in the analyses of the data after crossover.  
Interim analysis efficacy set: At the time of the interim analysis, many patients will be 
ongoing on study treatment and will not have completed all the visits. Thus, for any efficacy 
analysis at interim, only the subset of patients with adequate follow-up will be considered. 
1. For any efficacy analysis up to and including week 24 (e.g. MR4.5 at week 24), this 
subset will include only patients who were randomized at least 24 weeks prior to the 
cut-off date. 
2. For any efficacy analysis for week 48 (e.g. MR4.5 at week 48), this subset will include 
only patients who were randomized at least 48 weeks prior to the cut-off date. 
 


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Patient Classification 
Subjects 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 
2-4. 
Table 2-4 
Subject classification based on protocol deviations and non-PD 
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 
Interim analysis efficacy set 
No written inform consent 
See definition of Interim 
analysis efficacy set for 
selection of patients subsets 
MR4.5 Responder set 
Not applicable 
See definition of MR4.5 
Responder set 
Crossover set 
Not applicable 
See definition of Crossover 
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. 
Summary tables will only be generated if at least 5 patients are present in each subgroup. 
Efficacy 
The primary efficacy endpoint will be summarized by the following subgroups to examine the 
consistency of the rate of MR4.5 at 48 weeks  across the different subgroups: 
x prior imatinib duration: < 5 years versus \HDUV 
x molecular response at screening: 0.1%<BCR-ABLӊ1.0% versus 0.01%<BCR-ABLӊ0.1% 
No formal statistical test of hypotheses will be performed for the subgroups, only point 
estimates of the treatment effect and 90%-confidence intervals will be provided (see Section 
2.5.2 for further analysis details). The objective of the efficacy subgroup analysis is to 
demonstrate homogeneity of treatment effect in the above subgroups. 
Safety 
There is no plan to summarize safety by any subgroup. 


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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 subjects, 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. gender, age groups: 18 - <65, 65 - <85, and Ӌ 85 years, 
race, ethnicity) will be summarized by frequency counts and percentages; the number and 
percentage of subjects 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, 25th and 75th quantile, minimum and maximum). BMI (kg/m2) will be 
calculated as weight[kg] / (height[m]2) using weight at screening.  Demographic and baseline 
disease characteristics data will also be summarized using the crossover set. 
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, 25th and 75th quantile, minimum and maximum) and 
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. 
Other 
All data collected at baseline including 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 subjects and also by 
treatment arm using the FAS. The number (%) of randomized subjects included in the FAS will 
be presented overall and by treatment arm. The number (%) of screened and not - randomized 
subjects and the reasons for screening failure will also be displayed. The number (%) of subjects 
in the FAS who are still on randomized treatment, who discontinued the study phases 
(randomized treatment period and safety follow-up) and the reason for discontinuation will be 
presented overall and by treatment arm. The number (%) of subjects in the FAS randomized to 
the imatinib arm who crossed over to receive asciminib add-on treatment, who are still on 


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asciminib add-on treatment, who discontinued asciminib add-on treatment and the reason for 
discontinuation of asciminib add-on treatment after cross-over will also be presented. 
The following summaries will be provided (with % based on the total number of FAS subjects): 
x Number (%) of subjects who were randomized (based on data from IRT system) 
x Number (%) of subjects who were randomized but not treated (based on Study Treatment 
eCRF page not completed for any study treatment component) 
x Primary reason for not being treated (based on the Disposition eCRF page for event 
“Treatment disposition”) 
x Number (%) of subjects who were treated (based on Study Treatment eCRF pages of each 
study treatment completed with non-zero dose administered) 
x Number (%) of subjects who are still on randomized treatment (based on the Disposition 
eCRF page for event “Treatment disposition” not completed) 
x Number (%) of subjects who completed the randomized treatment phase (based on the 
Disposition eCRF page for event “Treatment disposition”) 
x Number (%) of subjects who discontinued the randomized treatment (based on the 
Disposition eCRF page for event “Treatment disposition”) 
x Primary reason for randomized treatment discontinuation (based on the Disposition eCRF 
page for event “Treatment disposition”) 
x Number (%) of subjects who crossed over from imatinib arm and received asciminib + 
imatinib (based on the Study Treatment eCRF page for study treatment “Asciminib” 
completed with non-zero dose administered ) 
x Number (%) of subjects who crossed over from imatinib arm to receive asciminib + imatinib 
and are still receiving asciminib + imatinib (based on the Disposition eCRF page for event 
“Crossover treatment disposition” not completed) 
x Number (%) of subjects who crossed over from imatinib arm to receive asciminib 60 mg + 
imatinib and discontinued asciminib + imatinib (based on the Disposition eCRF page for 
event “Crossover treatment disposition”) 
x Primary reason for cross-over phase discontinuation (based on the Disposition eCRF page 
for event “Crossover treatment disposition”) 
Protocol deviations 
The number (%) of subjects in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the Study Specification Document) overall and by treatment 
arm for the FAS. All protocol deviations will be listed. 
Analysis sets 
The number (%) of subjects in each analysis set (defined in Section 2.2) will be summarized by 
treatment arm. Reasons leading to exclusion from analysis sets will be listed by treatment arm 
as well as tabulated overall and by treatment arm. 


