A Phase 3b, Multi-center, Open-label, Treatment Optimization Study of Oral Asciminib in Patients With Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Previously Treated With 2 or More Tyrosine Kinase Inhibitors
Phase: PHASE3
Conditions: Chronic Myelogenous Leukemia
Sponsor: Novartis Pharmaceuticals

 
 
 
Novartis Research and Development 
Asciminib/ABL001 
Oncology Clinical Trial Protocol CABL001A2302 
A phase 3b, multi-center, open-label, treatment 
optimization study of oral asciminib in patients with 
Chronic Myelogenous Leukemia in chronic phase (CML-
CP) previously treated with 2 or more tyrosine kinase 
inhibitors 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 
Document type: 
Oncology Clinical Trial Protocol 
EUDRACT number: 
2020-006057-21 
Version number: 
01 (Amended Protocol – Clean) 
Clinical Trial Phase: 
IIIb 
Release date: 
10-Aug-2022 

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Protocol No. CABL001A2302 
 
Table of contents 
Table of contents ............................................................................................................. 2 
List of tables ................................................................................................................... 6 
List of figures .................................................................................................................. 6 
List of abbreviations ........................................................................................................ 7 
Glossary of terms ............................................................................................................ 9 
Amendment 01 (10-Aug-2022) ..................................................................................... 11 
Protocol summary ......................................................................................................... 14 
1 
Introduction .................................................................................................................. 17 
1.1 
Background ....................................................................................................... 17 
1.2 
Purpose .............................................................................................................. 20 
2 
Objectives and endpoints ............................................................................................... 21 
2.1 
Primary estimands ............................................................................................. 22 
2.2 
Secondary estimands .......................................................................................... 23 
3 
Study design ................................................................................................................. 23 
4 
Rationale ....................................................................................................................... 25 
4.1 
Rationale for study design .................................................................................. 25 
4.1.1 
Rationale for choice of background therapy ....................................... 25 
4.2 
Rationale for dose/regimen and duration of treatment ........................................ 25 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs .................................................................................................................. 28 
4.4 
Purpose and timing of interim analyses/design adaptations ................................ 29 
4.5 
Risks and benefits .............................................................................................. 29 
4.6 
Rationale for COVID-19 pandemic mitigation procedures ................................. 30 
5 
Study Population ........................................................................................................... 31 
5.1 
Inclusion criteria ................................................................................................ 31 
5.2 
Exclusion criteria ............................................................................................... 33 
6 
Treatment ...................................................................................................................... 35 
6.1 
Study treatment .................................................................................................. 35 
6.1.1 
Dosing regimen.................................................................................. 35 
6.1.2 
Additional study treatments................................................................ 36 
6.1.3 
Guidelines for continuation of treatment ............................................ 36 
6.1.4 
Treatment duration ............................................................................. 36 
6.2 
Other treatment(s) .............................................................................................. 36 
6.2.1 
Concomitant therapy .......................................................................... 37 
6.2.2 
Prohibited medication ........................................................................ 38 
6.3 
Preparation and dispensation .............................................................................. 38 

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6.3.1 
Handling of study treatment and additional treatment ......................... 39 
6.3.2 
Instruction for prescribing and taking study treatment ........................ 40 
6.4 
Participant numbering, treatment assignment, enrollment................................... 41 
6.4.1 
Participant numbering ........................................................................ 41 
6.4.2 
Treatment assignment ........................................................................ 41 
6.5 
Treatment blinding............................................................................................. 42 
6.6 
Dose escalation and dose modification ............................................................... 42 
6.6.1 
Dose escalation guidelines ................................................................. 42 
6.6.2 
Dose escalation .................................................................................. 42 
6.6.3 
Dose modifications ............................................................................ 42 
6.6.4 
Follow-up for toxicities ...................................................................... 49 
6.6.5 
Treatment compliance ........................................................................ 50 
6.6.6 
Emergency breaking of assigned treatment code ................................ 51 
7 
Informed consent procedure .......................................................................................... 51 
8 
Visit schedule and assessments...................................................................................... 52 
8.1 
Screening ........................................................................................................... 60 
8.1.1 
Eligibility screening ........................................................................... 61 
8.1.2 
Information to be collected on screening failures ............................... 61 
8.2 
Participant demographics/other baseline characteristics ..................................... 61 
8.3 
Efficacy ............................................................................................................. 62 
8.3.1 
Efficacy assessments .......................................................................... 62 
8.3.2 
Appropriateness of efficacy assessments ............................................ 64 
8.4 
Safety and tolerability assessments .................................................................... 64 
8.4.1 
Performance status ............................................................................. 65 
8.4.2 
Laboratory evaluations ....................................................................... 65 
8.4.3 
Electrocardiogram (ECG) .................................................................. 66 
8.4.4 
Pregnancy and assessments of fertility ............................................... 68 
8.4.5 
Appropriateness of safety measurements ............................................ 69 
8.5 
Additional assessments ...................................................................................... 69 
8.5.1 
Patient reported outcomes (PRO) ....................................................... 69 
8.5.2 
Pharmacokinetics ............................................................................... 70 
8.5.3 
Biomarkers ........................................................................................ 70 
8.5.4 
Imaging ............................................................................................. 71 
8.5.5 
Other Assessments ............................................................................. 71 
9 
Discontinuation and completion .................................................................................... 72 
9.1 
Discontinuation from study treatment and from study ........................................ 72 

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9.1.1 
Discontinuation from study treatment ................................................ 72 
9.1.2 
Discontinuation from study ................................................................ 74 
9.1.3 
Lost to follow up ................................................................................ 74 
9.2 
Withdrawal of informed consent/Opposition to use data/biological samples ....... 74 
9.3 
Study completion and post-study treatment ........................................................ 75 
9.4 
Early study termination by the sponsor .............................................................. 75 
10 Safety monitoring and reporting .................................................................................... 76 
10.1 
Definition of adverse events and reporting requirements .................................... 76 
10.1.1 
Adverse events ................................................................................... 76 
10.1.2 
Serious adverse events ....................................................................... 77 
10.1.3 
Adverse events of special interest ....................................................... 78 
10.1.4 
SAE reporting .................................................................................... 79 
10.1.5 
Pregnancy reporting ........................................................................... 79 
10.1.6 
Reporting of study treatment errors including misuse/abuse ............... 80 
10.2 
Additional Safety Monitoring ............................................................................ 81 
10.3 
Committees........................................................................................................ 81 
10.3.1 
Steering Committee ........................................................................... 81 
11 Data Collection and Database management ................................................................... 81 
11.1 
Data collection ................................................................................................... 81 
11.2 
Database management and quality control ......................................................... 82 
11.3 
Site monitoring .................................................................................................. 82 
12 Data analysis and statistical methods ............................................................................. 83 
12.1 
Analysis sets ...................................................................................................... 83 
12.2 
Participant demographics and other baseline characteristics ............................... 84 
12.3 
Treatments ......................................................................................................... 84 
12.4 
Analysis supporting primary objectives .............................................................. 85 
12.4.1 
Definition of primary endpoint ........................................................... 85 
12.4.2 
Statistical model, hypothesis, and method of analysis ......................... 85 
12.4.3 
Handling of intercurrent events of primary estimand .......................... 85 
12.4.4 
Handling of missing values not related to intercurrent event ............... 86 
12.4.5 
Sensitivity analyses ............................................................................ 86 
12.4.6 
Supplementary analysis ...................................................................... 87 
12.5 
Analysis supporting secondary objectives .......................................................... 87 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................. 88 
12.5.2 
Safety endpoints ................................................................................ 89 
12.5.3 
Biomarkers ........................................................................................ 91 

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12.5.4 
Patient reported outcomes .................................................................. 91 
12.6 
Analysis of exploratory endpoints ...................................................................... 92 
12.7 
Interim analyses ................................................................................................. 93 
12.8 
Sample size calculation ...................................................................................... 93 
12.8.1 
Primary endpoint(s) ........................................................................... 93 
13 Ethical considerations and administrative procedures .................................................... 93 
13.1 
Regulatory and ethical compliance ..................................................................... 93 
13.2 
Responsibilities of the investigator and IRB/IEC ............................................... 94 
13.3 
Publication of study protocol and results ............................................................ 94 
13.4 
Quality Control and Quality Assurance .............................................................. 94 
13.5 
Participant Engagement ..................................................................................... 94 
14 Protocol adherence ........................................................................................................ 95 
14.1 
Protocol amendments ......................................................................................... 95 
15 References .................................................................................................................... 96 
16 Appendices ................................................................................................................... 99 
16.1 
List of concomitant medications for patients on asciminib .................................. 99 
 

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List of tables 
Table 2-1 
Objectives and related endpoints ........................................................ 21 
Table 4-1 
Summary of simulated PK metrics of 40 mg b.i.d. and 80 mg q.d. ..... 27 
Table 6-1 
Investigational drug ........................................................................... 36 
Table 6-2 
Dose and treatment schedule .............................................................. 40 
Table 6-3 
Dose reduction schedule .................................................................... 43 
Table 6-4 
Criteria for dose reduction / interruption / discontinuation and re-
initiation of treatment for adverse drug reactions ................................ 43 
Table 6-5 
Clinical and diagnostic assessments to rule out possible alternative 
causes of observed LFT abnormalities ............................................... 50 
Table 8-1 
Assessment schedule .......................................................................... 54 
Table 8-2 
Blood samples (efficacy primary endpoint) ........................................ 63 
Table 8-3 
Physical examination, vital sign and height and weight assessments... 64 
Table 8-4 
ECOG Performance status scale ......................................................... 65 
Table 8-5 
Central clinical laboratory parameters collection plan ........................ 66 
Table 8-6 
Local ECG collection plan ................................................................. 67 
Table 8-7 
Biomarkers samples collection plan ................................................... 71 
Table 8-8 
Optional biomarker samples collection plan ....................................... 72 
Table 10-1 
Guidance for capturing the study treatment errors .............................. 80 
Table 16-1 
Concomitant medications to be used with caution for patients on 
asciminib ........................................................................................... 99 
List of figures 
Figure 3-1 
Study design ...................................................................................... 24 
Figure 4-1 
Simulated mean steady state PK profiles of asciminib 40 mg b.i.d. 
and 80 mg q.d. ................................................................................... 27 

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List of abbreviations 
ACA 
Additional Chromosomal Abnormalities 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AP/BC 
Accelerated Phase / Blast Crisis 
AST 
Aspartate Aminotransferase 
ATP 
Adenosine Triphosphate 
BCR-ABL1 
Breakpoint Cluster Region Tyrosine-protein kinase ABL1 
b.i.d. 
bis in die/twice a day 
BMA 
Bone Marrow Aspirate 
BUN 
Blood Urea Nitrogen 
CCyR 
Rate of complete cytogenetic response 
CMV 
Cytomegalovirus 
CML-CP 
Chronic Myelogenous Leukemia – Chronic Phase 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
dd-PCR 
Droplet Digital Polymerase Chain Reaction 
DILI 
Drug-Induced Liver Injury 
EBV 
Epstein–Barr virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
ELN 
European Leukemia Network 
EORTC 
QLQ-C30 
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire 
Core 30 
EOT 
End Of Trial 
ERCP 
Endoscopic Retrograde Cholangiopancreatography 
eSAE 
Electronic Serious Adverse Event 
eSource 
Electronic Source 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate Dehydrogenase 
HBV 
Hepatitis B Virus 
HbsAg 
antigen of the hepatitis B virus 
HCV 
Hepatitis C Virus 
HIV 
Human immunodeficiency virus 
HSV 
Herpes Simplex Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
Independent Ethics Committee 
IgM 
Immunoglobulins M 

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IgG 
Immunoglobulins G 
IMP 
Investigational Medical Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IS 
International Scale 
LFT 
Liver function test  
LLN 
lower limit of normal 
MCV 
Mean Cell Volume 
MDASI-CML 
MD Anderson Symptom Inventory – Chronic Myelogenous Leukemia 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
mL 
milliliter(s) 
MMR 
Major Molecular Response 
MRI 
Magnetic Resonance Imaging 
MR4 
Molecular response 4 log reduction from baseline 
MR4.5 
Molecular response 4.5 log reduction from baseline 
 
 
OS 
Overall Survival 
p.o. 
oral(ly) 
PFS 
Progression Free Survival 
Ph+ 
Philadelphia chromosome-positive 
PK 
Pharmacokinetic(s) 
PRO 
Patient Reported Outcomes 
q.d. 
Quaque Die / Once a day 
QTcF 
QT interval corrected by Fridericia’s formula 
RNA 
Ribonucleic acid 
RQ-PCR 
Real Time Quantitative Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBL 
Total Bilirubin 
TFR 
Treatment Free Remission 
TKIs 
Tyrosine Kinase Inhibitors 
TTF  
Time to Treatment Failure 
TSH 
Thyroid Stimulating Hormone 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell(s) 
WHO 
World Health Organization  
 
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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant  
Cohort 
A specific group of patients fulfilling certain criteria and generally treated at the 
same time 
Electronic Data Capture 
(EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive voice 
response systems and clinical laboratory interfaces. EDC includes the use of 
Electronic Case Report Forms (eCRFs) which are used to capture data 
transcribed from paper source forms used at the point of care 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last participant or at a 
later point in time as defined by the protocol  
Enrollment 
Point/time of participant entry into the study at which informed consent must be 
obtained  
Estimand  
A precise description of the treatment effect reflecting the clinical question posed 
by the trial objective. It summarizes at a population-level what the outcomes 
would be in the same patients under different treatment conditions being 
compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary for 
the variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest. 
International scale  
Definition of molecular response standardized using the definition of the IRIS 
study  
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Off-site 
Describes trial activities that are performed at remote location by an off-site 
healthcare professional, such as procedures performed at the participant’s home. 
Off-site healthcare 
Professional (OHP) 
A qualified healthcare professional, such as e.g. nurse, who performs certain 
protocol procedures for the participant in an off-site location such as a 
participant’s home. 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Personal data 
Participant information collected by the Investigator that is coded and transferred 
to Novartis for the purpose of the clinical trial. This data includes participant 
identifier information, study information and biological samples. 
Premature participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned 

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Remote 
Describes any trial activities performed with the participant at a location that is 
not the investigative site where the investigator will conduct the trial, but is for 
example the participant’s home or another appropriate location 
Randomization number 
A unique identifier assigned to each randomized participant 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study 
Source Data/Document 
Source data refers to the initial record, document, or primary location from where 
data comes. The data source can be a database, a dataset, a spreadsheet or 
even hard-coded data, such as paper or eSource 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed consent by 
the first participant 
Study treatment 
Any drug or combination of drugs or intervention administered to the patients as 
part of the required study procedures; includes investigational drug(s), control(s) 
or background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or may 
not also be the point/time of study discontinuation  
Tele-visit 
Procedures or communications conducted using technology such as telephone 
or video-conference, whereby the participant is not at the investigative site where 
the investigator will conduct the trial. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event. 
Withdrawal of study 
consent (WoC) / 
Opposition to use of data 
/biological samples 
Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data and biological samples (opposition to use data 
and biological samples) AND no longer wishes to receive study treatment AND 
does not agree to further protocol required assessments. This request should be 
in writing (depending on local regulations) and recorded in the source 
documentation. 
Opposition to use data/biological samples occurs in the countries where collection 
and processing of personal data is justified by a different legal reason than 
consent. 

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Amendment 01 (10-Aug-2022) 
Amendment rationale 
As of 10 August 2022, 111 patients have been screened in the study and 91 patients have been 
randomized and received treatment. The study is ongoing. 
The main purpose of this protocol amendment is to: 
Implement UK and Canada local protocols amendment changes within the global protocol  
• Add an exclusion criterion for recent participation in an interventional trial and clarify the 
IMP wash-out period required for study participation 
• Include guidance in Table 6-4 regarding dose withholding in patients, who experience 5- to 
20-fold ULN transaminase elevations while taking asciminib and dose modifications 
guidelines for patients having elevated levels at baseline. 
• Table 6-5 added regarding Clinical and diagnostic assessments to rule out possible 
alternative causes of observed LFT abnormalities 
• Clarify the guidance regarding dose modification criteria for recurrence of grade 3/4 
cytopenia and to elaborate the guidance for follow up of a participant having potential drug-
induced liver injury during the study. 
• Implement editorial changes throughout the protocol to correct typos and provide 
clarifications where required. 
Information on FDA marketing authorization for asciminib has been added. 
These amendment items are considered to contribute to improve readability and accessibility of 
the protocol. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using red underlined font for insertions. This amendment is considered substantial. 
The following sections, tables and figures were changed: 
• Section 1.1: inclusion of information concerning FDA approval of asciminib for adult 
patients with Ph+ CML -CP, previously treated with two or more TKIs. The recommended 
dose of asciminib is a total daily dose of 80 mg, taken either as 80 mg q.d. or 40 mg BID. 
The FDA also approved asciminib for adult patients with Ph+ CML in CP with T315I 
mutation. The recommended dose of asciminib in patients with Ph+ CML in CP with T315I 
mutation is 200 mg BID. 
• Section 2.1: updated wording on investigational treatment 
• Section 4.2: clarification regarding blood pressure assessment in supine position only 
• Figure 4-1: dose of “40 mg” is specified in the title 
• Section 5.2: addition of an exclusion criterion for recent participation in an interventional 
trial and clarify the IMP wash-out period required for study participation 

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• Section 5.2: removal of exclusion criteria regarding ‘history of active ongoing acute or 
chronic liver disease’ as it was not in sync with inclusion of patients having baseline 
moderate hepatic impairment (total bilirubin ≤ 3 x ULN)   
• Section 5.2: clarification regarding baseline evaluation of Hepatitis B parameters are added. 
HBV DNA estimations are required only if anti-Hbc is positive. Patients having HbsAg 
positivity will automatically be excluded, and HBV DNA estimations are not required in 
such scenario. 
• Section 5.2: statement added to contraception criteria based on FDA request regarding 
female contraception 
• Table 6-4: dose withholding guidelines were updated for patients who experience 5- to 20-
fold ULN transaminase elevations while taking asciminib. In addition, appropriate dose 
modifications guidelines in patients having elevated transaminase levels at baseline are 
added. This change has been implemented in the protocol in response to the MHRA 
comment to revise the current dosing recommendations for transaminase elevations of 5- to 
20-fold ULN in the protocol. 
• Section 6.6.4.1: Additional clarifications have been added to the guidance for the follow up 
of a participant having potential drug-induced liver injury during the study. Compared to 
the local protocol amendment approved in Canada, a statement related to pediatric patients 
has been removed. This study being conducted in adult, the statement is considered not 
relevant. 
• Section 8: updates regarding visit numbers two weeks post-dose escalation 
• Table 8-1: addition of a row with visit days and appropriate visit windows 
• Table 8-1: addition of a row with asciminib drug dispensation 
• Table 8-1: updates regarding urine pregnancy test to be performed monthly between visits 
from week 24 to week 132 
• Table 8-1: Mutational analysis by 
 at screening/baseline is removed 
• Section 8.1: correction regarding the bone marrow aspirate evaluation window prior 
randomization 
• Section 8.4.2: updated to allow local labs to be completed in case of central lab logistical 
challenges. Noted BCR-ABL1 still required to be completed centrally. 
• Section 8.4.4: clarification added in section pregnancy and assessments of fertility regarding 
contraception 
• Section 8.5.1: clarification explaining that completed PRO measures will not be reviewed 
for AEs by the investigator/study personnel 
• Section 8.4.3: addition of sentence below the table clarifying that ECGs are not required to 
be performed within a specified time frame (post-dose), after the week-2 visit. 
• Section 9.1.1: clarification regarding adverse events and re-occurrence of adverse events 
reference Table 6-4 
• Section 10.1.4: addition of a note within SAE reporting section if more stringent, local 
regulations regarding reporting timelines prevail 
• Section 11.3: addition to include the 15 year retention period for study conduct documents 
after study completion 
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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. Mutational analysis by 
 at screening/baseline is removed. 
The change does affect the Informed Consent. 
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Protocol summary 
Protocol 
number 
CABL001A2302 
Full Title 
A phase IIIb, multi-center, open-label, treatment optimization study of oral asciminib in 
patients with Chronic Myelogenous Leukemia in chronic phase (CML-CP) previously 
treated with 2 or more tyrosine kinase inhibitors 
Brief title 
Asciminib treatment optimization in ≥ 3rd line CML-CP 
Sponsor and 
Clinical Phase 
Novartis Global Medical Affairs, Phase IIIb 
Investigation 
type 
Drug 
Study type 
Interventional  
Purpose and 
rationale 
The purpose of the study is to optimize the treatment of asciminib in patients with chronic 
myelogenous leukemia in chronic phase (CML-CP) previously treated with 2 or more 
Tyrosine Kinase Inhibitors (TKIs). Patients for this study will be identified based on warning 
criteria and resistance definition following European Leukemia Network (ELN) 2020 
recommendations.  
In addition, the study will investigate the use of two different posologies. For this, patients 
will be randomized to either receive asciminib 40 mg twice a day (b.i.d.) or of 80 mg once a 
day (q.d.).  
In patients not achieving MMR at 48 weeks or not maintaining the response after the week 
48 assessment up to week 108, asciminib dose may be escalated to 200 mg q.d. if in the 
investigator’s opinion the patient may benefit from the escalation. In addition, there must 
not be any grade 3 or 4 toxicity while on therapy, or persistent grade 2 toxicity, possibly 
related to asciminib and unresponsive to optimal management. 
Primary 
Objective(s)  
The primary objective of the study is to estimate the major molecular response rate (MMR) 
of all the patients at week 48 with CML-CP following two or more prior TKI treatments and 
with no evidence of MMR at baseline. 
Secondary 
Objectives 
• 
To evaluate the safety and tolerability of asciminib in patients with CML-CP following 2 
or more prior TKI treatments 
• 
To assess the rate of MMR in patients without MMR at baseline and at alternative time 
points at weeks 12, 24, 36, 72, 96 and 144  
• 
To assess the rate of MMR at week 48 for patients with MMR at baseline  
• 
To assess the time to MMR 
• 
To assess the rate of early responses of BCR-ABL1 ≤10% and ≤1% at weeks 12, 24, 
36 and 48 
• 
To assess the rate of deep molecular responses (MR4 and MR4.5) at weeks 12, 24, 
36, 48, 72, 96 and 144  
• 
To assess cytogenetic response (% Ph+ metaphases) at weeks 48 and EOT.  
• 
To characterize the impact of additional cytogenetic abnormalities on efficacy 
• 
To assess cumulative molecular responses by all-time points 
• 
To assess duration of MMR 
• 
To assess sustained deep molecular responses as prerequisite for Treatment Free 
Remission (TFR) 
• 
To assess rate of progressions (PFS) 
• 
To assess overall survival (OS) 
• 
To assess time to treatment failure (TTF) 
• 
To evaluate patient reported outcomes and quality of life by using MDASI-CML 