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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, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized by treatment arm, separately for each component of study treatment. 
For the asciminib + imatinib arms, the duration of exposure will also be presented overall. 
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 
arm and component.  
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 any component of the study treatment, if applicable: 
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 and the date of first administration of study 
treatment are defined in Section 2.1.1.  
Summary of duration of exposure to study treatment in appropriate time units will include 
categorical summaries and continuous summaries (i.e. mean, standard deviation etc.) using 
appropriate units of time . 
Duration of exposure to each of the study treatment components 
Duration of exposure to one component of study treatment (days) = (last date of exposure to the 
considered component of study treatment) – (date of first administration of the considered 
component of study treatment) + 1.  
The date of last administration of each study treatment components and the date of first 
administration of each study treatment components are defined in Section 2.1.1.  
Summary of duration of exposure to each of the study treatment components in appropriate time 
units will include categorical summaries and continuous summaries (i.e. mean, standard 
deviation etc) using appropriate units of time. 
Cumulative dose 
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components.  
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the date of last administration of study treatment as defined in Section 
2.1.1. The calculation for the four study treatment components are: 
x Asciminib: 60 mg/administration × 1 (administration/day) × duration of exposure to 
study treatment (days) 


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x Asciminib: 40 mg/administration × 1 (administration/day) × duration of exposure to 
study treatment (days) 
x Imatinib: 400 mg/administration × 1 (administration/day) × duration of exposure to 
study treatment (days) 
x Nilotinib: 300 mg/administration × 2 (administration/day) × duration of exposure to 
study treatment (days) 
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 Study Treatment eCRF. It is 
the sum of the non-zero doses recorded over the dosing period. For subjects who did not take 
any drug, the actual cumulative dose is by definition equal to zero. 
Dose intensity and relative dose intensity 
Dose intensity (DI) for subjects 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 subjects who did not take any drug the DI is by definition equal to zero.  
Planned dose intensity (PDI) is defined as follows: 
PDI (mg/day) = Planned Cumulative dose (mg) / Duration of exposure to study treatment (day). 
Relative dose intensity (RDI) is defined as follows: 
RDI = DI (mg/day) / PDI (mg/day).   
DI and RDI will be summarized separately for each of the study treatment components, using 
the duration of exposure of each of the components (see Section 2.1.1).  
Dose reductions, interruptions or permanent discontinuation 
The number of subjects who have dose reductions, dose interruptions or permanent 
discontinuation, the reasons, and the number and duration of dose reductions and dose 
interruptions per subject will be summarized separately for each of the study treatment 
components.  
‘Dose changed’, ‘Dose interrupted’, and Dose permanently discontinued’  fields from the Study 
Treatment CRF pages will be used to determine the dose reductions, dose interruptions, and 
permanent discontinuations, respectively. 
The field ‘Reason for change’ will be used to summarize the reasons. 
Dose changed is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose. 
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 this 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 planned daily 
dose. Therefore any dose change to correct a dosing error will not be considered a dose 
reduction.  Only dose change is collected in the CRF, number of reductions will be derived 
programmatically based on the change and the direction of the change. 
 


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Dose adjustments and discontinuation of study treatment  will be summarized by treatment 
arm and component. A dose adjustment for the combination arms is a dose adjustment in one 
of the two drugs. A discontinuation of study treament for the combination arms is a 
discontinuation of study treatment of one of the tow drugs. 
 
2.4.2 
Prior, concomitant and post therapies 
Prior anti-cancer therapy 
The number and percentage of subjects who received any prior anti-neoplastic medications will 
be summarized by treatment arm and also by lowest ATC class and preferred term. Summaries 
will include total number of regimens.  
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD). 
Details regarding WHO-DD version will be included in the footnote in the tables/listings.  
The above analyses will be performed using the 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 arm by means of frequency counts and 
percentages using FAS. 
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.  
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 Anatomical Therapeutic Chemical 
(ATC) classification system and summarized by lowest ATC class and preferred term using 
frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term. 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. Data after crossover will be flagged. Any concomitant 
therapies starting and ending prior to the start of study treatment or starting more than 30 days 
after the last dose of study treatment will be flagged in the listing. The safety set will be used 
for all concomitant therapies tables and listings. 