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Study design 
The study is an international, multi-center, non-comparative, phase IIIb, treatment 
optimization study of daily 80 mg asciminib (randomized to either 40 mg b.i.d. or 80 mg 
q.d.) in patients previously treated with 2 or more TKIs and who are considered failing or in 
warning as per ELN 2020. 
In patients not achieving MMR at 48 weeks or losing the response after the week 48 
assessment up to week 108, asciminib dose may be escalated to 200 mg q.d. if in the 
investigator’s opinion the patient may benefit from the escalation. In addition, there must 
not be any grade 3 or 4 toxicity while on therapy, or persistent grade 2 toxicity, possibly 
related to asciminib and unresponsive to optimal management. 
Treatment duration is 144 weeks for the individual patient. This is the maximum treatment 
duration for each patient. 
Study 
population 
The trial will enroll a total of approximately 186 patients: 
• 
156 patients with CML-CP not in MMR at baseline who were treated with two or more 
TKIs and who were either resistant (ELN 2020 warning or failure) or intolerant to the 
last treatment will be enrolled. For this population, the primary endpoint for MMR at 48 
weeks will be assessed. 
• 
Up to 30 additional patients intolerant only to their last TKI treatment and in MMR at 
baseline will also be enrolled. This patient population will not be part of primary 
endpoint analysis; however, all assessments will be done as with the 156 patients from 
the population of the primary endpoint analysis.  
Key Inclusion 
criteria 
• 
Signed informed consent must be obtained prior to participation in the study 
• 
Male or female patients with a diagnosis of CML-CP ≥ 18 years of age 
• 
Treatment with a minimum of 2 or more prior TKIs (i.e. imatinib, nilotinib, dasatinib, 
bosutinib, radotinib or ponatinib) 
• 
Warning or failure (adapted from the 2020 ELN Recommendations) or intolerance to the 
most recent TKI therapy at the time of screening  
• 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2 
• 
Adequate end organ function (as per central laboratory tests) 
Key Exclusion 
criteria 
• 
Known presence of the BCR-ABL1 T315I mutation at any time prior to study entry 
• 
Known second chronic phase of CML after previous progression to AP/BC 
• 
Previous treatment with a hematopoietic stem-cell transplantation 
• 
Patient planning to undergo allogeneic hematopoietic stem cell transplantation 
• 
Uncontrolled cardiac repolarization abnormality 
• 
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 
• 
History of acute pancreatitis within 1 year of study entry or past medical history of 
chronic pancreatitis 
• 
Testing for Hepatitis B surface antigen (HbsAg) and Hepatitis B core antibody (HBcAb / 
anti HBc) will be performed at screening. Patients with active Hepatitis B Virus (HBV) 
infection (hepatitis B surface antigen [HbsAg] positive) will be excluded 
Study 
treatment 
The investigational treatment for this study is asciminib (80 mg daily, randomized to either 
40 mg b.i.d. or 80mg q.d.). In patients not achieving MMR at 48 weeks or losing the 
response after the week 48 assessment up to week 108, asciminib dose may be escalated 
to 200 mg q.d. per investigator decision. Novartis will supply asciminib to the investigational 
site as 20 mg and 40 mg tablets. 
Treatment of 
interest 
Asciminib 
Efficacy 
assessments 
• 
The efficacy of asciminib will be primarily assessed through molecular monitoring by 
Real Time Quantitative Polymerase Chain Reaction (RQ-PCR) of the BCR-ABL1 
transcripts in the peripheral blood, the standard methodology for assessing CML 
disease activity. RQ-PCR assessments will be performed at each study visit (except at 
Week 1 Day 1, Week 2 Day 1, Week 4 and Week 8 visits). For patients who escalate 

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dose an additional, 2-week post-escalation ECG visit will be performed, there will be no 
RQ-PCR assessment done for this visit. 
• 
At selected visits cytogenetic analyses will be performed locally to assess the number 
of Philadelphia-positive cells in the bone marrow and additional cytogenetic 
aberrations. Cytogenetic analysis is a second standard assessment of disease status 
and response to treatment in CML. 
• 
Additional routine assessments of cell counts in peripheral blood will be performed at 
every visit. Though these are less sensitive than molecular monitoring and 
cytogenetics, an increase in blast cells may indicate a lack of response and potential 
sign of disease progression.  
Key safety 
assessments 
• 
Adverse event monitoring 
• 
Physical examination 
• 
Vital Signs 
• 
Hematology and biochemistry (and pregnancy when applicable) 
• 
12-lead Electrocardiogram (ECG) 
Other 
assessments 
• 
Patient Reported Outcomes: MD Anderson Symptom Inventory – Chronic Myelogenous 
Leukemia (MDASI-CML)  
• 
Biomarker assessments (BCR-ABL1 resistance mutation analysis for ATP binding site 
and myristoyl binding site mutations) 
• 
  
Data analysis 
The primary estimand will be analyzed based on the data from the Full Analysis Set (FAS) 
and according to the Intention-To-Treat (ITT) principle. Exact test for single proportion will 
be used at the one-sided 2.5% level of significance. 
The null hypothesis is that the MMR rate at Week 48 is equal to 0.23. The alternative 
hypothesis is that the rate is greater than 0.23. 
Key words 
Randomized, non-comparative Phase IIIb  
CML chronic phase, after failure of or intolerance to 2 or more prior TKI 
Treatment optimization 
Asciminib 
ELN Recommendations 2020 
MMR rate at 48 weeks 
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1 Introduction 
1.1 Background 
Chronic myeloid leukemia (CML) is a hematologic malignancy characterized by the clonal 
myeloproliferative expansion of transformed primitive hematopoietic progenitor cells with an 
incidence of 1 to 2 cases per 100,000 people (Faderl et al 1999). If untreated, the disease 
progresses from an initial chronic phase with a duration of about 3 to 5 years to an accelerated 
phase of shorter duration to a fatal blast crisis (Sawyers et al 1999). The hallmark of CML is 
the occurrence of the Philadelphia (Ph) chromosome, a shortened version of chromosome 22 as 
a result of a reciprocal translocation t(9;22)(q34;q11) (Nowell et al 1960, Rowley et al 1973). 
The molecular consequence of the t(9,22) translocation is the creation of the fusion protein 
BCR-ABL1, a constitutively active cytoplasmic tyrosine kinase with increased signaling 
activity, that activate multiple signal-transduction cascades affecting the growth and 
differentiation of hematopoietic cells, allowing them to escape constraints on normal growth 
and to become leukemic. (Sawyers et al 1999). 
The management of Ph+, BCR-ABL1+ CML has undergone a profound evolution from the 
early use of cytotoxic agents to allogeneic stem cell transplantation and recombinant interferon-
alpha and to newer tyrosine-kinase inhibitors (TKI), which represent the standard of care in the 
treatment of CML (Baccarani et al 2013). TKIs are a class of compounds competitively binding 
against ATP for the ATP-binding site of ABL1 and thereby inhibiting the ability of ABL1 to 
phosphorylate and activate proteins downstream. Following the registration of the first TKI 
imatinib, later referenced as ‘1st generation TKI’ several other compounds have been developed 
with higher affinity to ABL1 such as the ‘2nd generation TKIs’ nilotinib, dasatinib and bosutinib, 
and the more recent ‘3rd generation TKI’ ponatinib. Four of the five TKIs: imatinib, nilotinib, 
dasatinib and bosutinib have been approved by the European Medical Agency and Food Drug 
Administration for the treatment of newly diagnosed CML. Ponatinib is approved for patients 
with a rare mutation variant of BCR-ABL1 T315I, which renders the other 4 TKI ineffective, 
and for patients with CML resistant to two or more TKIs. Although all 2nd gen TKIs eligible for 
the patient with newly diagnosed CML have been tested against imatinib, their activity has 
never been tested against each other (Hochhaus et al 2020a). Therefore, no consensus exists 
over the optimal treatment sequence of the different drugs in lines of treatment, and in case of 
treatment failure or intolerance of a TKI the next TKI may be chosen depending on the medical 
history, condition of the patient and treatment objective.  
These significant advances in the treatment of CML allow patients with good response to 
treatment to have an almost normal life expectancy or even stop treatment and eventually 
become treatment-free. 
Patients with chronic phase CML and failure of two or more prior treatments however still have 
a poor prognosis, with treatment failure rates of up to 75% in 3rd line and significantly reduced 
overall survival (Akard et al 2013).  
Patients with intolerance represent a major clinical challenge in particular in later lines of CML 
treatment (Garg 2009 et al, Giles 2010 et al, Ongoren 2018 et al). Patients with intolerance to 
two or more prior TKI treatments have a high risk of reoccurrence of the same adverse event, 
and long-term safety concerns over the use of ATP-site binding TKIs remain 

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(Steegmann 2016 et al). As a consequence, this population of multiple refractory/resistant or 
intolerant patients represents still a significant therapeutic challenge with a high medical need 
for a different treatment approach. 
Asciminib is a specific inhibitor of BCR-ABL1 with a different mode of action from all other 
TKI’s currently available on the market or in development (Wylie et al 2017, Hughes et al 2019). 
Asciminib is the first clinical compound in CML that specifically targets the ABL1 myristate 
pocket (Specifically Targeting the ABL Myristoyl Pocket STAMP, Cortes et al 2020). It inhibits 
ABL1 kinase activity by interacting with the myristate binding site and stabilizes the inactive 
conformation of the enzyme (Manley et al 2018). Because it does not bind to the ATP binding 
site it maintains activity against kinase domain mutations that would impairs the activity of 
ATP-competitive drugs (Manley et al 2020). Asciminib is active in patients that have failed two 
or more prior TKIs, with 48% of patients achieving a major molecular response (MMR) in a 
heavily pretreated population in the Phase I study CABL001X2101 (Hughes et al 2019). In 
addition, the selective binding of asciminib is predicted to reduce toxicity (Hughes et al 2019), 
which is a promising approach for patients where the side effects of previous ATP-competitive 
TKI treatments did require dose reductions or interruptions and therefore not allow for the 
durable administration of an efficacious dose.  
The ongoing Phase III ASCEMBL (CABL001A2301) study investigates the treatment of 
asciminib versus bosutinib randomized 2:1 in 233 patients with CML-CP who have failed or 
are intolerant to prior treatment with at least two ATP-binding site TKIs. The primary objective 
of the ASCEMBL study is the comparison of the MMR rate at 24 weeks between the two 
treatments. In the primary analysis, asciminib demonstrated statistically significant superiority 
and clinically meaningful efficacy when compared to bosutinib with a MMR rate of 25.5% over 
13.2% respectively. Median duration of follow-up for all patients was 14.9 months. Treatment 
discontinuation was 69.7% and 37.6% for bosutinib and asciminib respectively, with lack of 
efficacy accounting for 31.6% and 21.0% and adverse events accounting for 21.1% and 5.1% 
of the discontinuation for bosutinib and asciminib, respectively. All-grade AEs occurred in 
89.7 % and 96.1% of patients on asciminib and bosutinib, respectively. Grade 3/4 adverse 
events (AE) occurred in 50.6% of patients treated with asciminib and 60.5% of patients treated 
with bosutinib. Thrombocytopenia ≥ Grade 3 was the most commonly reported AE on asciminib 
in 17.3% patients, however only 5 patients (3.2%) discontinued the trial because of this AE. On 
the basis of these results, the authors concluded that the ASCEMBL results support the use of 
asciminib as a new treatment option in CML, particularly in patients with resistance/intolerance 
to ≥2 TKIs (Hochhaus et al 2020c).  
The treatment recommendations from the ELN are considered the most widely used therapeutic 
guidance for CML outside of the US with applications or translations in many country 
recommendations even outside of Europe (Hochhaus et al 2020a). The ELN recommendations 
are revised regularly and have been issued in 2006 (Baccarani et al 2006), 2009 (Baccarani et 
al 2009), 2013 (Baccarani et al 2013) and 2020 (Hochhaus et al 2020a) to reflect the changes 
in the treatment landscape and to allow for the best possible duration and quality of life for a 
given patient.  
For the ASCEMBL protocol created in 2018 the ELN 2013 recommendations were used to 
define the failure criteria to the most recent TKI as inclusion criteria (Hochhaus et al 2020c). 
While the 2013 recommendations still used different sets of criteria to define the response to 

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1st and 2nd treatment, the 2020 ELN recommendations represent only one set of criteria that is 
consistent for 1st line and 2nd line treatment. In general, these 2020 treatment milestone define 
a more ambitious set of response criteria over their 2013 counterpart: in the 2013 ELN 
recommendations, treatment failure in second-line was defined as: no CHR at 3 months, BCR-
ABL1>10% on the International Scale (IS) at 6 months or 12 months. For the 2020 
recommendations the milestones for treatment failure have been revised to BCR-ABL1>10% 
IS at 3 months (if confirmed between 1 and 3 months) and at 6 months, or BCR-ABL1>1% IS 
at 12 months of therapy. Warning criteria in 2nd line are identified as: BCR-ABL1>10% IS at 3 
months, BCR-ABL1>1-10% IS at 6 months and BCR-ABL1>0.1-1% IS at 12 months. As these 
recommendations represent the profound change of the therapeutic landscape over the last 7 
years (Hochhaus et al 2020a) it is considered important to re-evaluate the benefit of asciminib 
in a 3rd line population if the most recent treatment recommendations for failure and warning in 
2nd line are used as inclusion criteria.  
The ASCEMBL study investigated the efficacy and safety of a total daily dose of 80 mg 
asciminib given as one tablet of 40 mg b.i.d. Asciminib is required to be administered under 
fasting conditions with a food-free period of 2 hour before and 1 hour after the drug intake 
[Asciminib Investigator Brochure]. Non adherence to TKI therapy in CML has been correlated 
with poor therapeutic outcomes and is a principal factor contributing to the loss of cytogenetic 
responses and treatment failures in patients on long-term therapy (Ibrahim et al 2011) In a 
Finnish assessment, 21% of the CML patients were characterized to have low adherence, while 
physicians had a tendency to overestimate adherence (Keläle et al 2014). Nilotinib has a similar 
posology to that of asciminib as used in the ASCEMBL study, with twice daily dosing and the 
inclusion of a food-free period. In an analysis of 2546 patients in 63 countries. (Geissler et al 
2017) showed that the adherence to nilotinib was markedly lower than for imatinib and dasatinib, 
both of which can be taken on a once daily regimen.  
Thus, the posology of asciminib is expected to represent challenges for the optimal compliance 
for patients and with integration into the daily routine. Changing from a twice daily to once-
daily dosage for asciminib may therefore improve the ease of administration, increase the 
compliance with treatment and thus help to maintain treatment outcomes.  
Asciminib has demonstrated activity and tolerability in dosages of up to 200 mg b.i.d. (Hughes 
et al 2019). Following failure or intolerance of two TKIs, the number of treatment options for 
patients in 3rd line becomes severely reduced. Moving to another treatment may also bear the 
risk of additional challenges in the management as the efficacy or tolerability in the next line of 
treatment may also be inferior. In particular the use of second-generation TKI after failure to 2 
TKIs may induce responses, but these are usually not durable except in some CP patients. New 
treatment options are needed (Garg et al 2009). It is therefore of interest to investigate a dose 
escalation of asciminib with its novel MoA from the standard dose of 40 mg b.i.d. used in 
ASCEMBL in patients that do not achieve MMR from 48 weeks of treatment and where there 
are no side effects at the current dose that would indicate that the risk of the dose increase 
outweigh a potential benefit. 
Asciminib was granted accelerated approval by the US Food Drug Administration on 29-Oct-
2021 for adult patients with Ph+ CML -CP, previously treated with two or more TKIs. The 
recommended dose of asciminib is a total daily dose of 80 mg, taken either as 80 mg q.d. or 40 
mg BID. The FDA also approved asciminib for adult patients with Ph+ CML in CP with T315I 

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mutation. The recommended dose of asciminib in patients with Ph+ CML in CP with T315I 
mutation is 200 mg BID. 
1.2 Purpose 
The purpose of the study is to investigate the potential optimization of the treatment with 
asciminib 80 mg total daily dose in adult patients with chronic myelogenous leukemia in chronic 
phase (CML-CP) previously treated with 2 or more TKIs.  
Patient population: 
Patients for this study will be identified based on warning criteria and resistance definition 
following ELN 2020 recommendations or intolerance on their 2nd TKI (Hochhaus et al 2020a). 
This is an expanded population compared to the original ASCEMBL study as the inclusion 
criteria for the ASCEMBL-protocol was based on the ELN treatment recommendations from 
2013 (Hochhaus et al 2020c). Applying the newer ELN 2020 criteria will permit patients both 
with treatment failure as well as with warning signs to be included. This will allow for a 
population, with less advanced disease and lower risk of progression to enter the trial, which 
may benefit from a better and longer response to asciminib. 
Patients treated with two or more TKI and intolerance to the last TKI treatment represent a 
clinical challenge as the number of treatment options available to them are limited. For the 
primary analysis, patients with intolerance will be eligible with BCR-ABL1 ≥ 0.1 % (i.e. not in 
MMR). Additionally, 30 patients who are intolerant to ongoing TKI treatment but in MMR will 
be allowed to enter the trial. 
Simplified posology from b.i.d. to q.d. dosing:  
The study will investigate the use of two different dose regimens: All patients will be 
randomized at baseline to receive 80 mg total daily dose of asciminib either as 40 mg b.i.d. in 
agreement with the dose investigated in ASCEMBL or as 80 mg q.d. Though the trial will not 
be powered to compare both treatments, the descriptive data from both treatment groups is 
expected to provide additional insight into the optimal patient management.   
Dose escalation:  
Patients treated in later lines of CML often have few remaining therapeutic options. Asciminib 
has demonstrated activity and tolerability in dosages of up to 200 mg b.i.d. (Hughes et al 2019). 
With the limited treatment options available it is therefore of interest whether patients not in 
MMR at 48 weeks or thereafter could benefit from a potential dose escalation. Based on 
extensive PK modeling, a dose escalation from 40 mg b.i.d. / 80 mg q.d. asciminib to 200 mg 
q.d. asciminib was chosen for this approach. 
Taken together the data will provide valuable guidance for the clinical practice and use of 
asciminib in patients treated in agreement with most recent treatment recommendations and 
current clinical practice. 

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2 Objectives and endpoints 
Table 2-1 Objectives and related endpoints 
Objectives 
Endpoint(s) 
Primary:  
• 
To estimate the major molecular response 
(MMR) rate at week 48 of all patients (40 mg 
b.i.d. asciminib and 80 mg q.d.) with CML-
CP following two or more prior TKI 
treatments and with no evidence of MMR at 
baseline. 
 
• 
Major Molecular Response (MMR) rate at 
week 48. 
Secondary: 
• 
To evaluate the safety and tolerability of 
asciminib in patients with CML-CP following 
two or more prior TKI treatments. 
 
• 
Type, frequency and severity of adverse 
events, changes in laboratory values that fall 
outside the pre-determined ranges and 
clinically notable ECG and other safety data 
(vital signs, physical examination). 
• 
To assess the rate of major molecular 
responses (MMR) in patients without MMR 
at baseline, at alternative time points at 
weeks 12, 24, 36, 72, 96 and 144. 
• 
To assess the rate of molecular responses 
(MMR) at week 48 for patients with MMR at 
baseline  
• 
To assess the time to MMR  
• 
MMR rate at weeks 12, 24, 36, 72, 96 and 
144. 
 
 
• 
MMR rate at week 48 for patients with MMR at 
baseline. 
• 
Time from the date of randomization to the 
date of first documented MMR 
• 
To assess the rate of early responses of 
BCR-ABL1 ≤10% and ≤1% at weeks 12, 24, 
36 and 48 
• 
To assess the rate of deep molecular 
responses (MR4 and MR4.5) at weeks 12, 
24, 36, 48, 72, 96 and 144.  
• 
To assess cytogenetic response (% Ph+ 
metaphases) at weeks 48 and EOT. 
• 
To characterize the impact of additional 
cytogenetic abnormalities on efficacy 
• 
To assess cumulative molecular responses 
by all-time points. 
• 
To assess duration of MMR. 
• 
To assess sustained deep molecular 
responses as prerequisite for TFR. 
• 
To assess rate of progression (PFS). 
• 
To assess overall survival (OS). 
• 
To assess time to treatment failure (TTF). 
• 
To evaluate patient reported outcomes and 
quality of life by using QoL scale.  
• 
Rate of BCR-ABL1 ≤ 10% and ≤1% at weeks 
12, 24, 36 and 48 
 
• 
Rate of MR4 and MR4.5 at weeks 12, 24, 36, 
48, 72, 96 and 144. 
• 
 
• 
Rate of complete cytogenetic response 
(CCyR) at weeks 48 and EOT. 
• 
Additional chromosomal abnormalities and 
occurrence of high-risk ACAs 
• 
Rate of BCR-ABL1 ≤ 10%, BCR-ABL1 ≤1%, 
MMR, MR4 and MR4.5 by all-time points. 
• 
Duration of MMR. 
• 
Duration of MR4 without loss of MMR. 
• 
Time from randomization to death. 
• 
Time from randomization to treatment failure 
define as BCR-ABL1 > 1%. 
• 
Change in symptom burden and interference 
from baseline over time according to the 
MDASI-CML PRO instrument. 

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2.2 Secondary estimands 
Not applicable. 
3 Study design 
The study is an international, multi-center, non-comparative, phase IIIb, treatment optimization 
study of asciminib (randomized 1:1 to either 40 mg b.i.d. or 80 mg q.d.) in adult patients 
previously treated with 2 or more TKIs. Randomization is only used to have a balance in the 
allocation of treatment into either asciminib 40 mg b.i.d. or 80 mg q.d. 
In patients not achieving MMR at 48 weeks or losing the response after the week 48 assessment 
up to week 108, asciminib dose may be escalated to 200 mg q.d. if in the investigator’s opinion 
the patient may benefit from the escalation. In addition, there must not be any grade 3 or 4 
toxicity while on therapy, or persistent grade 2 toxicity, possibly related to asciminib and 
unresponsive to optimal management.  
BCR-ABL1 and 
 results are required before increasing asciminib dose, 
therefore the dose escalation can occur at next scheduled visit upon results review of the prior 
visit. In patients losing response after the week 48 assessment, the last possible time point to 
initiate the 200 mg dose will be the week 120 visit to ensure that efficacy and safety of the dose 
escalation can be sufficiently established during the remaining trial follow up period.  
If a dose decrease is required, patients will return to the initial dosing regimen (q.d. or b.i.d.) 
they were using before the dose increase which was considered tolerable. For this reason, if a 
patient e.g. escalates from 40 mg b.i.d. to 200 mg q.d., in case of a required dose decrease a use 
to 80 mg q.d. is not allowed and the patient will continue on 40 mg b.i.d. asciminib.  
All patients will be treated for a maximum duration of 144 weeks.  
The primary endpoint of the study is MMR rate at 48 weeks. As the ELN 2020 
recommendations do not give specific treatment guidance for milestones in 3rd line, the ELN 
2020 milestone at twelve months for optimal response in 2nd and 1st line was chosen to define 
the primary endpoint.  
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4 Rationale 
4.1 Rationale for study design 
The trial presented in this protocol is an open-label, treatment optimization study. Patients will 
receive asciminib as study treatment continuously for up to 144 weeks or until disease 
progression, treatment failure or intolerance to treatment. At treatment initiation, asciminib will 
be provided to all trial patients at a total daily dose of 80 mg. All patients will be randomly 
assigned 1:1 to 2 groups with 80 mg given either as 40 mg b.i.d. or 80 mg q.d., using IRT to 
avoid any selection bias. Considering the objective nature of the primary endpoint, an open 
label study is deemed acceptable. 
The ongoing ASCEMBL study is a phase III study, investigating the efficacy of treatment with 
asciminib versus bosutinib in CML-CP patients with at least 2 prior therapies. In the primary 
analysis, asciminib (40 mg b.i.d.) demonstrated statistically significant superiority and 
clinically meaningful efficacy when compared to bosutinib (500 mg q.d.) with a MMR rate at 
week 24 of 25.5% over 13.2% respectively. Following the release of the initial results, questions 
remain such as daily dosing schedule and escalation.  
Changing from a twice a day (b.i.d.) to once a day (q.d.) dosage for asciminib may improve the 
ease of administration, increase the compliance with treatment and thus help to maintain 
treatment outcomes. Though the trial will not be powered to compare both treatments, the 
descriptive data from both treatment groups is expected to provide additional insight into 
optimal patient management.  
Patients treated in later lines of CML often have few remaining therapeutic options. Considering 
asciminib has demonstrated activity and tolerability in dosages of up to 200 mg b.i.d.  
(Hughes et al 2019), it is of interest to investigate whether patients could benefit from a potential 
asciminib dose escalation. A single step dose escalation to 200 mg q.d. was chosen for this trial 
as it would allow for a substantial increase in asciminib exposure while at the same time the 
safety profile can be maintained.  
4.1.1 Rationale for choice of background therapy 
Not applicable. 
4.2 Rationale for dose/regimen and duration of treatment 
The primary dose chosen for the trial is total daily dose of 80 mg taken as either 40 mg b.i.d. or 
80 mg q.d (1:1 randomization). Following the primary endpoint assessment at week 48, the 
asciminib dose may be escalated to 200 mg q.d. in patients not achieving or not maintaining 
MMR at 48 weeks up to 108 weeks per investigator decision. 
Based on the results of study CABL001X2101, 40 mg b.i.d. was selected as the recommended 
dose for patients with CML-CP and was further evaluated as the standard dose in the pivotal 
registration study ASCEMBL (CABL001A2301). The study population in the ongoing 
ASCEMBL trial includes 222 patients with CML-CP, and treatment failure according to the 
ELN 2013 criteria (Baccarani et al 2013), who had prior treatment with 2 or more ATP binding 
TKIs. The results from this study confirmed that the dose of 40 mg b.i.d. was safe, efficacious 
and well tolerated (Hochhaus et al 2020c).  

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Extensive exposure-efficacy and exposure-safety analyses were performed based on pooled 
clinical asciminib data.  
The exposure-efficacy analysis of %BCR-ABL time course highlighted the existence of a 
slightly positive exposure-efficacy relationship, which did not translate into meaningful 
difference in median predicted MMR rates over the complete wide dose range tested (i.e. 20 mg 
to 400 mg total daily dose), regardless of PK metrics (daily AUC, Cmax and Cmin) used 
[
]. Similar efficacy for asciminib 80 mg q.d. compared to 40 mg 
b.i.d. in patients were predicted. In agreement with the observed data, the predicted MMR rate 
at 
 for asciminib 40 mg b.i.d. and 80 mg q.d. was 
% and 
%, 
respectively.  
For exposure-safety modelling, a repeated logistic regression model was used to describe the 
association between the probability of a safety event and PK exposure. Selected relevant safety 
endpoints included laboratory parameters (amylase, lipase, platelets count, neutrophils, 
hemoglobin, AST, ALT, total bilirubin, triglycerides and serum creatinine), vital signs (systolic 
blood pressure and diastolic blood pressure in supine position only) for hypertension, AEs for 
fatigue and asthenia, Grade ≥ 3 TEAEs and TEAEs leading to dose reductions and/or 
interruptions. Other safety analyses included time to first dose reduction due to an AE and effect 
of exposure on serum creatinine (for assessing the potential effect of asciminib on renal 
transporters). Based on this exposure-safety analysis there is no apparent correlation between 
the probability of a safety event and increase in exposure when using any PK metrics for 40 mg 
b.i.d. vs 80 mg q.d. [
]. 
Simulated steady state PK profiles and parameters, using the population estimates for 40 mg 
b.i.d. and 80 mg q.d. are presented in Figure 4-1 and Table 4-1, respectively. The simulated 
mean AUC0-24hr values were comparable between the two regimens. Compared to 40 mg b.i.d., 
Cmax and Cmin were approximately 
% higher and 
% lower for 80 mg q.d. 
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Figure 4-1 
Simulated mean steady state PK profiles of asciminib 40 mg b.i.d. and 80 
mg q.d. 
 
The shaded area represents the 10th – 90th percentile. The solid line represents the median. 
Source: [PopPK Report]. 
 
Table 4-1 Summary of simulated PK metrics of 40 mg b.i.d. and 80 mg q.d. 
Regimen 
Cmin (ng/mL) 
Cmax (ng/mL) 
AUC0-24hr (ng*hr/mL) 
40 mg b.i.d. 
302 (60%) 
908 (40%) 
12638 (43%) 
80 mg q.d. 
215 (77%) 
1463 (40%) 
12646 (43%) 
Arithmetic mean and %CV are presented 
Source: [PopPK Report]. 
Based on the population PK model there is no difference in clearance between 80 mg q.d. and 
40 mg b.i.d.  
In summary, based on the available clinical data as well as the extensive exposure-efficacy and 
efficacy-safety analyses, the risk/benefit ratio of asciminib administered at 80 mg q.d. in 
patients with CML not harboring the T315I mutation is not different than that of asciminib 40 
mg b.i.d.  
Treatment duration for the individual patient in this study is anticipated to be 144 weeks. In 
ASCEMBL (patients with CML-CP and treatment failure according to the ELN 2013 criteria), 
37.6% of patients treated with asciminib (40 mg b.i.d.) had discontinued their treatment with 
43.4 weeks median duration of exposure for asciminib (Hochhaus et al 2020c). The protocol 
presented here will be using the 2020 ELN milestones (Hochhaus et al 2020a). Applying the 
newer ELN 2020 criteria will permit patients both with treatment failure as well as with warning 

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signs to be included. This will allow for a population, with less advanced disease and lower risk 
of progression to enter the trial. It is believed that the less resistant patient population may 
benefit from longer treatment with asciminib. The overall trial duration was therefore selected 
as 144 weeks while it was 96 weeks in ASCEMBL. 
Patients treated in 3rd and later lines of CML often have few remaining therapeutic options with 
no established standards of care and disease monitoring. (ELN 2020). In this study patients not 
achieving MMR from 48 to 108 weeks of treatment with asciminib (40 mg b.i.d. or 80 mg q.d.) 
will be permitted a dose escalation to 200 mg q.d. It is anticipated that this dose of asciminib 
will lead to a marked increase in exposure that may lead to better efficacy while at the same 
time remains within the known side effect profile that has been assessed in the CABL001X2101 
study up to doses of 200 mg b.i.d.  
The protocols of both phase I (CABL001X2101) and phase III (ASCEMBL, CABL001A2301) 
did not include a planned approach dose escalation in response to a lack of efficacy. Dose 
escalation was permitted for individual patients at investigators judgement in the phase I 
(CABL001X2101) study. 
A dose of 200 mg q.d. was investigated in the CABL001X2101 protocol for patients with CML-
CP and AP (n=12) (CABL001X2101). All patients (n=12) with CML-CP/-AP treated with 
asciminib 200 mg q.d. single agent had at least one AE regardless of study treatment 
relationship. Overall, the most frequent AEs by PT reported [≥ 4 patients (33.3%) treated with 
200 mg q.d.] were fatigue and headache (50.0%), nausea and diarrhoea (41.7%), amylase 
increased, hypertension, lipase increased, abdominal pain, constipation, insomnia, depression, 
hypertriglyceridaemia, myalgia and palpitations (33.3% each). Grade ≥ 3 AEs (regardless of 
study treatment relationship) were reported in 8 patients (66.7%), with most common being 
lipase increased (33.3% patients), and hypertension, myocardial infarction and pancreatitis 
(16.7% each). SAEs suspected to be related to treatment with asciminib were reported in 3 
patients (25.0%). These suspected events were angina pectoris, myocardial infarction, 
pericardial effusion, pancreatitis, and pleural effusion (n=1 each). Overall, one patient 
discontinued asciminib treatment due to AEs – lipase increased and amylase increased, which 
were suspected to be related to asciminib treatment. No on-treatment death was reported in 
cohort taking asciminib 200 mg q.d. single agent for treatment of CML-CP/AP. Though less of 
patients were exposed to this dosage regimen in CABL001X2101 study, the safety analysis 
showed that incidence and severity of AEs treated with asciminib 200 mg q.d was comparable 
with the overall safety profile of asciminib single agent used in treatment of CML-CP/AP.  
The exposure-efficacy analysis of %BCR-ABL time course highlighted the existence of a 
slightly positive exposure-efficacy relationship, hence patients may benefit from such a dose 
escalation. Asciminib 200 mg q.d. is regarded to be safe and well tolerated, which is also 
supported by the observed flat exposure-safety relationship across all doses tested (i.e. up to 
400 mg total daily dose). To conclude, the risk/benefit ratio is believed to stay positive for 
asciminib 200 mg q.d. in the patients that fail to achieve MMR from 48 weeks. 
4.3 Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable. 

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4.4 Purpose and timing of interim analyses/design adaptations 
There are no formal interim analyses or design adaptation planned for this study. Please refer 
to Section 10 and Section 12.7 for details on data monitoring and reporting. 
4.5 Risks and benefits 
Appropriate eligibility criteria, as well as specific dose modification and stopping rules, are 
included in this protocol.  
Patients either failing or being intolerant to previous TKI therapy may have limited sensitivity 
to the remaining available TKIs or have mutations or comorbidities that prevent the use of 
specific TKIs. Importantly, with each line of treatment with TKIs, failure rates increase 
including the risk of progressing to advanced phases of the disease (Cortes et al 2013,  
Soverini et al 2014 and Soverini et al 2016). Therefore, the ultimate treatment goal is to reach 
optimal disease control to prevent disease progression in patients with CML-CP.  
In two independent clinical studies asciminib has demonstrated to be efficacious in patients 
pretreated in multiple lines of therapy combined with good tolerability. Results from the phase 
I study CABL001X2101 showed durable responses with asciminib in a heavily pretreated 
population who had resistance to or unacceptable side effects from TKIs. In the ASCEMBL 
study (CABL001A2301) asciminib demonstrated superiority in the molecular response over 
bosutinib in patients treated with two prior TKI (Hochhaus et al 2020c).  
This phase IIIb study aims to investigate the efficacy and safety of asciminib in an expanded 
population over the one from ASCEMBL, applying the newer ELN 2020 criteria and allowing 
patients both with treatment failure as well as with warning signs to be included. This will allow 
for a population with a less advanced disease and lower risk of progression to enter the trial, 
who may potentially benefit from a better response to asciminib. In addition, the tolerability of 
asciminib may allow for a more durable treatment with less side effects and lower risk of 
treatment discontinuation in this population. Using a second-generation TKI after failure of a 
prior second generation TKI appears to be of limited value (Hochhaus et al 2020b) and the 
results are often short-lived. With the demonstrated efficacy from ASCEMBL it appears 
therefore acceptable to expand the patient population to the ELN criteria 2020 and include 
patients with warning signs. 
Patients who are intolerant to ongoing TKI treatment but in MMR will also be allowed to enter 
the trial. Management of side effects represent a significant challenge with TKIs, in particular 
as patients may achieve a normal life expectancy. Data from ASCEMBL (Hochhaus et al 2020c) 
support a more favorable safety profile of asciminib compared with bosutinib. Patients with 
long-lasting side effects may therefore benefit from a switch to asciminib and an improved 
quality of life, while at the same time have little risk of losing the previously attained good 
response. All patients will also be closely monitored so any loss of molecular response will be 
detected early.  
The patient selection in this protocol is based on the ASCEMBL study, while expanding on the 
latest finding and results from this trial to reflect the optimum in safety management. Efficacy 
of the drug is assessed through molecular monitoring in central lab standardized to the 
international scale. With the exception of the bone marrow assessment required for response 

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monitoring, the protocol does not include invasive examination. Patient visits are aligned with 
the safety monitoring requirements as well as with current treatment recommendations and 
represent a common schedule that is also required in clinical practice outside of the study. It is 
therefore anticipated, that the protocol will take every precaution to allow for the best possible 
safety of the patients while at the same time carefully managing the additional burden of the 
trial to patients.  
Patients will be randomized 1:1 into two treatment groups treated with asciminib 40 mg b.i.d 
or 80 mg q.d. Based on the available clinical data as well as the extensive exposure-efficacy 
and efficacy-safety analyses, the risk/benefit ratio of asciminib administered at 80 mg q.d. in 
patients with CML not harboring the T315I mutation is not different than that of asciminib 40 
mg b.i.d.  
Patients not reaching MMR at 48 weeks or losing the response thereafter will be allowed to 
escalate the dose to 200 mg. The exposure-efficacy analysis of %BCR-ABL1 time course 
highlighted the existence of a slightly positive exposure-efficacy relationship, hence patients 
may benefit from such a dose escalation. Asciminib 200 mg q.d. is regarded to be safe and well 
tolerated, which is also supported by the observed flat exposure-safety relationship across all 
doses tested (i.e. up to 400 mg total daily dose). The risk/benefit ratio is believed to stay positive 
for asciminib 200 mg q.d. in the patients that fail to achieve MMR from 48 weeks. 
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 outlined in the 
exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study. 
There may be unforeseen risk with asciminib, which could be serious. Refer to the latest 
[Asciminib Investigator’s Brochure].  
This study carries no requirement for patients to be tested for SARS-CoV-2. Based on the 
known mechanism of action, asciminib is not expected to negatively impact known immune 
mechanisms involved in clearing SARS-CoV-2 infection. However, no studies were conducted 
to assess whether asciminib may possess an additional risk in case of exposure to SARS-CoV-
2. Subjects treated with asciminib should be informed there could be unknown side effects that 
may lead to complications of COVID-19. 
There is no known contraindication for the use of an inactivated, viral-vector-, or mRNA-based 
SARS-CoV-2 vaccine in patients with cancer who receive asciminib therapy. Recognizing that 
multiple vaccines may have various mechanisms of action with different associated potential 
risks, locally applicable public health and Health Authority guidance for SARS-CoV-2 vaccine 
should be followed, and Independent Review Boards (IRB)/Ethics Committees (EC) consulted 
if needed. For patients in the study, the decision and timing of vaccination against SARS-CoV-
2 should be made on a case-by-case basis and at the discretion of the treating physician. 
4.6 Rationale for COVID-19 pandemic mitigation procedures 
Due to the ongoing COVID-19 pandemic, mitigation procedures may be implemented to ensure 
participant safety and trial integrity. These are listed in the relevant sections of the protocol. 
Notification of these mitigation procedures should be discussed with Novartis prior to 