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2.5 
Analysis of the primary objective 
The primary objective of the study is to assess whether asciminib 40 mg + imatinib or asciminib 
60 mg + imatinib is more effective than continued imatinib in subjects with CML-CP who have 
received imatinib for at least one year (12-calendar months) and have not achieved DMR. 
2.5.1 
Primary endpoint 
The primary efficacy endpoint of the study is the rate of MR4.5 at 48 weeks, defined as the 
proportion of subjects still treated with the randomized treatment at 48 weeks and are in MR4.5 
(BCR-$%/UDWLRRI DWZHHNV (± assessment window), among all subjects 
randomized to the respective treatment arm. Subjects who discontinue the randomized 
treatment for any reason prior to 48 weeks are included in the denominator and considered as 
non-responders. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The rate of MR4.5 at 48 weeks will be calculated based on the FAS. 
The rate of MR4.5 at 48 weeks and its 90% confidence interval based on the Clopper-Pearson 
method will be presented by treatment arm (asciminib 60 mg + imatinib, asciminib 40 mg + 
imatinib and continued imatinib). The difference in rate of MR4.5 between 1) asciminib 60 mg 
+ imatinib versus continued imatinib and 2) asciminib 40 mg + imatinib versus continued 
imatinib with its 2-sided 90% confidence interval will be provided using the Wald method. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Only subjects still treated with the randomized treatment at 48 weeks with MR4.5 at 48 weeks 
are considered responders. In other words, any subject who achieves MR4.5 before 48 weeks, 
but is no longer in MR4.5 at 48 weeks, will be considered as a non-responder for this endpoint. 
Subjects discontinuing the randomized treatment prior to 48 weeks due to any reason will be 
considered as non-responders. One exception to the rule above is if the 48-week PCR evaluation 
is missing, but both a PCR evaluation at 36 weeks and a PCR evaluation at 60 weeks are 
available and indicate MR4.5, then the 48-week assessment is imputed as a ‘Response’. 
2.5.4 
Supportive analyses 
The following supportive analyses for the primary endpoint will be performed on the FAS. 
1.  The rate of MR4.5 at 48 weeks and its 90% confidence interval based on the Clopper-
Pearson method will be presented by treatment arm (asciminib 60 mg + imatinib, 
asciminib 40 mg + imatinib and continued imatinib) for the following subgroups if, 
within each treatment arm, each subgroup includes at least 5 subjects: 
x prior imatinib duration < 5 years versus \HDUV 
x molecular response at screening (0.1% < BCR-$%/versus 0.01% < 
BCR-$%/ 
No formal statistical test of hypotheses will be performed. No inferential statistics (p-values) 
will be produced for the subgroups. 


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2. A logistic regression of MR4.5 status at 48 weeks on treatment arm (asciminib 60 mg + 
imatinib, asciminib 40 mg + imatinib and continued imatinib), prior imatinib duration 
category and molecular response status at screening will be performed. 
2.6 
Analysis of the key secondary objective 
There is no key secondary objective. 
2.7 
Analysis of secondary efficacy objective(s) 
The secondary objectives are: 
x To estimate efficacy (Rate of MR4.5 at 48 weeks) of switch to nilotinib 
x To estimate the difference in efficacy (Rate of MR4.5 at 48 weeks) between asciminib 60 mg 
QD + imatinib and switch to nilotinib 
x To estimate the difference in efficacy between asciminib 40 mg QD + imatinib and switch 
to nilotinib 
x To assess additional parameters of the efficacy of asciminib 60 mg QD or 40 mg QD added 
to imatinib versus continued imatinib or switch to nilotinib 
2.7.1 
Secondary endpoints 
The secondary efficacy endpoints of this study are: 
x Rate of MR4.5 at 48 weeks (for switch to nilotinib and difference between asciminib + 
imatinib and nilotinib) 
x Sustained rate of MR4.5 at 96 weeks (for all 4 treatment arms) 
x Rate of MR4.5 at 96 weeks (for all 4 treatment arms) 
x Rate of MR4.5 by 48 and 96 weeks (for all 4 treatment arms) 
x Time to MR4.5 (for all 4 treatment arms) 
2.7.1.1 
Rate of MR4.5 at 48 weeks 
To estimate the efficacy of switch to nilotinib, the rate of MR4.5 at 48 weeks and its 90% 
confidence interval based on the Clopper-Pearson method will be presented for the switch to 
nilotinib arm using the FAS. 
In addition, the difference in efficacy will be estimated between 
x asciminib 60 mg + imatinib and switch to nilotinib 
and between 
x asciminib 40 mg + imatinib and switch to nilotinib 
To estimate the difference in efficacy between asciminib 60 mg + imatinib (or asciminib 40 mg 
+ imatinib) and switch to nilotinib, the difference in the rate of MR4.5 between asciminib 60 mg 
+ imatinib (or asciminib 40 mg + imatinib) and switch to nilotinib at 48 weeks and its 90% 
confidence interval will be provided using the Wald method. 


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2.7.1.2 
Rate of Sustained MR4.5 at 96 weeks 
The  rate of sustained MR4.5 at 96 weeks is defined as the proportion of subjects who are in 
MR4.5 at both 48 and 96 weeks (considering window) under randomized treatment and who 
have no loss of MR4.5 in between those two time points among all subjects randomized to the 
respective treatment arm.  
Loss of MR4.5 is defined as an increase of the BCR-ABL ratio to >0.0032% in a single blood 
sample, by International Scale. 
2.7.1.3 
Rate of MR4.5 at 96 weeks 
The rate of MR4.5 at 96 weeks is defined as the proportion of subjects who have been treated 
with the randomized treatment for at least 96 weeks and are in MR4.5 at 96 weeks, among all 
subjects randomized to the respective treatment arm. 
2.7.1.4 
Rate of MR4.5 by 48 and 96 weeks 
The rate of MR4.5 by 48 weeks (respectively 96 weeks) is defined as the proportion of subjects 
who have ever reached MR4.5 under the randomized treatment up to 48 weeks (resp. 96 weeks), 
among all subjects randomized to the respective treatment arm. 
2.7.1.5 
Time to MR4.5 
Time to MR4.5 is defined for subjects in the MR4.5 Responder set at the corresponding cut-off 
as: date of first MR4.5 – date of randomization + 1.  
2.7.2 
Statistical hypothesis, model, and method of analysis 
Rates of MR4.5 at and by time points 
These endpoints will be calculated based on the FAS. For each time point, the rate of MR4.5 and 
its 90% confidence interval based on the Clopper-Pearson method will be presented by 
treatment arm. 
The cumulative incidence of MR4.5 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 (e.g. up to 50% if half of 
the subjects in the analysis population are able to achieve MR4.5). 
Rate of Sustained   MR4.5 at 96 weeks 
Using the FAS, the  rate of sustained MR4.5 at 96 weeks and its 90% confidence interval based 
on the Clopper-Pearson method will be presented by treatment arm. 
Time to MR4.5 
The MR4.5 Responder set will be used. Descriptive statistics (range, median, quartiles, mean, 
SD) of time to MR4.5 will be provided for the 4 treatment arms separately. 