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implementation of mitigation procedures and permitted/approved by Local or Regional Health 
Authorities and Ethics Committees as appropriate.  
5 Study Population 
The trial will enroll a total of approximately 186 patients with CML-CP following treatment 
with two or more prior TKIs.  
One hundred fifty-six (156) patients with CML-CP not in MMR at baseline who have been 
previously treated with two or more TKIs and who were either resistant (ELN 2020 warning or 
failure) or intolerant to the last treatment will be enrolled. 
Up to 30 additional patients intolerant only to their last TKI treatment and in MMR at baseline 
will also be enrolled.  
The primary endpoint for MMR rate at 48 weeks will be assessed only in patients who are not 
in MMR at baseline.  
The definition of CML-CP will be according to the ELN 2020 criteria (Hochhaus et al 2020a) 
and is outlined below in the inclusion criteria. 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
5.1 Inclusion criteria 
Participants eligible for inclusion in this study must meet all the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Male or female patients with a diagnosis of CML-CP ≥ 18 years of age 
3. Patients must meet all the following laboratory values at the screening visit: 
• < 15% blasts in peripheral blood and bone marrow 
• < 30% blasts plus promyelocytes in peripheral blood and bone marrow 
• < 20% basophils in the peripheral blood 
• ≥ 50 x 109/L (≥ 50,000/mm3) platelets 
• Transient prior therapy related thrombocytopenia (< 50,000/mm3 for ≤ 30 days prior 
to screening) is acceptable 
• No evidence of extramedullary leukemic involvement, with the exception of 
hepatosplenomegaly 
4. Prior treatment with a minimum of 2 prior TKIs (i.e. imatinib, nilotinib, dasatinib, 
bosutinib, radotinib or ponatinib) 
5. Warning or failure (adapted from the 2020 ELN Recommendations) or intolerance to the 
most recent TKI therapy at the time of screening  
• Warning is defined as: 
• Three months after the initiation of treatment: BCR-ABL1 > 10% IS 
• Six months after the initiation of treatment: BCR-ABL1 >1-10% IS 
• Twelve months after the initiation of treatment BCR-ABL1>0,1-1% IS 

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• At any time after the initiation of therapy BCR-ABL1 >0.1-1% IS, loss of MMR 
(>0.1% with 5-fold increase of BCR-ABL1 transcripts). 
• In addition, patients with failure of treatment according to the ELN 2020 
recommendations will be eligible: 
• Three months after the initiation of treatment: BCR-ABL1 > 10% IS if confirmed 
within 1-3 months 
• Six months after the initiation of treatment: BCR-ABL1 >10% IS 
• Twelve months after the initiation of treatment BCR-ABL1 >1% IS 
• At any time after the initiation of therapy BCR-ABL1 >1% IS, emergence of 
resistance mutations, high-risk ACA 
• Intolerance is defined as: 
• Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on 
therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, 
including dose adjustments (unless dose reduction is not considered in the best 
interest of the patient if response is already suboptimal) 
• Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil 
count [ANC] or platelets) while on therapy that is recurrent after dose reduction 
to the lowest doses recommended by manufacturer 
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2 
7. Adequate end organ function as defined by: 
• Total bilirubin ≤ 3 x ULN; patients with Gilbert’s syndrome may only be included if 
Total bilirubin ≤ 3 x ULN or direct bilirubin ≤1.5 ULN       
• Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value must be 
considered not clinically significant and not associated with risk factors for acute 
pancreatitis 
• Alkaline phosphatase ≤ 2.5 x ULN  
• Creatinine clearance ≥ 30 mL/min as calculated using Cockcroft-Gault formula 
8. Patients must have the following electrolyte values within normal limits or corrected to be 
within normal limits with supplements prior to first dose of study medication: 
• Potassium (potassium increase of up to 6.0 mmol/L is acceptable at study entry if 
associated with creatinine clearance* within normal limits) 
• Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 
3.1 mmol/L is acceptable at study entry if associated with creatinine clearance* within 
normal limits) 
• Magnesium, with the exception of magnesium increase > ULN – 3.0 mg/dL; > ULN - 
1.23 mmol/L associated with creatinine clearance* within normal limits 
*calculated using Cockcroft-Gault formula 
9. Evidence of typical BCR-ABL1 transcripts [e14a2 and/or e13a2] at the time of screening 
which are amenable to standardized RQ-PCR quantification 

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5.2 Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Known presence of the BCR-ABL1 T315I mutation at any time prior to study entry 
2. Known history of AP/BC 
3. Previous treatment with a hematopoietic stem-cell transplantation 
4. Patient planning to undergo allogeneic hematopoietic stem cell transplantation 
5. Cardiac or cardiac repolarization abnormality, including any of the following: 
• History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft 
(CABG) within 6 months prior to starting study treatment 
• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II 
and third degree AV block, permanent pace maker) 
• QTcF at screening ≥450 msec (male patients), ≥460 msec (female patients) 
• Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome, or any of the following: 
• Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically significant/ 
symptomatic bradycardia 
• Concomitant medication(s) with a “Known risk of Torsades de Pointes” (per 
www.crediblemeds.org/) that cannot be discontinued or replaced 7 days prior to 
starting study drug by safe alternative medication. 
• Inability to determine the QTcF interval 
6. Severe and/or uncontrolled concurrent medical disease that in the opinion of the 
investigator could cause unacceptable safety risks or compromise compliance with the 
protocol (e.g. uncontrolled diabetes, active or uncontrolled infection, pulmonary 
hypertension) 
7. History of acute pancreatitis within 1 year of study entry or past medical history of chronic 
pancreatitis 
8. Patients with known history of Human Immunodeficiency Virus (HIV).  
9. Testing for Hepatitis B surface antigen (HbsAg) and Hepatitis B core antibody (HBcAb / 
anti HBc) will be performed at screening. Patients with active Hepatitis B Virus (HBV) 
infection (hepatitis B surface antigen [HbsAg] positive) will be excluded. HBV-DNA 
testing will also be performed at screening, if anti Hbc is positive. Note: Patients with 
antecedent but no active HBV (i.e., hepatitis B core antibody [HBcAb] positive, and both 
HbsAg and HBV-deoxyribonucleic acid negative) are eligible. In these cases, patients may 
be on anti-HBV prophylaxis and should be monitored for reactivation via monthly HBV-
DNA evaluations.  
10. Positive test for Hepatitis C Virus (HCV) ribonucleic acid (RNA). Testing for Hepatitis C 
antibody (HCV Ab) will be performed at screening. HCV-RNA testing will also be 
performed at screening if HCV Ab are positive.  

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11. 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) 
12. Previous treatment with or known/ suspected hypersensitivity to asciminib or any of its 
excipients. 
13. Pregnant or nursing (lactating) women 
14. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 3 days after last dose of asciminib. 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 sterilization (have had surgical bilateral oophorectomy (with or without 
hysterectomy) total hysterectomy or bilateral tubal ligation at least six weeks before 
taking study treatment). In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that 
participant.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), total hysterectomy 
or bilateral tubal ligation at least six weeks before taking study medication. In the case of 
oophorectomy alone, women are considered post-menopausal and not of child-bearing potential 
only when the reproductive status of the woman has been confirmed by follow up hormone 
level assessment. 
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the Inform Consent Form (ICF). 
15. Participation in a prior investigational study within 30 days prior to randomization or 
within 5-half-lives of the investigational product, whichever is longer. 

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Exception: The investigator has the discretion to include/exclude a subject in the study, who 
will be found to have symptoms representative of COVID-19 during the screening phase. Such 
subjects should be managed as per the country specific guidelines related to COVID-19.  
Of note, neutropenia was reported as a common adverse event in CML patients treated with 
asciminib in ongoing clinical studies. However, lymphopenia was not frequently reported in 
these patients. In addition, no effects on lymphocytes were observed in rats, dogs or monkeys.  
Based on the known mechanism of action, asciminib is not expected to negatively impact 
known immune mechanisms involved in clearing SARS-CoV-2 infection. However, no studies 
were conducted to assess whether asciminib may possess an additional risk in case of exposure 
to SARS-CoV-2. Subjects treated with asciminib should be informed there could be unknown 
side effects that may lead to complications of COVID-19. 
6 Treatment 
6.1 Study treatment 
The investigational treatment for this study is asciminib (40 mg b.i.d. or 80 mg q.d. as assigned 
by IRT). Novartis will supply asciminib to the investigational site as 20 mg and 40 mg tablets.  
In patients not achieving MMR at 48 weeks or losing the response (confirmed loss of MMR in 
two consecutive tests) after the week 48 assessment up to week 108, asciminib dose may be 
escalated to 200 mg q.d. if in the investigator’s opinion the patient may benefit from the 
escalation. In addition, to participate in the dose escalation, there must not be any grade 3 or 4 
toxicity while on therapy, or persistent grade 2 toxicity, possibly related to asciminib and 
unresponsive to optimal management. 
Dose escalation may happen at next schedule visit upon receipt of BCR-ABL1 and 
 
. 
6.1.1 Dosing regimen 
Asciminib 
Asciminib will be supplied to the investigational site as 20 mg and 40 mg tablets. Asciminib 
will be administered orally twice a day (b.i.d.) or once a day (q.d.) as assigned by IRT upon 
eligibility confirmation, without food, for patients on standard dose of 80 mg daily.  
Upon dose escalation to 200 mg, asciminib 40 mg tablets will be administered orally once a day 
(q.d.).  
If a dose decrease from 200 mg q.d. is required, patients will return to the initial dosing regimen 
(q.d. or b.i.d.) they were using before the dose increase which was considered tolerable. For this 
reason, if a patient e.g. escalates from 40 mg b.i.d. to 200 mg q.d., in case of a required dose 
decrease a use to 80 mg q.d. is not allowed and the patient must continue on 40 mg b.i.d. 
asciminib 
Asciminib tablets should be ingested as described in Section 6.3.2. 
CCI

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Study drug 
Table 6-1 Investigational drug 
Study Drug 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor 
(global or 
local) 
Asciminib (ABL001) 20 
mga 
Tablet 
Oral use 
Open-label 
supply, bottle 
Sponsor 
(global) 
Asciminib (ABL001) 40 
mg 
Tablet 
Oral use 
Open-label 
supply, bottle 
Sponsor 
(global) 
a20 mg tablets will be dispensed to patients in the instance of dose reduction. 
6.1.2 Additional study treatments 
No additional treatment beyond investigational drug are included in this trial. 
6.1.3 Guidelines for continuation of treatment 
See Section 6.6. 
6.1.4 Treatment duration 
The planned duration of treatment is up to 144 weeks unless patient discontinue from treatment 
due to unacceptable toxicity, disease progression and/or if treatment is discontinued at the 
discretion of the investigator or the participant prior to week 144. 
At the end of the treatment period, for patients who in the opinion of the investigator are still 
deriving clinical benefit from asciminib, every effort will be made to continue provision of the 
drug through alternative options if asciminib is not commercially available. Options includes, 
but are not limited to, roll over trial or provision of the treatment in a non-trial setting (known 
as post-study drug supply), in accordance with local laws and regulations.  
6.1.4.1 Treatment beyond disease progression 
Not applicable. 
6.2 Other treatment(s) 
Anti-emetics 
Use of anti-emetics is allowed. Prophylactic anti-emetics should be started only once the patient 
experiences nausea or vomiting, at the discretion of the investigator. It is recommended that 
patients use drugs that do not cause QT prolongation. Please note that some anti-emetics have 
a known risk for Torsade de Pointes (refer to Section 6.2.2 and Section 16 Appendix 1). 
Bisphosphonates 
The use of bisphosphonates regardless of indication is allowed. 

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Contraceptives 
Hormonal contraceptives are allowed as contraception methods. Highly effective contraception 
should be maintained throughout the study and for 3 days after study treatment discontinuation. 
Anticoagulation agents 
All anticoagulants or anti-aggregation agents may be administered under the discretion of the 
investigator. 
Therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative 
anticoagulants should be used with caution and fully avoided whenever possible because of its 
known interaction with many commonly used medications and certain foods. As warfarin has 
a narrow therapeutic range, and asciminib is a weak inhibitor of CYP2C9, the major 
metabolizing enzyme of S-warfarin (R-warfarin is metabolized by multiple CYP enzymes), 
warfarin should be carefully monitored whenever used. 
Caution is also advised when asciminib is co-administered with anti-platelet pro-drugs such as 
clopidogrel, ticlopidine and prasugrel, which require metabolic activation by CYP3A4 and 
CYP2C9. Patients using anti-platelet pro-drugs should still be carefully monitored. 
Direct Thrombin inhibitors (DTIs) and Factor Xa inhibitors are allowed as anticoagulants. 
Individual medications from each of the classes should be checked if they are not prohibited 
due to other drug-drug-interactions with asciminib. Alternatively, therapeutic anticoagulation 
may be accomplished using low-molecular weight heparin. 
Drugs that affect gastric pH 
Drugs that elevate gastric pH do not affect asciminib absorption. All acid reducing agents are 
allowed. 
6.2.1 Concomitant therapy 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug and including 
over-the-counter treatment and nutritional or vitamin supplements) and significant non-drug 
therapies (including physical therapy, herbal/natural medications and blood transfusions) 
administered during the study must be listed on the “Concomitant Medications/Significant 
nondrug therapies” section of the eCRF.  
Chronic medication should be maintained at the same dose and schedule throughout the study 
period, as medically feasible. 
All prior antineoplastic surgery, chemotherapy, biologic, immunologic and radiation therapy 
must be recorded in the “Prior antineoplastic therapy” section of the eCRF. 
In general, concomitant medications and therapies deemed necessary for the supportive care 
and safety of the patient are allowed, provided their use is documented in the patient records 
and on the appropriate case report form, including the medication’s duration (start and end dates 
or if continuing at final exam). These include blood and platelet transfusions for patients with 
anemia and with thrombocytopenia. 

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All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms. 
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 
starting participant on treatment or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study. 
6.2.1.1 Permitted concomitant therapy requiring caution and/or action 
Following drugs should be used with caution: 
• CYP3A4/5 substrates with narrow therapeutic index (NTI) 
• CYP2C9 substrates with NTI 
• Strong CYP3A4 inducers  
QT prolonging agents 
As far as possible avoid co-administering drugs with a “Known”, “Possible” or “Conditional” 
risk of Torsades de Pointes (per www.crediblemeds.org/) during the course of the study: 
• If during the course of the study, concomitant administration of a drug with “Known risk’ 
or “Possible risk” or “Conditional risk of Torsades de Pointes” is required, based on the 
investigator assessment and clinical need, study treatment may be continued under close 
ECG monitoring to ensure patient safety. 
A list of drugs associated with QT prolongation and/or Torsades de Pointes is available online 
at www.crediblemeds.org/. 
6.2.2 Prohibited medication 
Other anticancer agents 
The administration of any other anticancer agents including chemotherapy and biologic agents 
is not permitted except for anti-cancer treatments of newly diagnosed solid cancers (e.g. prostate 
cancer) that would not impact the level of minimal residual disease of patients. These patients 
may remain in the current study after consultation with Novartis. The administration of other 
tyrosine kinase inhibitors indicated for treatment of CML is not allowed.  
Rescue medication 
Not applicable. 
6.3 Preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the appropriate eCRF. 

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As per Section 4.6, if the COVID-19 pandemic limits or prevents on-site study visits, delivery 
of IMP directly to a participant’s home may be permitted (if allowed by Local or Regional 
Health Authorities and Ethics Committees as appropriate) in the event the Investigator has 
decided that an on-site visit by the participant is no longer appropriate or possible, and that it is 
in the interest of the participant’s health to administer the study treatment even without 
performing an on-site visit. Delivery of IMP to participants home should be limited to these 
cases and standard dispensation of IMP at site should resume as soon as patients are able to visit 
study sites again. The decision on how long a patient can receive IMP delivery at home will be 
assessed on a case-by-case basis by the Investigator.  
The dispatch of IMP from the site to the participant’s home remains under the accountability of 
the Investigator. In this case, regular phone calls or virtual contacts as outlined in the visit 
schedule (or more frequently if needed) will occur between the site and the participant for 
instructional purposes, safety monitoring, compliance, investigation of any adverse events, 
ensuring participants continue to benefit from treatment and discussion of the participant´s 
health status until the participants can resume visits at the study site. 
6.3.1 Handling of study treatment and additional treatment  
6.3.1.1 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 in the [Asciminib Investigator Brochure]. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant 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. Drug accountability is also be maintained under the 
accountability of the Investigator. If the COVID-19 pandemic limits or prevents on-site study 
visits, study treatment may be shipped to patient if permitted by local and national regulations. 
Monitoring of drug accountability will be performed by monitors during site visits or remotely 
and at the completion of the trial. Participants 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. 
6.3.1.2 Handling of additional treatment 
Not applicable. 

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6.3.2 Instruction for prescribing and taking study treatment 
• Asciminib should be administered in the fasted state: avoid food for at least 2 hours before 
the dose is taken and for at least 1 hour after the dose is taken. Water is permitted during 
this period. 
• Asciminib should be taken with approximately 8 ounces (240 mL) of water. 
• Asciminib should be swallowed whole and not chewed or crushed. 
• If vomiting occurs within the first hour after taking the drug, re-dosing is allowed before 
the next scheduled dose. 
• If the patient on q.d. regimen does not take asciminib within 12 hours after the 
approximate time of the usual dosing time, that dose should be skipped and treatment 
should continue with the next daily dose at the prescribed level. 
• If the patient on b.i.d. regimen does not take asciminib within 6 hours after the 
approximate time of the usual dosing time, that dose should be skipped and treatment 
should continue with the next scheduled dose at the prescribed level. 
Table 6-2 Dose and treatment schedule 
Study 
treatments 
Pharmaceutical 
form and route 
of 
administration 
Target 
dose/ 
Daily 
dose 
Use 
Tablet 
Strength  
Number of tablets 
Regimen 
Asciminib  
Tablets for oral 
use 
80 mg 
Standard Dose 
40 mg 
1 tablet of 40 mg  
b.i.d. 
Asciminib 
Tablets for oral 
use 
80 mg 
Standard Dose 
40 mg 
2 tablets of 40 mg  
q.d. 
Asciminib 
Tablets for oral 
use 
40 mg 
Dose 
reduction for 
standard dose 
b.i.d. 
20 mg 
1 tablet of 20 mg  
b.i.d. 
Asciminib 
Tablets for oral 
use 
40 mg 
Dose 
reduction for 
standard dose 
q.d. 
40 mg 
1 tablet of 40 mg  
q.d. 
Asciminib 
Tablets for oral 
use 
200 mg 
Dose 
escalation 
from standard 
dose* 
40 mg 
5 tablet of 40 mg  
q.d. 
Asciminib 
Tablets for oral 
use 
80 mg 
Dose 
reduction from 
200mg q.d.** 
40 mg 
2 tablets of 40 mg  
q.d.** 

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Study 
treatments 
Pharmaceutical 
form and route 
of 
administration 
Target 
dose/ 
Daily 
dose 
Use 
Tablet 
Strength  
Number of tablets 
Regimen 
Asciminib 
Tablets for oral 
use 
80 mg 
Dose 
reduction 
from 200mg 
q.d.** 
40 mg 
1 tablet of 40 mg  
b.i.d.** 
All kits of study treatment will be recorded via the IRT. 
* Dose escalation may only occur based on investigators decision after week 48, from week 60 onwards and up 
to week 120 based on week 108 data. 
** Patients on 200 mg q.d. needing a dose de-escalation will revert to 80 mg total daily dose of asciminib and 
will follow initial dosing schedule, either q.d. or b.i.d., as initially assigned by IRT. 
6.4 Participant numbering, treatment assignment, enrollment 
6.4.1 Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned within EDC system when the participant is screened and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be changed. 
If the patient fails to be enrolled or start treatment for any reason, (i.e if a patient is screen failed) 
the reason will be entered into the Screening Disposition page. IRT must be notified by 
investigator or his/her delegate within 2 days of visit that the patient was enrolled or not. 
6.4.2 Treatment assignment 
One to one randomization to asciminib 40 mg b.i.d. and asciminib 80 mg q.d. will be performed 
by IRT for all patients (who were treated with two or more TKIs and who were either resistant 
or intolerant to the last treatment; and also on the additional patients intolerant only to their last 
TKI treatment and in MMR at baseline) upon eligibility confirmation. B.i.d. or q.d. dosing 
allocated at trial start must be maintained for patients who remain at standard dose, or need to 
de-escalate after increase to 200 mg q.d. 

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6.4.2.1 Replacement policy 
Patients that drop out of the study for any reason after having taken the first tablet of study 
medication will not be replaced. 
6.5 Treatment blinding 
Not applicable. 
6.6 Dose escalation and dose modification 
The standard dose for all patients in this study is asciminib 40 mg b.i.d. or 80 mg q.d. For 
patients not achieving MMR at 48 weeks or losing the response after the week 48 assessment 
up to week 108, a dose escalation to 200 mg q.d. may be considered per investigator decision.  
6.6.1 Dose escalation guidelines 
6.6.1.1 Starting dose 
The starting dose for patients will either be asciminib 40 mg b.i.d. or 80 mg q.d. as assigned by 
IRT upon eligibility confirmation. The q.d. or b.i.d. regimen allocated at randomization must 
be maintained throughout the study for patients who do not need to escalate dose, or need to 
de-escalate from 200 mg q.d. 
6.6.2 Dose escalation 
For patients not in MMR at 48 weeks or losing the response after the week 48 assessments up 
to week 108, a dose escalation to 200 mg q.d. may be considered for patients on 40 mg b.i.d. or 
80 mg q.d., if in the investigator’s opinion the patient may benefit from the escalation. In 
addition, there must not be any grade 3 or 4 toxicity while on therapy, or persistent grade 2 
toxicity, possibly related to asciminib and unresponsive to optimal management. 
Patients with dose reduction to 40 mg due to side effects may receive a dose escalation to 200 
mg daily if the event requiring the dose reduction has disappeared and the patient has been 
treated at least 3 months on the standard dose of 80 mg.  
 will be performed in patients not reaching MMR at 48 weeks or patients 
losing the response after the week 48 assessments up to week 108, and for whom a dose 
escalation might benefit the patient, to identify potential BCR-ABL mutations that could confer 
resistance to asciminib. With the limited information on mutations no general treatment 
recommendations can be given for individual mutations. 
Dose escalation may be performed at week 60 for patients not in MMR at week 48. For patients 
losing the response after week 48 up to week 108, dose escalation may be performed up to week 
120 after confirmed loss of MMR in 2 consecutive tests and 
 results are 
available. 
6.6.3 Dose modifications 
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions, 
and/or reductions are either recommended or mandated in order to allow participants to continue 
the study treatment.  
CCI
CCI

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Table 6-3 Dose reduction schedule 
*Dose reduction 
 
 
Starting dose level 0 
Dose level – 1 
Asciminib  
CML-CP  
40 mg b.i.d. (total daily 
dose 80 mg) 
20 mg b.i.d. (total daily 
dose 40 mg) 
CML-CP 
80 mg q.d. (total daily dose 
80 mg) 
40 mg q.d. (total daily 
dose 40 mg) 
CML-CP 
200 mg q.d. (total daily 
dose 200 mg) 
80 mg q.d. or 40 mg b.i.d. 
(total daily dose 80 mg)** 
*Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
**Patients on 200 mg q.d. needing a dose de-escalation will revert to 80 mg total daily dose of asciminib, 
according to pre-escalation dosing schedule (q.d. or b.i.d. regimen assigned at enrollment).  
Asciminib dose reduction below total daily dose of 40 mg (20 mg b.i.d. or 40 mg q.d.) is not allowed. 20 mg 
tablets will be dispensed to patients having 20 mg b.i.d. regimen in the instance of dose reduction. 
These dose modifications, in addition to permanent treatment discontinuations, are summarized 
in (Table 6-4). Deviations to mandatory dose interruptions and/or reductions are not allowed.  
These dose changes must be recorded on the appropriate CRF.   
A patient must discontinue treatment with asciminib if, after treatment is resumed at a lower 
dose level, the toxicity recurs with the same or worse severity, except for recurrence of 
cytopenias (Table 6-4). If a patient requires a dose interruption of > 28 days for each non-
hematologic toxicity, then the patient must be discontinued from the study treatment. If a 
hematologic toxicity (cytopenia Grade 3 or 4) last for more than 42 days without recovery to at 
least a Grade 2, despite asciminib interruption and adequate management (including 
hematopoietic growth factors), then the patient must be discontinued from study treatment. 
Table 6-4 Criteria for dose reduction / interruption / discontinuation and re-initiation 
of treatment for adverse drug reactions 
Dose modifications for asciminib  
Please note that if a patient requires a dose interruption of > 28 days for any toxicity, and > 42 days for 
hematologic toxicity, then the patient should be discontinued from study treatment 
Worst toxicity 
CTCAE Version 5.0 
Asciminib 
Investigations (hematologic): If a hematologic toxicity (cytopenia grade 3 or 4) lasts for more than 42 
days without recovery to at least grade 2, despite asciminib interruption and adequate management 
(including hematopoietic growth factors), then the patient should be discontinued from study 
treatment. 
Neutropenia (ANC) 
Grade 1 (ANC < LLN – 1.5 x 
109/L) 
Recommendation: Maintain dose level 
 
Grade 2 (ANC < 1.5 – 1.0 x 109/L) 
Recommendation: Maintain dose level 
Grade 3 (ANC < 1.0 – 0.5 x 109/L) 
Mandatory: Hold dose until resolved to grade ≤ 2 (recheck CBC 
2x/week), then: 
if resolved in ≤ 14 days, then maintain dose level 
If resolved in > 14 days, then reduce dose  1 dose level  
Grade 4 (ANC < 0.5 x 109/L) 
Mandatory: Hold dose until resolved to grade ≤ 2, (recheck CBC 
2x/week), then: 
if resolved in ≤ 14 days, then maintain dose level 
if resolved in > 14 days, then reduce dose  1 dose level  

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Dose modifications for asciminib  
Please note that if a patient requires a dose interruption of > 28 days for any toxicity, and > 42 days for 
hematologic toxicity, then the patient should be discontinued from study treatment 
Worst toxicity 
CTCAE Version 5.0 
Asciminib 
Febrile neutropenia (ANC < 1.0 x 
109/L, fever ≥ 38.5°C) 
Mandatory: Hold dose until resolved, then reduce dose  1 dose level 
Thrombocytopenia 
Grade 1 (PLT < LLN – 75 X 109/L) 
Recommendation: Maintain dose level 
Grade 2 (PLT < 75 - 50 x 109/L) 
Recommendation: Maintain dose level 
Grade 3 (PLT < 50 - 25 x 109/L) 
Mandatory: Hold dose until resolved to grade ≤ 2 (recheck CBC 
2x/week), then: 
if resolved in ≤ 14 days, then maintain dose level 
if resolved in > 14 days, then reduce dose  1 dose level 
Grade 4 (PLT < 25 x 109/L) 
Mandatory: Hold dose until resolved to grade ≤ 2 (recheck CBC 
2x/week), then: 
if resolved in ≤ 14 days, then maintain dose level 
if resolved in > 14 days, then reduce dose  1 dose level 
Recurrence of any cytopenia 
Recommendation: Hold dose until resolved to grade ≤ 2, then maintain 
current dose level  
For recurrent Grade 3/4 cytopenia, please refer to above guidelines 
for neutropenia and thrombocytopenia; no further dose reduction is 
allowed for already reduced dose. 
Non-hematologic adverse reactions except where further specified in individual sections 
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 until resolved to grade ≤ 1, then reduce dose  1 
dose level 
Grade 4 
Mandatory: Permanently discontinue patient from treatment 
Investigations (renal) 
Serum creatinine 
 
Grade 1 (> ULN - 1.5 x ULN) 
Recommendation: Maintain dose level 
Grade 2 (> 1.5 - 3.0 x ULN) 
Recommendation: Hold dose until resolved to grade ≤ 1 or baseline, 
then maintain dose level 
Grade 3 (> 3.0 - 6.0 x ULN) 
Mandatory: Permanently discontinue patient from treatment 
Grade 4 (> 6.0 x ULN) 
Mandatory: Permanently discontinue patient from treatment 
Investigations (hepatic) 
Isolated total bilirubin elevation 
> ULN – 1.5 x ULN, if baseline 
was normal  
Recommendation: Maintain dose level 
> 1.5 - 3.0 x ULN if baseline was 
normal 
Recommendation: Maintain dose. Repeat Liver Function Tests (LFT) 
within 48-72 hours then monitor LFTsb weekly, or more frequently if 
clinically indicated, until resolved to ≤ 1.5 x ULN or baseline: 
if resolved in ≤ 14 days, then maintain dose level 
if resolved in > 14 days, then reduce dose  1 dose level 
> 3.0 - 10.0 x ULN (irrespective of 
the baseline levels) * 
Mandatory: Hold dose. Repeat LFTs within 48-72 hours then monitor 
LFTsb weekly, or more frequently if clinically indicated, until resolved to ≤ 
1.5 x ULN or baseline: 
if resolved in ≤ 14 days, then reduce dose  1 dose level 
if resolved in > 14 days, then discontinue patient from treatment.  

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Protocol No. CABL001A2302 
 
Dose modifications for asciminib  
Please note that if a patient requires a dose interruption of > 28 days for any toxicity, and > 42 days for 
hematologic toxicity, then the patient should be discontinued from study treatment 
Worst toxicity 
CTCAE Version 5.0 
Asciminib 
The patient should be monitored weekly (including LFTsb), or more 
frequently if clinically indicated, until total bilirubin level has resolved to 
baseline or has stabilized over 4 weeks 
> 10.0 x ULN (irrespective of the 
baseline levels) * 
See footnote**** - otherwise discontinue study treatment 
The patient should be monitored weekly (including LFTsb), or more 
frequently if clinically indicated, until total bilirubin level has resolved to 
baseline or has stabilized over 4 weeks 
Isolated AST or Alanine Aminotransferase (ALT) elevation 
If normal at baseline: 
> 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: Omit 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, resume at prior dose level 
If resolved in > 14 days, resume with reduced dose ↓ 1 dose level 
> 10.0 - 20.0 x ULN  
Mandatory: Omit dose. Repeat 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 resume with reduced dose  1 dose level 
> 20.0 x ULN 
Mandatory: Permanently discontinue 
If elevated at baseline: 
> Baseline - 3.0 x Baseline AND ≤ 
5 x ULN 
Recommendation: Maintain dose level 
> 3.0 x Baseline AND > 5.0 x ULN 
(duration less than 2 weeks) 
Recommendation: Maintain dose level. Repeat 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 ≤ ULN or baseline 
> 3.0 x Baseline AND > 5.0 x ULN 
(duration more than 2 weeks): 
Mandatory: Omit dose. 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 ≤ ULN or 
baseline. If resolved, resume with reduced ↓ 1 dose level. 
> 5.0 x Baseline AND > 8.0 x ULN 
(irrespective of the duration): 
Mandatory: Omit dose. Repeat 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 ≤ ULN or 
baseline. If resolved, resume with reduced ↓ 1 dose level. 
> 20.0 x ULN 
Permanently discontinue 
Combinedc elevations of AST or ALT and total bilirubin 

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Protocol No. CABL001A2302 
 
Dose modifications for asciminib  
Please note that if a patient requires a dose interruption of > 28 days for any toxicity, and > 42 days for 
hematologic toxicity, then the patient should be discontinued from study treatment 
Worst toxicity 
CTCAE Version 5.0 
Asciminib 
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 > 3 x baseline OR 
[AST or ALT > 8.0 x ULN], 
whichever is lower combined with 
total bilirubin > 2 x baseline AND 
> 2.0 x ULN 
Note: For participants with 
Gilbert’s syndrome, at least 2-fold 
increase in direct bilirubin 
Mandatory: Hold dose 
 
Repeat liver tests 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. Please refer to  
Section 6.6.4.1 for additional follow-up evaluations as applicable.  
 
If DILI confirmed: permanently discontinue patient from study drug 
treatment  
 
If not DILI – interrupt treatment. Treat identified cause according to 
institutional guidelines. If resolved, then reduce dose  1 dose level, if 
cause is treatment related. 
Investigation (metabolic) 
Amylase and/or lipase elevation 
Grade 1: > ULN - 1.5 x ULN 
Recommendation: Maintain dose level, measure 2x per week 
Grade 2: > 1.5 - 2.0 x ULN; 
>2.0 - 5.0 x ULN and 
asymptomatic  
Recommendation: Maintain dose level, measure 2x per week 
Grade 3: > 2.0 - 5.0 x ULN with 
signs or symptoms; >5.0 x ULN 
and asymptomatic 
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 and with 
signs or symptoms 
Mandatory: Permanently discontinue patient from treatment. Obtain 
appropriate imaging (i.e., MRI, CT scan, or ultrasound) ** 
Vascular disorders 
Hypertension 
Systolic BP 140-159 mm Hg or 
Diastolic BP 90-99 mm Hg 
Mandatory: If recurrent or persistent (>=24 hrs), or if symptomatic 
increase by >20 mm Hg (diastolic) or to >140/90 mm Hg; monotherapy 
anti-hypertensive treatment indicated;  
Maintain asciminib dose level, with regular monitoring of blood pressure. 
Systolic BP >=160 mm Hg or 
Diastolic BP >=100 mm Hg 
Medical intervention indicated: Initiate antihypertensive therapy (if not 
currently being treated with antihypertensive). If already taking anti-
hypertensive drugs; intensive treatment with increased dose of existing 
anti-hypertensive/ more than one anti-hypertensive drugs than previously 
used 
Hold asciminib dose until resolved to grade ≤ 2, then reduce dose  1 
dose level 
CTCAE Grade 4 
Mandatory: Permanently discontinue patient from treatment 
Gastrointestinal 
Pancreatitis 

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Protocol No. CABL001A2302 
 
Dose modifications for asciminib  
Please note that if a patient requires a dose interruption of > 28 days for any toxicity, and > 42 days for 
hematologic toxicity, then the patient should be discontinued from study treatment 
Worst toxicity 
CTCAE Version 5.0 
Asciminib 
Grade 2 (radiologic findings for 
pancreatitis as per CTCAE v5.0, 
for increased enzymes please see 
table for asymptomatic amylase 
and/or lipase elevation) 
Mandatory: If asymptomatic radiologic pancreatitis, hold treatment until 
recovery of the radiologic findings. If treatment delay is ≤ 21 days, then 
reduce dose  1 dose level. If treatment delay > 21 days, discontinue 
treatment and keep monitoring with appropriate imaging (i.e., MRI, CT 
scan, or ultrasound) ** 
Grade ≥ 3 
Mandatory: Permanently discontinue patient from treatment. Obtain 
appropriate imaging (i.e., MRI, CT scan, or ultrasound) 
Diarrhea*** 
Grade 1 
Recommendation: Maintain dose level but initiate anti-diarrhea 
treatment 
Grade 2 
Recommendation: Hold dose until resolved to grade ≤ 1, then maintain 
dose level 
If diarrhea returns as grade ≥ 2, hold dose until resolved to grade ≤ 1, 
then reduce dose  1 dose level 
Grade 3 
Recommendation: Hold dose and discontinue patient from treatment 
Grade 4 
Mandatory: Permanently discontinue patient from treatment 
Skin and subcutaneous tissue disorders 
Rash/photosensitivity 
Grade 1 
Recommendation: Maintain dose level. Consider initiating 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, reduce dose  1 dose level 
If resolved in > 7 days (despite appropriate skin toxicity therapy), 
discontinue patient from treatment 
Grade 4, despite skin toxicity 
therapy 
Mandatory: Permanently discontinue patient from 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, maintain dose level 
If resolved in > 7 days, reduce dose  1 dose level 
All dose modifications should be based on the worst preceding toxicity. 
a Common Terminology Criteria for Adverse Events (CTCAE Version 5.0). 
b Core LFTs consist of ALT, AST, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x ULN), 
and alkaline phosphatase (ALP) (fractionated [quantification of isoforms], if ALP > 2.0 x ULN). 
c “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold. 
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g. discontinue treatment at the situation when hold dose is 
needed for one parameter and discontinue treatment is required for another parameter). After all elevations 
resolve to the defined thresholds that allow treatment re-initiation, re-start the treatment either at the same 
dose or at one dose lower if meeting a criterion for dose reduction. 

Novartis 
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Protocol No. CABL001A2302 
 
Dose modifications for asciminib  
Please note that if a patient requires a dose interruption of > 28 days for any toxicity, and > 42 days for 
hematologic toxicity, then the patient should be discontinued from study treatment 
Worst toxicity 
CTCAE Version 5.0 
Asciminib 
d “Cholestasis” defined as ALP elevation (> 2.0 x ULN and R value < 2) in patients  
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 should be performed 
within 1 week of the first occurrence of any grade ≥ 3 amylase and/or lipase elevation. If asymptomatic grade 3 
elevations of lipase and/or amylase occur again at the reduced dose, patients will be discontinued permanently 
from study treatment. If asymptomatic grade 2 re-occur at reduce dose, closed monitoring of lipase and 
amylase will be required. 
*** Note: Antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools, or 
overt diarrhea. 
**** Note: An isolated bilirubin elevation is not typical for drug-induced liver injury. Bilirubin can be elevated 
either as part of a “Hy’s law” constellation with a preceding elevation of ALT/AST, or as part of a cholestatic 
reaction with simultaneous elevation of other cholestatic parameters (ALP, GGT). Isolated bilirubin can be seen 
in conjunction with drugs that inhibit bilirubin conjugation or excretion, but both scenarios do not typically 
represent liver injury. Alternative causes of bilirubin elevation should therefore, be ruled out before basing dose 
modification decisions on bilirubin values alone. 
6.6.3.1 Dose adjustments for QTcF prolongation 
If QTcF >500 msec or QTcF prolongation >60 msec from baseline is observed at any point 
during study treatment, and confirmed, the below guidance must be followed: 
1. Assess the quality of the ECG recording and the QT value and repeat if needed 
2. Interrupt study treatment until confirmed resolution of QTcF to ≤ 480 msec  
3. Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug treatment. 
4. Review concomitant medication associated with QT prolongation, including drugs with a 
“Known”, “Possible”, or “Conditional risk of Torsades de Pointes” (refer to 
www.crediblemeds.org), and drugs with the potential to increase the risk of study drug 
exposure related QT prolongation. 
5. Check study drug dosing schedule and treatment compliance. 
Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 480 msec.  
• After resolution to ≤ 480 msec, consider re-introducing treatment at reduced dose, with 
increase ECG monitoring for the next treatment  
• If QTcF remains ≤ 500 msec after dose reduction, continue planned ECG monitoring 
during subsequent treatment  
• If QTcF recurs > 500 msec after dose reduction, discontinue patient from trial.  