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2.7.3 
Handling of missing values/censoring/discontinuations 
Rates of MR4.5 at a specific time point 
All randomized subjects will be included in the denominator. In the analysis “at” a specific time 
point, only subjects with MR4.5 under randomized treatment at this specific time point are 
considered as responders. A subject who has achieved MR4.5 before this specific time point, but 
who is no longer in MR4.5 at this specific time point, will be considered as a non-responder at 
this specific time point. Subjects who discontinue the randomized treatment for any reason prior 
to a specific time point will be considered as non-responders for that time point. 
Rates of MR4.5 by a specific time point 
All randomized subjects will be included in the denominator. In the analyses “by” a specific 
time point, subjects who had achieved MR4.5 under randomized treatment at or before the time 
point will be displayed as responders, whether they lost the response/discontinued treatment or 
not. Therefore this response rate represents the best observed rate of MR4.5 under randomized 
treatment up to that specific time point. Response assessments after discontinuation of the 
randomized treatment or after a specific time point will be ignored for that time point. 
Sustained rate of MR4.5 at 96 weeks 
All randomized subjects will be included in the denominator. Subjects who discontinue the 
randomized treatment for any reason prior to 96 weeks will be considered as non-responders. 
Time to MR4.5 
Subjects who have not reached MR4.5 under randomized treatment will be excluded from the 
time to MR4.5 analysis. Response assessments after discontinuation of the randomized treatment 
will be ignored. Censoring will not be needed. 
2.8 
Safety analyses 
All safety analyses will be based on the safety set. All listings and tables will be presented by 
treatment arm. Data after crossover will be summarized separately for subjects in the crossover 
set who received at least one dose of asciminib (see Section 2.13.2). 
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. 


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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 sort order for 
the preferred term will be based on their frequency in the asciminib 60 mg + imatinib 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. 
 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
Data analysis of AESIs 
An adverse event of special interest 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), HGLTs (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 case retrieval strategy (CRS) prior to the respective 
database lock will be used.  
For each specified AESI, number and percentage of subjects 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.).  
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.  
2.8.2 
Deaths 
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by treatment arm, system organ class and preferred term.  
All deaths will be listed, 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 
On analyzing laboratory data, 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 or one day before the 


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first administration of asciminib for patients who cross over to receive asciminib + imatinib 
(see Section 2.1.1). 
The following summaries will be produced separately for hematology and biochemistry 
laboratory data (by laboratory parameter and treatment): 
x Worst post-baseline CTC grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline. 
x Shift tables using CTC grades to compare baseline to the worst on-treatment  value  
x For laboratory tests where CTC 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 for the laboratory data: 
x Listings of all laboratory data, with CTC grades and classification relative to the laboratory 
normal range. Lab data collected during the post-treatment period will be flagged.   
x Listing of all CTC grade 3 or 4 laboratory toxicities 
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of subjects with worst post-baseline values as per Novartis 
Liver Toxicity guidelines will be summarized: 
 
The following summaries will be produced: 
x ALT or AST > 3xULN  
x ALT or AST > 5xULN 
x ALT or AST > 10xULN 
x ALT or AST > 20xULN 
x ALP > 1.5xULN 
x TBL > 1.5xULN 
x TBL > 2xULN 
x ALT or AST > 3xULN & TBL > 1.5xULN 
x ALT or AST > 3xULN & TBL > 2xULN  
 
Risk Handling for Q2 Roche Magnesium Testing 
Q2 solutions identified an issue with serum Magnesium (Mg) results from Roche Diagnostics 
Cobas analyzer in the UK lab (only) from 05 Jun- 09 Jul 2018 and 22 Nov 2018- 02 Jan 2019. 
Some magnesium values for three patients (7500001, 4200001, 4200002) were not valid; one 
of these patients (4200002) was a screen failure not linked to the magnesium testing, and finally 
randomized. The invalid values are flagged in the database 3; these values will be excluded 
from the analysis but listed in the CSR to discuss potential impact.  
 