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6.6.4 Follow-up for toxicities 
Patients whose treatment is permanently discontinued due to a study drug related adverse event 
or clinically significant laboratory value, must be followed up for 30 days or, until resolution or 
stabilization of the event. Appropriate clinical specialist 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. 
6.6.4.1 Follow up on potential drug-induced liver injury (DILI) cases 
Patients with transaminase increase combined with TBL increase may be indicative of 
potentially severe Drug-induced liver injury (DILI), and should be considered as clinically 
important events and assessed appropriately to establish the diagnosis. The required clinical 
information, as detailed below, should be sought to obtain the medical diagnosis of the most 
likely cause of the observed laboratory abnormalities. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBL value; 
patients meeting any of the following criteria will require further follow-up as outlined below: 
• For patients with normal ALT and AST and TBL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBL > 2.0 x ULN 
• For participant with elevated AST or ALT or TBL value at baseline: [AST or ALT > 3 x 
baseline] OR ALT or AST > 8.0 x ULN], whichever occurs first, combined with [TBL > 
2.0 x baseline AND > 2.0 x ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered, and their role clarified before DILI is assumed as the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any preexisting 
liver conditions or risk factors, should be collected. 
Laboratory tests should include ALT, AST, TBL, direct and indirect bilirubin, GGT, 
prothrombin time (PT)/INR, alkaline phosphatase, albumin, and creatine kinase. If available, 
testing of Glutamate Dehydrogenase (GLDH) is additionally recommended. 
Evaluate status of underling malignancy for an extra-medullary hepatic involvement. 
Perform 
relevant 
examinations 
(Ultrasound 
or 
MRI, 
Endoscopic 
retrograde 
cholangiopancreatography (ERCP)) as appropriate, to rule out an extrahepatic cause of 
cholestasis. Cholestasis (is defined as an Alkaline Phosphatase (ALP) elevation > 2.0 x ULN 
with R value < 2 in patients without bone metastasis, or elevation of the liver-specific ALP 
isoenzyme in patients with bone metastasis). 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT 
can be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, 
since GGT can also be elevated by enzyme induction or by ethanol consumption. It is more 
sensitive than ALP for detecting bile duct injury. Table 6-5 provides guidance on specific 

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clinical and diagnostic assessments which can be performed to rule out possible alternative 
causes of observed Liver function test (LFT) abnormalities. 
Table 6-5 Clinical and diagnostic assessments to rule out possible alternative causes 
of observed LFT abnormalities 
Disease 
Assessment 
Hepatitis A, B, C, E 
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti- HCV, HCV 
Ribonucleic acid (RNA), IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti- EBV 
Autoimmune hepatitis 
Antinuclear Antibodies (ANA) & Anti-Smooth Muscle Antibody (ASMA) titers, 
total IgM, IgG, 
IgE, IgA 
Alcoholic hepatitis 
Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
Ultrasound or MRI 
Hypoxic/ ischemic hepatopathy 
Medical history: acute or chronic congestive, heart failure, hypotension, 
hypoxia, hepatic venous occlusion. Ultrasound or MRI 
Biliary tract disease 
Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if <40 yrs old) 
Caeruloplasmin 
Hemochromatosis 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
Alpha-1-antitrypsin 
Other causes should also be considered based upon patients’ medical history (hyperthyroidism 
/ thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic hepatitis – ECG, prior 
hypotensive episodes; Type 1 diabetes / glycogenic hepatitis). 
Obtain PK sample to determine exposure to study treatment and metabolites. 
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes of 
liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant”, and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential treatment -induced liver injury”. All events should be followed up with the outcome 
clearly documented. 
6.6.4.2 Additional treatment guidance 
6.6.5 Treatment compliance 
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.  
Total daily dose of study treatment administered with start and end date and dosing will be 
collected on the appropriate eCRF page. Name, start and end dates of any Concomitant 

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Medications and Surgical and Medical procedures will be collected on the Prior and 
Concomitant medications and Surgical and Medical procedures eCRFs respectively. 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
dispensing patient visit. 
6.6.6 Emergency breaking of assigned treatment code 
Not applicable. 
7 Informed consent procedure 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participant’s representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
As per (Section 4.6), if the covid-19 pandemic challenges the ability to obtain a standard written 
informed consent due to limits that prevent an on-site visit, the Investigator may conduct the 
informed consent discussion remotely (e.g. telephone, videoconference) if allowable by a local 
Heath Authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
Information about common side effects already known about the investigational drug can be 
found in the Asciminib Investigator's Brochure (IB). This information will be included in the 
participant informed consent and should be discussed with the participant during the study as 
needed. Any new information regarding the safety profile of the investigational drug that is 
identified between IB updates will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the participant. 
The following informed consents are included in this study: 
• Main study consent, which also includes: 

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• A subsection that requires a separate signature for tests that are optional. This section 
refers to optional participation in the 
 
research collaboration that will be conducted in Europe and Russia. Refer to  
(Section 8.1). 
• A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study. 
• A subsection that requires a separate signature for the ‘Optional consent for activities 
that may be done outside of the study site’ to allow some study activities to be done 
outside of the study site (for example, at participants home or at another suitable 
offsite location) due to measures implemented as a result of the COVID-19 pandemic, 
such as travel restrictions or closures of local hospitals and patient treatment facilities. 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements for the duration 
of the study. If there is any question that the patient will not reliably comply, they should not 
be entered in the study. 
The study includes an optional consent for additional research component which requires a 
separate signature if the participant agrees to participate as mentioned above. It is required as 
part of this protocol that the Investigator presents this option to the participants, as permitted by 
local governing regulations. The process for obtaining consent should be exactly the same as 
described above for the main informed consent. 
Declining to participate in these optional studies will in no way affect the participant’s ability 
to participate in the main research study. 
The study also includes an optional consent for home-nursing visits “activities that may be done 
outside of the study site” which requires a separate signature if the participant agrees to 
participate as mentioned above. If certain clinical trial procedures need to be done off site due 
to temporary inability to perform on site visit due to COVID-19, participant may be proposed 
this option, if permitted by local laws and feasible. 
The process for obtaining consent should be exactly the same as described above for the main 
informed consent. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
8 Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all the assessments and indicates with an “X”, the 
visits when they are performed. All data obtained from these assessments must be documented 
in the participant’s source documentation. Patients can be consented for study participation 
prior to study day -28.  
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Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. 
Participants who discontinue from study treatment are to return for the end of treatment visit as 
soon as possible, and attend the follow-up visits as indicated in the Assessment Schedule. 
Participants who discontinue from study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications not previously reported must be recorded on the CRF. 
As per Section 4.6, if the COVID-19 pandemic limits or prevents on-site study visits, alternative 
methods of providing continuing care may be implemented by the investigator as the situation 
dictates. If allowed by local Health Authority and depending on operational capabilities, phone 
calls, virtual contacts (e.g. tele consult) or visits by site staff/ home nursing staff to the 
participant´s home, can replace on-site study visits, for the duration of the disruption due to the 
pandemic until it is safe for the participant to visit the site again. Screening visit and week 1 
day 1 visits must be done on site. 
The “X” in the table denotes the assessments to be recorded in the clinical database or received 
electronically from a vendor. The “S” in the table denotes the assessments that are only in the 
participant’s source documentation and do not need to be recorded in the clinical database. 
 No eCRF will be used as a source document. 
(S) is defined as “Source” 
(D) is defined as “Data Based” 
Study visits from Week 1 Day 1 to Week 2 Day 1 should be completed on the designated date 
[with an allowed “visit window” of +/- 1 day for Week 1 Day 1 and Week 2 Day 1] 
Study visits from Week 4 to Week 12 should be completed every 4 weeks on the designated 
date [with an allowed “visit window” of +/- 2 day] 
Study visits after Week 12 (from Week 24) to EOT should be completed every 12 weeks on the 
designated date [with an allowed “visit window” of +/- 7 days]. 
Safety follow-up should be completed 30 days from the last dose of study treatment [with an 
allowed “visit window” of +/- 7 days]. 
Visit at weeks 62, 74, 86, 98, 110 or 122 that is two weeks post dose escalation should be 
completed once after dose escalation on the designated date [with an allowed “visit window” 
of +/- 1 day]. 
A delayed visit will have no impact on the next planned visit. The next visit should be completed 
as scheduled in order to avoid accumulation of additional weeks. 

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Table 8-1 Assessment schedule 
 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
 
EOT (week 144) 
/Early 
Discontinuation 
Safety 
follow-
up13 
 
 
Visit name 
 
 
Screening/ 
Baseline 
Week 1 Day 1 
Week 2 Day1 
Week 4 
Week 8 
Week 12 
Week 24 
Week 36 
Week 48 
Every 12 
weeks up to 
week 132 (w60, 
w72, w84, w96, 
w108, w120, 
w132) 
Week 62/74/86/98/ 
110/122 
for patient dose 
escalating 
 
 
 
Days (+/- X days) 
 
 
 
Day -28 to -1 
1 
(+/- 
1 
day) 
8 
(+/- 1 
day) 
29 
(+/- 2 
days) 
57 
(+/- 2 
days) 
85 
(+/- 2 days) 
169 
(+/- 7 
days) 
253 
(+/- 7 
days) 
337 
(+/- 7 
days) 
(+/- 7 days) 
(+/- 1 day) 
 
(+/- 7 days) 
 
(+/- 7 
days) 
Obtain Informed 
Consent 
 
 
D 
 
X 
(Screening 
window - 28 
days) 
 
 
 
 
 
 
 
 
 
 
 
 
IRT 
 
 
 
 
Eligibility checklist/ 
registration 
 
S 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
D 
6.4.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography 
D 
8.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
D 
5.1 – 5.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
D 
8.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Disease History 
D 
8.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Mutation status 
D 
8.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior antineoplastic 
therapy 
D 
8.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior TKI therapy 
D 
8.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 

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Category 
 
Protocol 
Section 
 
Screening 
Phase 
Treatment Phase 
EOT (week 144) 
/Early 
Discontinuation 
Safety 
follow-
up13 
 
 
Visit name 
 
 
Screening/ 
Baseline 
Week 1 Day 1 
Week 2 Day 1 
Week 4 
Week 8 
Week 12 
Week 24 
Week 36 
Week 48 
Every 12 
weeks up to 
week 132 (w60, 
w72, w84, w96, 
w108, w120, 
w132) 
Week 62/74/86/98/ 
110/122 
for patient dose 
escalating 
 
 
 
 
 
 
Days (+/- X days) 
 
 
Day -28 to -1 1 
(+/- 
1 
8 
(+/- 1 
day) 
29 
(+/- 2 
days) 
57 
(+/- 2 
days) 
85 
(+/- 2 days) 
169 
(+/- 7 
days) 
253 
(+/- 7 
days) 
337 
(+/- 7 
days) 
(+/- 7 days) 
(+/- 1 day) 
 
(+/- 7 days) 
 
(+/- 7 
days) 
Prior/concomitant 
medications 
D 
8.2 
 
X 
Continuous 
Physical 
Examinations 
S 
8.4 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Extra medullary 
Involvement 
D 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
Performance status 
D 
8.4.1 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Height 
D 
8.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
D 
8.4 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
Vital signs1 
D 
8.4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Laboratory 
assessments 
 
8.4.2 
 
Hematology 
D 
8.4.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Chemistry2 
D 
8.4.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Coagulation 
D 
8.4.2 
X 
As clinically indicated 
 

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Category 
 
Protocol 
Section 
 
Screening 
Phase 
Treatment Phase 
EOT (week 144) 
/Early 
Discontinuation 
Safety 
follow-
up13 
 
 
Visit name 
 
 
Screening/ 
Baseline 
Week 1 Day 1 
Week 2 Day 1 
Week 4 
Week 8 
Week 12 
Week 24 
Week 36 
Week 48 
Every 12 
weeks up to 
week 132 (w60, 
w72, w84, w96, 
w108, w120, 
w132) 
Week 62/74/86/98/ 
110/122 
for patient dose 
escalating 
 
 
 
Days (+/- X days) 
 
 
Day -28 to 
-1 
1 
(+/- 1 
day) 
8 
(+/- 1 
day) 
29 
(+/- 2 
days) 
57 
(+/- 2 
days) 
85 
(+/- 2 days) 
169 
(+/- 7 
days) 
253 
(+/- 7 
days) 
337 
(+/- 7 
days) 
(+/- 7 days) 
(+/- 1 day) 
 
(+/- 7 days) 
 
(+/- 7 
days) 
Serum Pregnancy 
test (if applicable) D 
8.4.4 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine Pregnancy 
test (if applicable) 
S 
8.4.4 
 
X 
 
X 
X 
X 
Monthly between visits3 
 
 
 
Hepatitis markers D 
8.4.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
 
 
 
Blood collection for 
BCR-ABL1 
quantification by RQ-
PCR 
D 
8.3.1.1 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
Bone marrow 
Aspirate / 
Cytogenetics - 
Scheduled 
D 
8.3.1.2 
X 
(Screening 
window- 56 
days) 
 
 
 
 
 
 
 
X 
 
 
X4 
 
Biomarker 
assessments 
 
 
 

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Category 
 
Protocol 
Section 
 
Screening 
Phase 
Treatment Phase 
EOT (week 144) / 
Early 
Discontinuation 
Safety 
follow-
up13 
 
 
Visit name 
 
 
Screening/ 
Baseline 
Week 1 Day 1 
Week 2 Day 1 
Week 4 
Week 8 
Week 12 
Week 24 
Week 36 
Week 48 
Every 12 
weeks up to 
week 132 (w60, 
w72, w84, w96, 
w108, w120, 
w132) 
Week 
62/74/86/98/110/122 
for patient dose 
escalating 
 
 
 
Days (+/- X days) 
 
 
Day -28 to -1 1 
(+/- 
1 
day)
8 
(+/- 1 
day) 
29 
(+/- 2 
days) 
57 
(+/- 2 
days) 
85 
(+/- 2 days) 
169 
(+/- 7 
days) 
253 
(+/- 7 
days) 
337 
(+/- 7 
days) 
(+/- 7 days) 
(+/- 1 day) 
 
(+/- 7 days) 
 
(+/- 7 
days) 
Echocardiogram 
D 
8.4.3.1 
X 
 
 
 
 
 
X11 
 
 
 
 
X 
 
Adverse events / 
Serious adverse 
events 
D 
10.1.1 
Continuous 
Patient Reported 
Outcomes 
 
 
 
MDASI-CML 
D 
8.5.1 
X 
 
 
X 
 
X 
X 
 
X 
X12 
 
X 
 
Asciminib drug 
dispensation 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Asciminib drug 
administration 
D 
6.3.2 
 
Continuous 
 
 
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
D 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 

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8.1 Screening 
Molecular pre-screening 
Not applicable. 
Screening 
Written informed consent must be obtained before any study specific medical procedures are 
performed.  
All screening/baseline assessments (with the exception of cytogenetic assessment of Bone 
Marrow Aspirate) should occur within 28 days before Week 1 Day 1. 
The screening visit window for cytogenetic assessment Bone Marrow Aspirate (BMA) is 56 
days prior to Week 1 Day 1. Should bone marrow assessments have been performed before the 
main informed consent is signed but within 56 days of Week 1 Day 1, no further bone marrow 
sampling will be required at screening and results from prior bone marrow assessment will be 
collected. At Week 48, and at end of treatment for patient completing trial for lack of efficacy, 
a bone marrow aspirate must be collected even if the screening/baseline bone marrow aspirate 
sample was not collected.  
During the screening visit, inclusion and exclusion criteria will be assessed. Screening 
assessments to confirm eligibility must be performed prior to study enrollment. The results of 
the central real time quantitative polymerase chain reaction (RQ-PCR) and the local cytogenetic 
assessment (BMA, performed locally within 56 days of Week 1 Day 1) must be available prior 
to enrollment and first dose of study treatment. Central mutation analysis will be performed 
during the course of the study and data not available prior to enrollment. 
Screening assessments include: demographics, laboratory baseline assessments (including 
hematology, chemistry, coagulation, serum pregnancy test and hepatitis markers), physical 
examination including extramedullary involvement, peripheral blood collection for BCR-ABL1 
RQ-PCR, bone marrow aspirate for cytogenetic assessment (if prior bone marrow aspirate 
evaluation was more than 56 days before Week 1 Day 1) and 
 
. Other assessments includes performance 
status, ECG, echocardiogram, height, weight and vital signs, as well as evaluation of all relevant 
medical history including cardiovascular risk factors, CML disease history including T3151 
mutation status, prior TKI therapy and antineoplastic medication. Assessment of prior and 
concomitant medication must be performed prior to the first dose of study treatment. For details 
of assessments required during screening please refer to Table 8-1. 
Patients with potassium, and/or magnesium and/or total calcium levels that are < LLN at 
screening, must have their potassium, and/or magnesium, and/or calcium replenished through 
supplementation and the levels must be within normal limits prior to the first dose of study drug. 
A patient who has laboratory test (peripheral blood test) results that do not satisfy the entrance 
criteria may have the tests repeated. These tests may be repeated as soon as the investigator 
believes the re-test results are likely to be within the acceptable range to satisfy the entrance 
criteria, but should be completed within the screening window. In this case, the subject will not 
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be required to sign another Informed Consent Form (ICF), and the original patient ID number 
assigned by the investigator will be used. In the event that the laboratory tests cannot be 
performed within the screening visit window, or the re-tests do not meet the entrance criteria, 
or other eligibility criteria have changed and are not met anymore, the patient is considered a 
screen failure, and must be discontinued from the study. 
A new ICF will need to be signed if the investigator chooses to re-screen the patient after a 
patient has screen failed and a new patient ID will be assigned. All required screening activities 
must be performed when the patient is re-screened for participation in the study. No further 
bone marrow sampling will be done at re-screening if a previous assessment was done within 
56 days of Week 1 Day 1. After 56 days, new bone marrow aspirate samples for cytogenetic 
assessment should be re-collected at the time of the bone marrow assessment. An individual 
patient may be re-screened up to three times for the study. Once the number of patients screened 
and enrolled is likely to ensure target enrollment, the Sponsor may close the study to further 
screening. In this case, the patients who screen failed will not be permitted to re-screen. 
8.1.1 Eligibility screening 
Following registering in the IRT for screening, participant eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
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 but fail to be enrolled for any reason will be considered 
a screen failure. The reason for not being enrolled will be entered on the Disposition Page. The 
demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for Screen Failure patients. No other data will be entered into the clinical database 
for patients who are screen failures, unless the patient experienced a Serious Adverse Event 
during the Screening Phase (see Section 10.1.4 for SAE reporting details). If the patient fails to 
be enrolled, the IRT must be notified within 2 days of the screen fail that the patient was not 
enrolled. The reason for screen failure should be recorded on the appropriate Case Report Form. 
8.2 Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
Patient demographics and baseline characteristics collected will include the following: age at 
consent, gender (and childbearing potential for female), race/ethnicity, height, weight, all 
relevant medical history including cardiovascular disease history, CML disease history, 
including mutation status, and prior and concomitant medication including prior TKI therapy 
and antineoplastic medication. 
Participant race/ethnicity data are collected and analyzed to identify any differences in the 
safety and/or efficacy profile of the treatment due to these characteristics. In addition, we need 
to assess the diversity of the study population as required by Health Authorities. 
Physical examination including extramedullary involvement, ECOG performance status, vital 
signs, ECGs, Echocardiography, and laboratory assessments will be performed at screening. 