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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. 
Data handling 
The average of the triplicate ECG parameters at each time point will be used in the analyses. 
Data analysis 
The number and percentage of subjects with notable ECG values will be presented by treatment 
arm. Notable values are defined below: 
x QT, QTcF 
o 1HZYDOXHRI!DQGPV 
o 1HZYDOXHRI!DQGPV 
o New value of > 500 ms 
o ,QFUHDVHIURPEDVHOLQHRI!PVWRPV 
o Increase from baseline of > 60 ms 
x RR 
o Increase from baseline >25% and to a value > 100 bpm 
o Decrease from baseline >25% and to a value < 50 bpm 
x PR 
o Increase from baseline >25% and to a value > 200 ms 
o New value of > 200 ms 
x QRS 
o Increase from baseline >25% and  to a value > 120 ms 
o New values of QRS > 120 ms 
Change from baseline ECG parameters by timepoint will also be summarized by treatment. 
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.  
2.8.4.2 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters will be 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 the on-
treatment period will be flagged in the listings. 


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Data analysis 
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-5 
below. 
Table 2-5 
Clinically notable changes in vital signs 
Vital sign 
(unit) 
Clinically notable criteria 
 
above normal value  
below normal value 
Weight (kg) 
increase > 10% from Baseline 
decrease  > 10% from Baseline 
Systolic blood 
pressure 
(mmHg) 
>=180 with increase from baseline 
of >=20 
<=90 with decrease from baseline 
of >=20 
 
Diastolic blood 
pressure 
(mmHg) 
>=105 with increase from baseline 
of >=15 
<=50 with decrease from baseline 
of >=15 
 
Pulse rate 
(bpm) 
>=100 with increase from baseline 
of >25% 
<=50 with decrease from baseline of  
> 25% 
 
Body 
temperature 
>= 39.1  
- 
 
The number and percentage of subjects with notable vital sign values (high/low) 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 the on-treatment period will be 
flagged. 
2.9 
Pharmacokinetic endpoints   
PK parameters 
The PK parameters that will be determined are shown in Table 2-6. For imatinib metabolite  
(CGP74588), only Cmax, Tmax, AUClast and the metabolite-to-parent AUC ratio will be 
calculated. The PK parameters are derived based on the non-compartmental methods using 
Phoenix WinNonlin® software version 8. 
 
Table 2-6 
Non-compartmental PK parameters 
 
 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x 
time x volume-1) (only for Week 2 Day 14) 
AUClast 
The AUC from time zero to the last measurable plasma concentration sampling 
time (Tlast) (ng*hr*mL-1) (only for Week 2 Day 14)  
Cmax 
The maximum (peak) observed plasma concentration (ng/mL) (Week 2 Day 14 
and Week 4 Day 28) 


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Tmax 
The time to reach maximum (peak) plasma concentration (hr) (Week 2 Day14 and 
Week 4 Day 28) 
Tlast 
Time of last measurement (time) (Week 2 Day 14 and Week 4 Day 28) 
 
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 
Pharmacokinetic analysis set for all PK parameters defined Table 2-6 in except Tmax, where 
only n, median, minimum and maximum will be presented.  
All individual PK parameters will be listed by treatment for the Pharmacokinetic analysis set. 
Descriptive statistics (n, m (number of non-zero concentrations), mean, CV% mean, SD, 
median, geometric mean, CV% geo-mean, minimum and maximum) for asciminib and imatinib 
concentrations will be presented at each scheduled time point by treatment for the 
Pharmacokinetic analysis set. 
 
Individual concentration-time profiles for asciminib and imatinib concentrations with median 
will be displayed graphically by treatment and visit/sampling time point (Week 2 Day 14 and 
Week 4 Day 28) for the Pharmacokinetic analysis set on the semi-log view. 
In addition, the mean (+/- SD) and geometric mean concentration-time profiles for asciminib 
and imatinib by treatment over time will be displayed graphically for the Pharmacokinetic 
analysis set on the linear and semi-log view. 
All individual plasma asciminib and imatinib concentration data will be listed for patients from 
the asciminib + imatinib arms in the Safety set. 
Handling of PK data below LLOQ or missing 
All concentration values below the lower limit of quantitation (LLOQ) (<1.00 ng/mL for 
asciminib and <20.0 ng/mL for imatinib) 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. 
2.10 
PD and PK/PD analyses 
The potential relationship between asciminib exposure (e.g. trough concentration) and primary 
efficacy endpoint or most critical safety endpoints may be assessed by graphic exploration 
and/or statistical modeling as appropriate. If applicable, the details of the analyses and results 
will be described in a separate analysis plan and reported separately. 
2.11 
Patient-reported outcomes 
See Section 2.13.3. 
2.12 
Biomarkers 
As a project standard, only biomarkers collected in the clinical database will be analyzed. 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 