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Significant findings that were present prior to the signing of informed consent must be included 
in the Relevant Medical History/Current Medical Conditions page on the subject’s eCRF. 
Significant new findings that begin or worsen after informed consent must be recorded on the 
AE page of the patient’s eCRF. 
The local reading of the screening ECG, echocardiograms as well as the central results of the 
qualitative PCR, RQ-PCR and the local cytogenetic assessment (BMA) within 56 days before 
Week 1 Day 1 must be available prior to enrollment and first dose of study treatment to evaluate 
eligibility. Central mutation analysis will be performed during the course of the study and not 
available prior to enrollment. 
8.3 Efficacy 
8.3.1 Efficacy assessments  
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of 
providing continuing care may be implemented. Phone calls, virtual contacts (e.g. teleconsult) 
or visits by site staff/home nursing service to the participant´s home depending on local 
regulations and capabilities, can replace on-site study visits, for the duration of the pandemic or 
until it is safe for the participant to visit the site again.  If participants cannot visit the site for 
protocol specified assessments and that visit by site staff/home nursing service to the 
participant’s home may not be done, an alternative laboratory (local) collection may be used.  
8.3.1.1 Molecular response 
Molecular response (MR) will be assessed in all patients.  
Levels of BCR-ABL1 transcripts will be determined by real-time quantitative PCR (RQ-PCR) 
testing of peripheral blood and analyzed centrally. Log reduction in BCR- ABL1 transcripts 
levels from the standardized baseline value, or the percent ratio of BCR-ABL1 transcripts 
versus control gene (ABL1) transcripts converted to a reference standard, international scale 
(IS) (Hughes and Branford 2006), will be calculated for each sample. 
Major molecular response and related variables are defined as the following: 
• Rate of MMR where MMR is defined as a ≥ 3.0 log reduction in BCR-ABL1 transcripts 
compared to the standardized baseline equivalent to ≤0.1 % BCR-ABL1/ABL1 % by IS as 
measured by RQ-PCR, confirmed by duplicate analysis of the same sample, 
• Time to MMR defined as the time from the date of enrollment to the date of the first 
documented MMR, 
• Duration of MMR defined as the time from the date of first documented MMR to the earliest 
date of loss of MMR, progression to AP or BC, or CML-related death. 
• Rate of Deep Molecular Responses MR4 and MR4.5 are defined as a ≥4 log or ≥4.5 log 
reduction in BCR-ABL1 transcripts compared to the standard baseline equivalent to 0.01 % 
or 0.0032% BCR-ABL1/ABL by IS as measured by RQ-PCR, confirmed by duplicate 
analysis of the same sample with at least 10,000 or 32,000 ABL1 transcripts, respectively. 
Loss of MMR is defined as increase of BCR-ABL1/ABL to > 0.1% by international scale (IS) 
in association with a ≥ 5-fold rise in BCR-ABL1 from the lowest value achieved on study 

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treatment and replicated by a second analysis of the same sample. Loss of MMR confirmed by 
subsequent sample analysis within 4 to 6 weeks showing loss of MMR associated with a ≥ 5-
fold rise in BCR-ABL1 from the lowest value achieved on study treatment, unless it is 
associated with confirmed loss of CHR or loss of CCyR or progression to AP/BC or CML- 
related death. The blood samples will be taken as described in Table 8-1 and Table 8-2. 
If at one visit the sample is missing during transit to the central PCR laboratory, or the PCR 
result is difficult to interpret or sample not analyzable, or if the PCR sample was not collected, 
a subsequent unscheduled visit sample must be collected within 4 weeks either at the next 
scheduled visit (week 4 or week 8) or as an unscheduled visit. 
Table 8-2 Blood samples (efficacy primary endpoint) 
Sample Type 
Volume 
Visit 
Blood for BCR-ABL1 
quantification by RQ-PCR 
20 mL 
Screening/Baseline 
20 mL 
Week 12 
20 mL 
Week 24 
20 mL 
Week 36 
20 mL 
Week 48 
20 mL 
Every 12 weeks thereafter up to week 132 (w60, w72, 
w84, w96, w108, w120, w132) 
20 mL 
End of Treatment 
8.3.1.2 Bone marrow analysis and cytogenetics 
Cytogenetic response will be assessed as the percentage of Ph+ metaphases in the bone marrow 
and is defined as the following (a review of a minimum of 20 metaphases is required): 
• Major (MCyR) - 0 to 35% Ph+ metaphases 
• Complete (CCyR) - 0% Ph+ metaphases 
• Partial (PCyR) - >0 to 35% Ph+ metaphases 
• Minor (mCyR) - >35 to 65% Ph+ metaphases 
• Minimal - >65 to 95% Ph+ metaphases 
• None - >95 to 100% Ph+ metaphases. 
Bone marrow aspirate for cytogenetic analyses will be performed at screening/baseline 
(performed up to 56 days prior to Week 1 Day 1), at Week 48 and at EOT (only required if the 
patient discontinues from the study early due to lack/loss of response). Should bone marrow 
assessments have been performed before the main informed consent is signed but within 56 
days of Week 1 Day 1, no further bone marrow sampling will be required at screening and local 
assessment data will be collected. 
Quantification of the percentage of Ph+ chromosome metaphases, number of metaphases, 
number positive for Ph chromosome, additional chromosomal abnormalities as well as data 
from cytologic evaluation (microscopic analysis) of percentage of blasts and promyelocytes 

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will be recorded on the Bone Marrow eCRF. These exams will be performed and analyzed 
locally.  
8.3.1.3 Hematologic response 
A complete hematologic response (CHR) is defined as all of the following present for ≥ 4 weeks: 
• WBC count <10 x 109/L 
• Platelet count <450 x 109/L 
• Basophils <5% 
• No blasts and promyelocytes in peripheral blood 
• Myelocytes + metamyelocytes < 5% in peripheral blood 
• No evidence of extramedullary disease, including spleen and liver 
8.3.2 Appropriateness of efficacy assessments  
Assessing molecular response with RQ-PCR is considered as standard in CML therapy and 
recommended in treatment guidelines (Hochhaus et al 2020a). In order to review individual 
responses against the milestones in treatment recommendations and to allow for the comparison 
of trial results against other data, the molecular responses will be reported as standardized 
results to International Scale (IS) (Cross et al 2015).  
8.4 Safety and tolerability assessments 
Safety will be monitored by the assessments described below, in addition to the collection of 
adverse events at every visit. For details on AE collection and reporting, refer to Section 10. 
Significant findings that were present prior to the signing of informed consent must be included 
in the Relevant Medical History/Current Medical Conditions page on the patient’s eCRF. 
Significant new findings that begin or worsen after informed consent must be recorded on the 
AE page of the patient’s eCRF. 
As per Section 4.6, if the COVID-19 pandemic limits or prevents on-site study visits, regular 
phone or virtual calls can occur as outlined in the Visit Schedule (or more frequently if needed) 
for safety monitoring and discussion of the participant´s health status until it is safe for the 
participant to visit the site again. If participants cannot visit the site for protocol specified safety 
lab assessments or that central laboratory analysis cannot be performed due to COVID-19 
pandemic consequences, an alternative laboratory (local) collection site may be used.  
Assessments of blood pressure, heart rate, weight, ECG and blood collection may also be 
conducted off-site by healthcare professional visits to the participant’s off-site location (please 
refer to Section 4.6). 
Table 8-3 Physical examination, vital sign and height and weight assessments 
Assessment 
Specification 
Physical examination 
A complete physical examination will include the 
examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, 
vascular and neurological. Information about the 
physical examination must be present in the source 

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documentation at the study center and will be 
collected at the visits specified in Table 8-1. 
Presence of extramedullary leukemic involvement will 
be checked at the physical examination at 
screening/baseline. Findings on physical examination 
consistent with extra- medullary leukemic involvement 
will be recorded (e.g. liver and spleen size, any other 
organ involvement). 
Vital signs 
Vital signs include blood pressure (supine position 
when ECG is collected), pulse measurement, and body 
temperature and are performed at the visits as 
specified in Table 8-1. 
Height and weight 
Height in centimeters (cm) and body weight (to the 
nearest 0.1 kilogram (kg)) will be measured as 
specified in Table 8-1. 
8.4.1 Performance status 
ECOG Performance status scale will be used as described in Table 8-4 at the visits specified in 
Table 8-1.  
Table 8-4 ECOG Performance status scale 
Description 
Grade 
Fully active, able to carry on all pre-disease activities without restriction. 
0 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature e.g. light housework, office work. 
1 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours. 
2 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
3 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
4 
Dead. 
5 
8.4.2 Laboratory evaluations 
Central laboratory will be used for analysis of hematology, biochemistry, coagulation, serum 
pregnancy and hepatitis marker specimens collected (safety monitoring) as specified in  
Table 8-1. The time windows granted for laboratory evaluations are identical with the 
corresponding visit time windows for each visit (see Section 8). 
Additional unscheduled blood draws may be performed at the discretion of the investigator at 
any time during the study. For example, if the PCR sample was lost during transit or result is 
difficult to analyze, to confirm a loss of response to study treatment or as clinically indicated. 
If the COVID-19 pandemic limits or prevents on-site study visits, if pre-agreed with Novartis 
and considered by the Investigator it is in the interest of the participant’s health to perform study 
procedures remotely, safety samples that can be collected remotely will be collected and 
analyzed in line with the study laboratory manual. If participants cannot visit the site for 
protocol specified safety lab assessments or in case of central lab logistical challenges an 
alternative laboratory (local) collection site may be used. Please note that BCR-ABL1 
quantification must be performed centrally. Where samples are collected and analyzed at a local 
laboratory instead of the central laboratory, Novartis will ensure the results reported for 

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hematology and chemistry described below are equivalent to central laboratory collection and 
analysis by collecting the local normal ranges. 
Table 8-5 Central clinical laboratory parameters collection plan 
Test category 
Test Name 
Hematology 
Hemoglobin, platelets, red blood cells, white blood 
cells, WBC morphology with differential (basophils, 
eosinophils, lymphocytes, monocytes, neutrophils, 
promyelocytes, myelocytes, metamyelocytes, blast 
and other) 
Chemistry 
Albumin, alkaline phosphatase, ALT (SGPT), AST 
(SGOT), total calcium, total calcium (corrected for 
albumin), creatinine, creatine kinase, potassium, 
magnesium, 
sodium, 
phosphate 
(inorganic 
phosphorus), direct bilirubin, indirect bilirubin, total 
bilirubin, total cholesterol, LDL cholesterol, HDL 
cholesterol, total protein, triglycerides, blood urea or 
Blood Urea Nitrogen (BUN), uric acid, amylase, lipase, 
serum glucose (fasting), Hemoglobin A1c (at screening 
only), Creatinine clearance (Cockcroft-Gault formula) 
Coagulation 
International Normalized Ratio (INR), Activated Partial 
Thromboplastin Time (aPTT) 
Hepatitis markers 
HbsAg, HbcAb /anti-Hbc, HBV-DNA (if anti-Hbc and 
HbsAg are positive), HCV Ab, HCV-RNA (if HCV Ab is 
positive). 
Liver assessments (for DILI)  
(see Section 6.6.4.1) 
ALT, AST, albumin, creatinine kinase, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time 
(PT)/INR and alkaline phosphatase 
Pregnancy Test 
Serum beta fraction of human chorionic gonadotropin 
(ß-HCG) testing (at screening and EOT). Urine 
pregnancy test will be done monthly for women of 
childbearing potential (will be done locally). 
8.4.3 Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed as described in Table 8-6.  
ECG assessment needs are similar for all patients up to week 48.  
Patients dose escalating to 200 mg q.d. (as outlined in Section 6.6.2) must have ECG 
assessments performed:  
• on the day of dose escalation (pre-dose and between 2h to 3h post-dose ECGs are 
required), 
• two weeks post-dose escalation, 
• at next 2 quarterly visits (at 3 and 6 months post-dose escalation),  
• every 6 months thereafter.  
Please refer to (Table 8-6) below for more details. 
After the subject has rested approximately 5 minutes in a supine position, standard 12- lead 
ECGs must be obtained in triplicate with a recommended interval of 5 minutes between each 
ECG reading. 

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The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs and then blood sampling. The Fridericia QT correction formula 
(QTcF) should be used for clinical decisions. The investigator must calculate QTcF if it is not 
auto-calculated by the ECG machine. 
ECGs will be locally collected and evaluated. Interpretation of the tracing must be made by a 
qualified physician and documented on the ECG CRF page. Each ECG tracing should be 
labeled with the study number, patient initials (where regulations permit), subject number, date, 
and kept in the source documents at the study site. 
Table 8-6 Local ECG collection plan 
Week 
Day 
Time 
Screening/Baseline 
Day -28 to -1 
3 serial, 12 lead ECGs 
1 
 
3 serial, 12 lead ECGs between 2h to 3h post-
dose 
2 
 
3 serial, 12 lead ECGs between 2h to 3h post-
dose 
4 
 
3 serial, 12 lead ECGs  
12 
 
3 serial, 12 lead ECGs  
24, 48 
 
3 serial, 12 lead ECGs  
For patients not dose escalating: Week 
60, 84, 108, 132 
 
3 serial, 12 lead ECGs 
For patients dose escalating: 
Dose escalation visit (Week 60 or Week 
72, 84, 96, 108, 120)  
 
3 serial, 12 lead ECGs pre-dose and between 
2h to 3h post-dose 
Two weeks post dose escalation visit 
(Week 62 or Week 74, 86, 98 110, 122) 
 
3 serial, 12 lead ECGs 
Twelve weeks post dose escalation visit 
(Week 72 or Week 84, 96, 108, 120, and 
132).  
 
3 serial, 12 lead ECGs 
Twenty-four weeks post dose escalation 
visit (Week 84 or Week 96, 108, 120, 132 
and EOT) 
 
3 serial, 12 lead ECGs 
EOT 
 
3 serial, 12 lead ECGs 
Unscheduled or Unplanned ECG 
3 serial, 12 lead ECGs 
Three serial ECGs (in triplicate) should be taken approximately 5 minutes apart. QTc 
prolongation will be based on the average seen in the scans for each time point. The enrollment 
of patients will be based on locally assessed QTcF time. The patient may not be dosed if the 
average of the 3 ECGs confirm a QTcF ≥ 450 msec (male) or ≥ 460 msec (female). 
Dose adjustments in case of QTcF prolongation should be performed per Section 6.6.3.1. 
ECGs are not required to be performed within a specified time frame (post-dose), after the 
week-2 visit. 
Additional unscheduled ECGs may be performed 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. For any ECGs with participant safety concerns, two 
additional ECGs must be performed to confirm the safety finding. ECG safety monitoring, or a 

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review process, should be in place for clinically significant ECG findings at baseline before 
administration of study treatment and during the study. 
Clinically significant ECG abnormalities present at screening must be reported on the Medical 
History eCRF page. New or worsened clinically significant findings occurring after informed 
consent must be recorded on the Adverse Events eCRF page. 
If the COVID-19 pandemic limits or prevents on-site study visits, if pre-agreed with Novartis 
and considered by the Investigator it is in the interest of the participant’s health to perform study 
procedures remotely and if feasible, study visits ECG can be collected remotely by home nurse 
at patient home. 
8.4.3.1 Cardiac imaging - Echocardiogram 
Echocardiograms will be performed to monitor cardiac safety. Assessments are scheduled at 
screening/baseline, Week 24 (+/- 4 weeks) and end of treatment visit. The echocardiogram will be 
performed and evaluated locally. Any clinically significant findings will be collected and 
reported in the database (i.e. reported as adverse events).  
8.4.3.2 Cardiac enzymes 
Not applicable.  
8.4.3.3 Estimation of cardiac risk factors 
Personal and family history (consisting of father, mother and siblings) of the following medical 
conditions is to be taken at the screening visit: Coronary artery disease, Hyperlipidemia, Type 
1 diabetes mellitus, Type 2 diabetes mellitus, Hypertension, medication taken or not for 
hypertension for personal history, Myocardial infarction or Cerebrovascular accident. In 
addition, history of smoking, low physical activity and unhealthy diet has to be taken at the 
screening/baseline and at the end of the treatment.  
8.4.4 Pregnancy and assessments of fertility 
All women of childbearing potential have to complete a serum pregnancy test (Serum ß-HCG) 
at screening in order to confirm study eligibility and at EOT. Pregnancy testing is not required 
for patients who are determined to be post-menopausal.  
A woman is considered of childbearing potential from menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. Medical documentation of oophorectomy, 
hysterectomy, or tubal ligation must be retained as source documents. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile. 
In absence of 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. 
Urine pregnancy tests have to be performed every 4 weeks during trial. Test results performed 
at home should be recorded onto a subject diary and brought to each scheduled visit for the site 

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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. 
Pregnancies diagnosed in female patients participating in the study should be recorded on a 
Clinical Trial Pregnancy Form and reported by the investigator to the Oncology Novartis Chief 
Medical Office and Patient Safety (CMO&PS) Department. 
During the whole study, women of childbearing potential should employ the use of highly 
effective contraception. Additional pregnancy testing might be performed if requested by local 
requirements. 
8.4.5 Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 Additional assessments 
Not applicable. 
8.5.1 Patient reported outcomes (PRO) 
The MDASI-CML PRO instrument will be used to compare data on the patient’s disease-related 
symptoms and health-related quality of life from baseline to EOT.  
Patients with an evaluable baseline score and at least one evaluable post baseline score during 
the treatment period will be included in the change from baseline analyses. Missing data items 
in a scale will be handled according to the manual for each instrument. No imputation will be 
applied if the total or subscale scores are missing at a visit. 
The participant must be given the PRO measure to be completed at the scheduled visit before 
any clinical assessments are conducted. Participant’s refusal to complete all or any part of a 
PRO measure should be documented in the study data capture system and should not be 
captured as a protocol deviation.  
Participant questionnaires should be completed in the language most familiar to the participant. 
The participant should be given sufficient space and time to complete the PRO measure. 
The site personnel (referring to who could be responsible for administering and checking 
completions of PRO measure) should check PRO measure for completeness and ask the 
participant to complete any missing responses. The original questionnaire will be kept with the 
patient’s file as the source document and responses reported in EDC by site personnel. 
Patients should be made aware that completed PRO measures are not reviewed for AEs by the 
investigator/study personnel and if they experience an AE, they should report the event to the 
investigator/study personnel.  
If the COVID-19 pandemic limits or prevents on-site study visits, if pre-agreed with Novartis 
and considered by the Investigator it is in the interest of the participant’s health to perform study 
procedures remotely and feasible, MDASI-CML PRO can be provided to patient by home nurse. 
If home nursing is not feasible, MDASI-CML will not be completed. 

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• Patients fulfilling treatment failure criteria above but without alternative treatment 
options may however be continued on study drug if in the investigators opinion they 
are obtaining benefit from the drug. Patients with BCR-ABL 1 greater than 10% after 
48 weeks of treatment or patients with signs of progression to AP and BC must 
however be discontinued.  
• Patients with newly emerging T315I mutation and lack or loss of response. While 
asciminib has known activity against CML with additional T315I mutation, the 
recommended dose of 200 mg BID for the treatment of T315I is not in use in the study. In 
case a patient demonstrates a new T315I mutation on asciminib, patients should not 
continue in the study.  
• In the event of disease progression, the patient must be discontinued from the study 
treatment. The following events are considered disease progression. 
• CML-related death (any death during treatment or follow-up if the principal cause of 
death is marked as “study indication” in the eCRF by the investigator, or if the death 
occurred subsequent to documented progression to AP/BC and the cause of death is 
reported as “unknown” or not reported by the investigator) 
• Accelerated phase (AP) as defined by any of the following: 
• ≥ 15% blasts in the peripheral blood or bone marrow aspirate, but < 30% blasts in 
both the peripheral blood and bone marrow aspirate 
• ≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow aspirate 
• ≥ 20% basophils in the peripheral blood 
• Thrombocytopenia (<100 x 109/L) that is unrelated to therapy 
• Blast crisis (BC) as defined by any of the following: 
• ≥ 30% blasts in peripheral blood or bone marrow aspirate 
• Appearance of extramedullary involvement other than hepatosplenomegaly 
proven by biopsy (i.e., chloroma). 
Any value of AP or BC within the first 4 weeks of study treatment is not defined as progression 
to AP/BC within the study unless the subject discontinues study treatment due to progression.  
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information. 
Participants who discontinue from study treatment agree to return for the end of treatment and 
follow-up visits indicated in the Assessment Schedule (refer to Section 8). 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule. 
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 

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The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
9.1.2 Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8). 
9.1.3 Lost to follow up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g. 
dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed or until the end of the study. 
9.2 Withdrawal of informed consent/Opposition to use data/biological 
samples 
Withdrawal of consent/opposition to use data/biological samples occurs when a participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/opposition to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 

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If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 
9.3 Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision (e.g. Each participant will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them). Completion of the study 
will be when the last participant has completed end of study follow up. 
All enrolled and/or treated participants should have a safety follow-up visit or 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 10.1.4. Documentation of attempts to contact the participant should be recorded in the 
source documentation. 
At the end of the treatment period, for patients who in the opinion of the investigator are still 
deriving clinical benefit from asciminib, every effort will be made to continue provision of the 
drug through alternative options if asciminib is not commercially available. Options includes, 
but are not limited to, roll over trial or provision of the treatment in a non-trial setting (known 
as post-study drug supply), in accordance with local laws and regulations. Safety will be 
monitored and reported to Health Authorities per regulatory requirements. 
9.4 Early study termination by the sponsor  
The study can be terminated by Novartis at any time. 
Reasons for early termination may be: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendation from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from study treatment. The end of treatment visit for 
discontinued or withdrawn patients should be scheduled and performed as described in  
Table 8-1. The investigator may be informed of additional procedures to be followed in order to 
ensure that adequate consideration is given to the protection of the participant’s interests. The 
investigator will be responsible for informing IRBs/IECs of the early termination of the trial. 