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General Data Handling and preprocessing 
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.  
2.12.1 
Somatic mutation biomarker data handling and analysis 
Handling of somatic biomarker data 
Overall, somatic mutation status will be derived from the interrogated exons for the BCR-ABL1 
gene. 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 in the form of 
contingency tables with the rows containing the different mutations assayed, and the treatment 
groups in the columns. 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 
 data  and outcome data (with or without MR4.5 at and by 48 and 96 
weeks using FAS) will be listed for each subject listed by treatment group. 
2.13 
Other Exploratory analyses 
2.13.1 
Proportion of subjects eligible for TFR at end of study 
The proportion of subjects eligible for TFR at end of study is defined as the proportion of 
subjects who have been treated with the randomized treatment up to the end of study and 
achieved sustained MRD (Minimal Residual Disease) based on the last 5 quarterly performed 
PCR assessments, i.e. (1) both first and last assessments are MR4.5, (2) no assessment is worse 
than MR4, and (3) no more than two assessments are between MR4 and MR4.5, among all 
patients randomized to the respective treatment arm. 
Using the FAS, the proportion of subjects eligible for TFR at end of study and its 90% 
confidence interval based on the Clopper-Pearson method will be presented by treatment arm. 
All randomized subjects will be included in the denominator. Subjects who discontinue the 
randomized treatment for any reason prior to end of study will be considered as non-eligible for 
TFR. 
2.13.2 
Efficacy and safety evaluation after cross-over 
Separate analyses of efficacy and safety events will be conducted for patients randomized to 
the imatinib arm who will cross-over to receive asciminib 60mg + imatinib, i.e. crossover set. 
Efficacy 
Time to MR4.5from first administration of asciminib is defined as: date of first MR4.5 on 
asciminib treatment– date of first administration of asciminib + 1.  


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Using the subset of subjects in the crossover set who will achieve MR4.5 under asciminib + 
imatinib during the crossover period, descriptive statistics (range, median, quartiles, mean, sd) 
of time to MR4.5 will be provided. 
Subjects who will not have reached MR4.5 under asciminib + imatinib during the crossover 
period will be excluded from this time to MR4.5 analysis. Response assessments after 
discontinuation of asciminib will be ignored. Censoring will not be needed. 
Safety 
Safety analyses will be based on the subjects in the crossover set who will have received at least 
one dose of asciminib. 
AE summaries will include all AEs occurring during the cross-over period (see Section 2.1.1).  
The following adverse event summaries will be produced: 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 following summaries will be produced separately for hematology and biochemistry 
laboratory data (by laboratory parameter and treatment) (see Section 2.8.3): 
x Worst post-baseline CTC grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline. 
x Shift tables using CTC grades to compare baseline to the worst on-treatment value  
x For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-treatment 
value. 
They will include all assessments available for the lab parameter collected from the first 
administration of asciminib to 30 days after the last administration of asciminib + imatinib (see 
Section 2.1.1). 
Specific summaries for the liver function parameters will also be produced (see Section 2.8.3). 
The following summaries for ECG and vital signs data will be produced: 
x Number and percentage of subjects with notable ECG values 
x Number and percentage of subjects with notable vital sign values (high/low) 
 
2.13.3 
Patient-reported outcomes 
The EORTC QLQ-C30 questionnaire along with the disease-specific chronic myeloid leukemia 
module (EORTC QLQ-CML24), TSQM and FACIT GP5 will be used to collect data on the 
patient-reported outcome measures of health-related quality-of life, treatment satisfactions and 
treatment-related side effects from baseline to EOT by treatment arms. All tools require 
patient’s direct completion and will be administered utilizing electronic device for data 
collection at scheduled time points from baseline to end of treatment.  
 
The compliance to the schedule of administration of PRO will be summarized by treatment arm, 
for baseline and post-baseline on-treatment time points.  


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The following categories, as collected on the eCRF, will be used to describe whether the 
questionnaire was completed at a specific time point: 
x yes, fully completed  
x yes, partly completed  
x no, patient refused due to poor health  
x no, patient refused (unrelated to health)  
x no, questionnaire not available in appropriate language  
x no, institutional error  
x no, technical issues 
x no, other.  
 
The FAS will be used for analyzing PRO data unless specified differently.  
Descriptive statistics (n, mean, SD, median, 25th and 75th percentiles) will be used to summarize 
all scores by treatment arm over time using time windows as described in Section 2.1.1. 
Additionally, change from baseline in the scores at the time of each scheduled assessment will 
be summarized. No formal statistical tests will be performed. 
The scoring system for each PRO is described in the Appendix. 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. 
Results from the qualitative subject interview will be analyzed and reported separately. 
 
2.14 
Interim analysis 
An interim analysis will be performed in order to have an early assessment of benefit and risk 
of treating patients with asciminib + imatinib arms vs continued imatinib arm and switch to the 
nilotinib arm in Ph+CML-CP patients. This interim analysis will be performed on all 
randomized patients when at least 40 (50%) patients have been randomized and have been 
followed for their 24 weeks visit assessment or have discontinued treatment.. The interim 
analysis will include all randomized patients data until the date of data cutoff. All patients in 
the safety set will be used for safety analysis. The interim analysis efficacy set will be used for 
efficacy analysis as defined in Section 2.2. 
No formal comparison is planned between the treatment arms at the time of the interim analysis, 
and only descriptive analyses will be conducted. The following summaries will be provided by 
treatment arm: 
x Patient disposition, baseline and disease characteristics as well as treatment exposure 
will be summarized..  
x Descriptive summaries of BCR-ABL1 levels over time will be provided, as well as MR4 
and MR4.5 rates over time with 90% confidence intervals . In addition, patient-level 
listings as well as lasagna plots will also be produced to visualize each subject’s 
trajectory of the molecular response status (based on BCR-ABL1 levels) over time.  


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x Adverse event summaries will be produced by SOC, PT and worst grade (separately for 
all AEs and for AEs suspected to be related to study treatment). For hematology and 
biochemistry laboratory data the worst post-baseline CTC grade will be summarized. 
Listings of all adverse events, deaths, hematology and biochemistry values will also be 
provided.  
 
An interim CSR will not be produced based on this interim analysis. 
2.15 
COVID-19 related analysis 
Additional analyses may be performed to assess the impact of COVID-19 pandemic on the 
study (reporting of adverse events, missing visits, protocol deviations, etc.). 
3 
Sample size calculation 
3.1 
Primary objective 
Based on the subset data in ENESTcmr [CAMN107A2405] and ENESTnd [CAMN107A2303], 
it is assumed that the rate of MR4.5 at 48 weeks is ranging between 3% and 10% in the continued 
imatinib arm.  
With 20 subjects per arm enrolled in the two asciminib + imatinib arms and the continued 
imatinib arm, the precision of the estimates of the difference between 1) asciminib 60 mg + 
imatinib versus continued imatinib and 2) asciminib 40 mg + imatinib versus continued 
imatinib for different scenarios is shown in Table 3-1. 
Table 3-1 
90% Confidence intervals for 30% difference rate between the arms 
Continued imatinib 
MR4.5 rate 
Asciminib + imatinib 
MR4.5 rate 
Difference 
90% CI 
3% 
33% 
30% 
[12% - 48%] 
5% 
35% 
30% 
[11% - 49%] 
7% 
37% 
30% 
[10% - 50%] 
10% 
40% 
30% 
[9% - 51%] 
With 20 subjects per arm, the width of the two-sided 90% confidence interval for the difference 
in MR4.5 rate at 48 weeks between each asciminib + imatinib and switch to nilotinib will not be 
larger than 0.520 (corresponding to the situation when the estimated MR4.5 rate is 0.5 in both 
arms (i.e. no difference)). Its lower bound will exclude 0 assuming a true 30% difference in the 
MR4.5 rate at 48 weeks. 
In addition, the two-sided 90% Clopper-Pearson confidence interval for the MR4.5 rate at 48 
weeks will have a width not larger than 0.396 (the worst case corresponding to the situation 
when the MR4.5 rate at 48 weeks is 0.5).  
These calculations were made using the software package PASS 11. 
There will however be no adjustment for repeated hypothesis testing due to the interim analysis 
as there is no formal comparison to be performed between the treatment arms, and only the 
estimation of effect sizes is planned.   


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3.2 
Secondary objective 
For the primary objective, 20 subjects per arm will be enrolled in the two asciminib + imatinib 
arms and the continued imatinib arm. With the same number of subjects, i.e. 20 subjects, in the 
switching to nilotinib arm, the two-sided 90% Clopper-Pearson confidence interval for the 
MR4.5 rate at 48 weeks will have a width not larger than 0.396 (the worst case corresponding to 
the situation when the MR4.5 rate at 48 weeks is 0.5). 
In addition, the width of the two-sided 90% confidence interval for the difference in MR4.5 
proportions rate at 48 weeks between each asciminib + imatinib and switch to nilotinib will not 
be larger than 0.520 (corresponding to the situation when the estimated MR4.5 rate is 0.5 in both 
arms (i.e. no difference). 
These calculations were made using the software package PASS 11. 
4 
Change to protocol specified analyses 
No change to protocol specified analyses was made. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Missing dates for study drug administraton should be queried and will not be imputed. 
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made.  
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 
x No imputation will be done for completely missing dates 
day, month 
x 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.  
x If available year > year of study treatment start date then 01JanYYYY 
x If available year < year of study treatment start date then 01JulYYYY 


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Missing 
Element 
Rule 
day 
x 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. 
x If available month and year > month and year of study treatment start 
date then 01MONYYYY   
x 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 
x 
Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period*  
day, month 
x 
If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period *  
day 
x 
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.  
 
For the imputation of dates with day available and month missing, the day available will be 
ignored and the imputation rule for when day and month are missing will be used. 
 
 


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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 5.0. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). 
5.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. The criteria to assign CTCAE grades are given in Novartis internal criteria 
for CTCAE grading of laboratory parameters. The latest available version of the document 
based on the underlying CTCAE version v5.0 at the time of analysis will be used.  
For laboratory tests where grades are not defined by CTCAE v5.0, results will be graded by the 
low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia. 
Imputation Rules 
CTCAE grading for blood differentials is based on absolute values. However, this data may not 
be reported as absolute counts but rather as percentage of white blood cells (WBC). 
If laboratory values are provided as ͂<X̓ (i.e. below limit of detection) or ͂>X̓ , 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 u100) / WBC count 


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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 PAXgeneTM Blood RNA tubes from MMD laboratory 
will be used in this study. The conversion factor will be provided by the lab for each sample. 
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 
Molecular response 
BCR-ABL ratio 
Log-reduction category 
MR4.5 
Yes 
 
-log reduction 
 
No 
>0.0032% 
<4.5-log reduction 
 
 
 
 
MR4 
Yes 
1% 
-log reduction 
 
No 
>0.01% 
<4-log reduction 
Loss of MR4.5 is defined in Section 2.7.1.2. 
5.5 
Statistical models 
5.5.1 
Primary analysis 
The rate of MR4.5 at 48 weeks will be calculated based on the FAS. 


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The rate of MR4.5 at 48 weeks and its 2-sided 90% confidence interval will be provided for each 
treatment arm using exact binomial confidence interval (implemented using SAS procedure 
FREQ with EXACT statement for one-way table (Clopper and Pearson 1934) for all patients 
and by subgroups (described in Section 2.5.4). The 2-sided 95% confidence interval within each 
treatment arm will also be computed using the same technique but for information purposes 
only.  
 
The 2-sided 90% confidence interval for the difference in rate of MR4.5 at 48 weeks between 1) 
asciminib 60 mg + imatinib versus continued imatinib and 2) asciminib 40 mg + imatinib versus 
continued imatinib will be provided using the Wald method (implemented via SAS procedure 
FREQ with RISKDIFF option in the TABLES statement, under the default CL =WALD and 
VAR=SAMPLE). If the 2x2 table is with asciminib + imatinib in row 1, continued imatinib in 
row 2, MR4.5 in column 1 and No MR4.5 in column 2, then the SAS output will give the estimate 
of (risk for MR4.5 at 48 weeks in asciminib + imatinib – risk for MR4.5 at 48 weeks in continued 
imatinib). The 2-sided 95% confidence intervals for these two differences will also be computed 
using the same technique but for information purposes only. 
A logistic regression of MR4.5 status at 48 weeks on treatment arm (asciminib 60 mg + imatinib, 
asciminib 40 mg + imatinib and continued imatinib), prior imatinib duration category and 
molecular response status at screening will be performed. An adjusted odds ratio for the 
treatment effect will be derived from the logistic regression model (implemented using SAS 
procedure LOGISTIC, with treatment, prior imatinib duration category and molecular response 
status at screening specified as explanatory variables in the CLASS statement) which allows 
for including adjustments for covariates (both categorical and continuous).  
The odds ratio will be determined using exact logistic regression, and the odds ratio presented 
with exact 90% confidence limits. In these cases, SAS PROC LOGISTIC with EXACTONLY 
option will be used. The 2-sided 95% confidence interval will also be computed using the same 
technique but for information purposes only.  
5.5.2 
Key secondary analysis 
Not applicable. 
5.6 
Scoring system for PROs 
5.6.1 
EORTC QLQ-C30  
The EORTC QLQ-C30 is composed of both multi-item scales and single-item measures. These 
include five functional scales, three symptom scales, a global health status / QoL scale, and six 
single items. Each of the multi-item scales includes a different set of items - no item occurs in 
more than o ne scale. 
EORTC QLQ-C30 subscale scores will be calculated by first obtaining the raw scores through 
adding up the item responses on the questions which make up each scales and then applying the 
linear transformation to the raw scores in accordance with the respective scoring manual 
provided by the developer (Fayers 2001). If at least half of the items comprising the scale have 
been answered, the score for this scale will be calculated. For single item scales with missing 


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responses and scales where less than half of the items have been answered, the score for these 
scales will be set to missing. 
5.6.2 
EORTC QLQ-CML24 
The Chronic Myeloid Leukemia Module is a supplementary questionnaire module to be employed 
in conjunction with the QLQ-C30. It consists of four multi-item scales to assess symptom burden, 
impact on worry/mood, impact on daily life, and satisfaction with care and information. In 
addition, two single items assess body image problems and satisfaction with social life.  
The scoring approach for the QLQ-CML24 is identical in principle to that for the symptom 
scales/single-items of the QLQ-C30. All scoring information specific to the QLQ-CML24 is 
presented in the EORTC QLQ-CML Scoring Manual (Efficace 2014). 
5.6.3 
FACIT-GP5  
This is a single item scale. Then, the score for this scale will be either set to the item response 
or set to missing in case the response is missing. 
5.6.4 
TSQM 
Version 1.4 of the TSQM consists of 14 items that results in four specific domains: Effectiveness, 
Side Effects, Convenience, and one global scale item, Global Satisfaction. TSQM scale scores for 
each domain will be computed by adding the TSQM items in each domain and then 
transforming the composite score into a value ranging from from 0 to 100 according to the rules 
defined in the TSQM user manual (The lowest possible score is subtracted from the composite 
score and divided by the greatest possible score range. This provides a transformed score 
between 0 and 1 that is then multiplied by 100.). A score can be computed for a domain only if 
no more than one item is missing from that domain. 
6 
Reference 
References are available upon request 
Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrical, 26, 404-413. 
Efficace F, Baccarani M, Breccia M, et al (2014) International development of an EORTC 
questionnaire for assessing health-related quality of life in chronic myeloid leukemia patients: 
the EORTC QLQ-CML24. Qual Life Res p. 825-36. 
Fayers PM (2001) Interpreting quality of life data: population-based reference data for the 
EORTC QLQ-C30. Eur. J. Cancer.