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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 clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant 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 participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments such as PRO.  
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. Adverse events will be assessed and graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. Its duration (start and end dates or ongoing) and the outcome must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. Its outcome (i.e. recovery status or whether it was fatal) 

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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 participant. 
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 loss of response, progression to accelerated phase or blast 
crisis and death due to disease progression) should not be reported as a serious adverse event, 
except if the investigator considers that progression of malignancy is related to study treatment. 
Adverse events separate from the progression of malignancy (i.e. deep vein thrombosis at the 
time of progression or hemoptysis concurrent with finding of disease progression) will be 
reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. 
10.1.2 Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 

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Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. Selected AESIs are discussed in detail in the [Asciminib Investigators Brochure].  

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10.1.4 SAE reporting  
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the patient has stopped study treatment, 
must be reported to Novartis safety immediately, without undue delay, under no circumstances 
later than within 24 hours of obtaining knowledge of the events (Note: If more stringent, local 
regulations regarding reporting timelines prevail). Detailed instructions regarding the 
submission process and requirements are to be found in the investigator folder provided to each 
site. Information about all SAEs is collected and recorded on the eSAE Serious Adverse Event 
Report Form; all applicable sections of the form must be completed in order to provide a 
clinically thorough report. 
SAEs occurring after the participant has provided informed consent until the time the participant 
is deemed a Screen Failure must be reported to Novartis. 
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 24 hours from 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. 
The following SAE reporting timeframes/ conditions apply: 
1. Treated patients: SAEs collected between time patient has provided informed consent until 
30 days after the patient has discontinued or stopped study treatment, irrespective of 
investigator’s assessment of causality 
2. Patients who are screened but have not received any study treatment: ALL SAEs 
occurring after the patient has provided informed consent must be reported to Novartis 
until the time the patient is deemed a Screen Failure and/ or dropped-out the study due any 
reason. 
Any SAEs experienced after the 30-day period should only be reported to Novartis if the 
investigator suspects a causal relationship to study treatment, unless otherwise specified by 
local law/regulations. If the SAE is not previously documented in the Investigator’s Brochure 
or Package Insert (new occurrence) and is thought to be related to the study treatment, a CMO 
& PS Department associate may urgently require further information from the investigator for 
health authority reporting. Novartis may need to issue an Investigator Notification (IN) to 
inform all investigators involved in any study with the same study treatment that this SAE has 
been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
10.1.5 Pregnancy reporting 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 

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given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported on a Clinical Trial Pregnancy Form 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 asciminib any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported.  
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
Follow-up of the newborn should be according to the following schedule: 
• Tracking of pregnancy cases occurs until Expected Delivery Date (EDD) for all prospective 
pregnancy cases  
• EDD +1 month (mandatory for all cases). Requesting the pregnancy outcome and other 
clinically relevant pregnancy data or changes in data. 
• EDD +2 month (mandatory if no answer is obtained after request at EDD+1 month). A 
reminder letter for the outcome. 
• The follow up at EDD +3 months is mandatory for all cases of live birth. Information on 
the status of the baby 3 months after delivery and information on any development issue or 
abnormality that would not be seen at birth must be collected. 
• The follow up at EDD +12 months is mandatory for all cases of live birth. Information on 
the status of the baby 12 months after delivery and information on any development issue 
or abnormality that would not be seen at birth must be collected. 
10.1.6 Reporting of study treatment errors including misuse/abuse  
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the study treatment CRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE.  
Table 10-1 Guidance for capturing the study treatment errors 
Treatment error type 
Document in Study 
Treatment CRF 
(Yes/No) 
Document in AE eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an 
SAE 

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For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 Additional Safety Monitoring 
HBV reactivation can occur in chronic carriers of HBV infection (HBsAg-positive, 
undetectable or low HBV DNA, and normal ALT) who are not on HBV therapy, or in 
individuals who have serologic evidence of a resolved prior HBV infection (i.e., HBsAg-
negative and anti-HBc–positive). While HBsAg-negative, anti-HBc–positive patients are at 
lower risk of HBV reactivation compared with HBsAg-positive patients, risk of HBV 
reactivation should be monitored.  
10.3 Committees 
10.3.1 Steering Committee 
The Steering Committee (SC) will be established comprising investigators with international 
expertise in the CML field participating in the trial, a patient advocate and Novartis 
representatives from the Clinical Trial Team. Details will be described in further detail in the 
SC charter.  
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. Novartis will make final 
decisions on trial conduct based on SC recommendations. 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 
Data not requiring a separate written record will be defined in the protocol and the Assessment 
Schedule (Table 8-1) and can be recorded directly on the CRFs. All other data captured for this 
study will have an external originating source (either written or electronic) with the CRF not 
being considered as source. All data should be recorded, handled, and stored in a way that 
allows its accurate reporting, interpretation, and verification. 
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs, allow modification and/or verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 

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After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
The MDASI-CML Questionnaire Data Collection: 
The MDASI-CML questionnaire data will be completed using paper PRO. The data will be 
entered by the subjects at the site or at home if the visit is conducted during home nursing. The 
designated site personnel will transcribe the responses from paper PRO to eCRF.  
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 Database management and quality control 
Novartis personnel (or designated 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 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screening(s), enrollment, screen failures and treatment as well as study completion, as 
well as data about all study treatment (s) dispensed to the participant and 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/moved to restricted 
area to be accessed by independent programmer and statistician. Any changes to the database 
after that time can only be made after written agreement by Novartis development management. 
11.3 Site monitoring 
Before study initiation, at a site initiation or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, 
the progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 

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performed by a centralized Novartis/Clinical Research Associate 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 participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. 
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 
participants will be disclosed. 
12 Data analysis and statistical methods 
The data will be analyzed by Novartis and/or designated CRO. It is planned that the data from 
participating centers in this protocol will be combined, so that an adequate number of patients 
will be available for analysis. 
Except where categorically stated, all analyses, including the primary analysis will be 
conducted on all participant data (excluding the additional patients who were intolerant to the 
last TKI and achieved MMR at baseline). The purpose of having two randomized groups is not 
for comparison, but to provide data on different dosing regimen. The cut-off date for the end of 
study treatment analysis is defined as 30 days after the end of study treatment period to ensure 
that all available treatment phase data from all patients up to the last dose of study drug taken 
in this study, will be analyzed and summarized in the end of study treatment phase Clinical 
Study Report (CSR). 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 Analysis sets 
The patient population for the study includes patients resistant or intolerant to 2 or more prior 
TKI treatments without MMR at baseline, and an additional group of patients who were 
intolerant to the last TKI and were in MMR at baseline.  
The Analysis Sets are stated as follows: 

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The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned and who received at least one dose of study treatment except the additional patients 
who were intolerant to the last TKI and were in MMR at baseline.  
The Full Analysis Set 2 (FAS 2) comprises only the additional patients who were intolerant to 
the last TKI and were in MMR at baseline and to whom study treatment has been assigned and 
received at least one dose of study treatment.  
The Safety Set (SAF) includes all participants who received at least one dose of study treatment 
except the additional patients who were intolerant to the last TKI and were in MMR at baseline.  
The Safety Set 2 (SAF 2) includes only the additional patients who were intolerant to the last 
TKI and achieved were in MMR at baseline and who received at least one dose of study 
treatment. 
Unless otherwise stated, the analysis sets will be applied as below: 
• For the patients resistant or intolerant to 2 or more prior TKI treatments without MMR at 
inclusion to the trial 
• The FAS will be used for demographics and baseline characteristics (except disease 
characteristics) and all efficacy analyses including PROs 
• The SAF will be used for baseline disease characteristics, exposure and all safety 
analyses 
• For the additional patients who were intolerant to the last TKI and were in MMR at 
baseline 
• The FAS 2 will be used for demographics and baseline characteristics (except disease 
characteristics) and selected efficacy analyses including PROs  
• The SAF 2 will be used for baseline disease characteristics, exposure and selected 
safety analyses  
12.2 Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term. 
12.3 Treatments 
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, as well as the dose intensity (computed as the 
ratio of actual cumulative dose received and actual duration of exposure) and the relative dose 

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intensity (computed as the ratio of dose intensity and planned dose intensity) will be 
summarized by means of descriptive statistics. 
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized and all dosing data will be listed. 
Analyses of patients with dose escalation will be specified in the SAP. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system. 
The additional patients who were intolerant to the last TKI and were in MMR already at baseline 
will be assessed for the duration of exposure in days to asciminib, 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 means of descriptive statistics using SAF 2. 
12.4 Analysis supporting primary objectives 
12.4.1 Definition of primary endpoint 
The primary endpoint of the study is Major Molecular Response (MMR) rate achieved at week 
48 while on study treatment (asciminib 40 mg b.i.d. and asciminib 80 mg q.d.). A patient will 
be counted as having achieved MMR at week 48 if he/she meets the MMR criterion (BCR-
ABL1 ≤ 0.1% IS) at week 48 while on study treatment. 
12.4.2 Statistical model, hypothesis, and method of analysis 
The primary estimand will be analyzed based on the data from the FAS and according to the 
Intention-To-Treat (ITT) principle. Exact test for single proportion will be used at the one-sided 
2.5% level of significance. 
The null hypothesis is that the MMR rate at Week 48 is equal to 0.23. The alternative hypothesis 
is that the rate is greater than 0.23. 
H0: π=0.23 vs. H1: π >0.23 
where π is the major molecular response (BCR-ABL1 ≤0.1% IS) rate at Week 48. MMR rate 
and its 95% confidence interval based on the Pearson-Clopper method will also be presented. 
The null hypothesis will be rejected when the lower bound of the two-sided 95% CI is above 
23%. 
Summary statistics of MMR at week 48 will also be presented by randomized groups. 
12.4.3 Handling of intercurrent events of primary estimand 
The primary estimand is described by the following attributes:  
1. The target population comprises CML Patients with resistance or intolerance to 2 or more 
prior TKI per the 2020 ELN recommendations. 

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2. Endpoint: Major Molecular Response (MMR) rate achieved at week 48 while on study 
treatment without meeting any treatment failure criteria prior to week 48. A patient will be 
counted as having achieved MMR at week 48 if he/she meets the MMR criterion (BCR-
ABL1 ≤ 0.1% IS) at week 48 while on study treatment unless the patient met any 
treatment failure criteria prior to week 48. 
3. Treatment of interest: the investigational treatment asciminib received for at least 48 
weeks, with or without dose modification, dose interruption or any intake of concomitant 
medications, or intake of prohibited medications. 
4. The intercurrent events are the events occurring after first dose of study drug that may 
impact the treatment effect. The intercurrent events of interest are: 
a. Treatment discontinuation (i.e. having performed an EOT visit) prior to week 48 due 
to any reason (e.g. death from any cause, intolerance, treatment failure, other reasons) 
b. Dose modification or dose interruption, or any intake of concomitant medications 
c. Intake of prohibited medications (Section 6.2.2) 
5. The summary measure is the MMR rate and its 95% confidence interval at week 48. 
Handling of the intercurrent events. 
The approach of accounting for intercurrent events is as follows: 
• For the intercurrent events 4a: The composite strategy will be applied for treatment 
discontinuation due to death from any cause, intolerance, and treatment failure. Define 
treatment discontinuation due to death from any cause, intolerance, and treatment failure 
as non-responders. The hypothetical strategy will be applied for treatment discontinuation 
due to other reasons (lost to follow up, withdrawal of consent, investigator decision etc.). 
The interest focuses on the treatment effect if patients stay on treatment for 48 weeks, if 
possible. 
• For the intercurrent events 4b: The treatment policy strategy will be applied. Meaning, 
the actual values of the variable (BCR-ABL1 % IS) will be used, regardless of whether the 
intercurrent event has occurred.  
• For the intercurrent events 4c: The hypothetical strategy will be applied for the intake 
of any prohibited medication. The interest focuses on the treatment effect if patients had 
not taken prohibited medications prior to week 48. 
12.4.4 Handling of missing values not related to intercurrent event 
Patients with missing PCR evaluations at 48 weeks will be considered as non-responders. 
However, if the 48-week PCR evaluation is missing, but both a PCR evaluation at 36 weeks 
and a PCR evaluation at 60 weeks indicate MMR, the 48-week assessment is imputed as a 
‘Response’, assuming that MMR is maintained between 36 and 60 weeks. 
12.4.5 Sensitivity analyses  
The hypothetical strategy of handling intercurrent events in Section 12.4.4 is based on missing 
completely at random (MCAR) assumption. To explore the robustness of analysis, sensitivity 
analyses exploring different assumptions will be performed. The details will be provided in 
SAP.  

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In addition, due to the COVID-19 (Coronavirus) pandemic, there is a risk that planned visits 
are cancelled, potentially resulting in missing PCR evaluations. The impact of COVID-19 
(including potential missing data or having clinic visits replaced by home nursing staff visit to 
the participant´s home) on the primary endpoint will also be analyzed if sufficient (to be detailed 
in SAP) number of patients are affected. 
12.4.6 Supplementary analysis 
Subgroup analyses of the primary efficacy endpoint to assess the homogeneity of the treatment 
effect across demographic and baseline disease characteristics may be conducted on the 
following subgroups, if there are enough patients in each category: 
• Gender: Male and Female 
• Race: Asian, Caucasian, or others 
• Age at baseline (≥18-< 65 years, ≥ 65 years, ≥ 75 years) 
• Reason for discontinuation of the last prior TKI: Warning or failure (i.e. lack of efficacy) 
or intolerance (i.e. adverse event, lack of tolerability) to the most recent TKI therapy at the 
time of screening  
Note: Only one reason for discontinuation is allowed for each prior therapy. 
• Number of prior TKI therapies: 2, 3 or ≥4 
• Cytogenetic response status at baseline 
• Prior TKI treatment 
• Prior ponatinib: Yes or No  
• Mutation status at baseline: Wild type or mutant  
Other subgroup as appropriate, may be analyzed and described in Statistical Analysis Plan 
(SAP).  
12.5 Analysis supporting secondary objectives 
The secondary objectives in this study are as follows: 
• To evaluate the safety and tolerability of asciminib in patients with CML-CP following 
two or more prior TKI treatments. 
• To assess the rate of MMR in patients with no evidence of MMR at baseline, at alternative 
time points at weeks 12, 24, 36, 72, 96 and 144. 
• To assess the rate of MMR at week 48 for patients with MMR at baseline  
• To assess the time to MMR 
• To assess the rate of early responses of BCR-ABL1 ≤10% and ≤1% IS at weeks 12, 24, 36 
and 48 
• To assess the rate of deep molecular responses (MR4 and MR4.5) at weeks 12, 24, 36, 48, 
72, 96 and 144.  
• To assess cytogenetic response (% Ph+ metaphases) at weeks 48 and EOT. 
• To characterize the impact of additional cytogenetic abnormalities on efficacy 
• To assess cumulative molecular responses by all-time points. 

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• To assess duration of MMR. 
• To assess sustained deep molecular responses as prerequisite for TFR. 
• To assess rate of progression (PFS). 
• To assess overall survival (OS). 
• To assess time to treatment failure (TTF). 
• To evaluate patient reported outcomes and quality of life by using QoL scales. 
12.5.1 Efficacy and/or Pharmacodynamic endpoint(s) 
Unless otherwise stated the FAS will be used for the analysis of all secondary efficacy endpoints.  
No statistical testing of secondary efficacy endpoints will be performed. 
• Molecular Response MMR rate at weeks 12, 24, 36, 72, 96 and 144  
• MMR rate at week 48 for patients with MMR at baseline 
• Rate of MR4 and MR4.5 at weeks 12, 24, 36, 48, 72, 96 and 144 
• Rate of BCR-ABL1 ≤10% and ≤1% at Weeks 12, 24, 36 and 48  
• Rate of BCR-ABL1 ≤ 10%, BCR-ABL1 ≤1%, MMR, MR4 and MR4.5 by all-time points 
For each endpoint above, the rate and the associated 95% confidence interval based on the 
Pearson-Clopper method will be presented.  
Additional chromosomal abnormalities and occurrence of high-risk ACAs will be analyzed.  
The details will be provided in SAP. 
Duration of MMR is defined in Section 8.3.1.1 as the time from the date of first documented 
MMR to the earliest date of loss of MMR, progression to AP or BC, or CML-related death. The 
time will be censored at the last molecular assessment (PCR) date while on treatment for 
patients who have not experienced any of the above events. 
Duration of MMR will be analyzed by K-M method and presented by K-M plots. The estimated 
rates of patients who are still responding at various time points will also be provided using K-
M method. 
Duration of MR4 without loss of MMR will be analyzed in a similar fashion to the analysis of 
duration of MMR. 
The cumulative incidence of MMR will be graphically displayed by an increasing step function. 
This curve will increase each time (after randomization) at which a new responder is observed 
and thus will increase up to the best observed response rate (e.g. up to 50% if half of the patients 
in the analysis population are able to achieve response). 
The additional patients who were intolerant to the last TKI and were in MMR already at baseline 
will be assessed for the duration of MMR using FAS 2.  
Time to MMR is defined in Section 8.3.1.1 and calculated as: date of first documented MMR 
- date of randomization +1. Descriptive statistics (minimum, maximum, median, quartiles, 
mean, SD) of time to MMR will be provided. 

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Cytogenetic Response 
Patients in FAS will be categorized with counts and percentages provided for cytogenetic 
response at week 48 and EOT. Shift tables will also be employed to examine the changes in 
cytogenetic response category from baseline. 
CCyR rates at Weeks 48 and EOT and the associated 95% confidence intervals based on the 
Pearson-Clopper method will be presented. 
Treatment failure, disease progression and survival 
Progression-Free-Survival (PFS) is defined as the time from the date of randomization to the 
earliest occurrence of documented disease progression to AP/BC or the date of death from any 
cause before the cut-off date. 
The time will be censored at the date of last study assessment (PCR, cytogenetic, hematologic 
or extramedullary) or last post-treatment follow-up for patients without event. 
Overall survival (OS) is defined as the time from the date of randomization to the date of death. 
Patients who are alive at the time of the analysis data cutoff date will be censored at the date of 
last contact before the cut-off date. 
Time to treatment failure (TTF) is defined as the time from date of randomization to an event 
of treatment failure define as BCR-ABL1 > 1% IS. The following events will constitute 
‘treatment failure’, and are based on the ELN criteria 2020 defining failure of a second line 
treatment adapted to include discontinuation of randomized treatment as an event: 
• Twelve months (48 weeks) after the initiation of treatment BCR-ABL1 >1% IS 
• Emergence of resistance mutations, high-risk ACA 
For patients who have not reached treatment failure, their TTFs will be censored at the time of 
last study assessment (PCR, cytogenetic, hematologic or extramedullary) before the cut-off date. 
TTF, PFS and OS will be estimated and graphically displayed using the K-M approach on FAS. 
The estimated rates by K-M method at various time points will be provided. 
12.5.2 Safety endpoints 
For all safety analyses, the safety set (SAF) will be used, except where stated otherwise.  
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of participant’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 

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3. Post-treatment period: starting at day 31 after last dose of study medication. 
Adverse events 
All the summary tables for adverse events (AEs) and deaths will be tabulated by randomized 
groups. 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. All information obtained on adverse 
events will be displayed by primary system organ class, preferred term and maximum severity. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized, system organ class and/or preferred term, severity (based on CTCAE grades), type 
of adverse event, relation to study treatment. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment. 
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI) 
during the on-treatment period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths and serious adverse events (including those from the pre-treatment, on-
treatment and post-treatment periods) will be listed and those collected before or after the on-
treatment period will be flagged. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. Selected AESIs are discussed in detail in the [Asciminib Investigator’s Brochure]. 
The following will also be summarized both for a) all patients using combined sets (SAF and 
SAF 2), and for b) SAF 2 only: 
• All deaths 
• Serious adverse events and adverse events of special interest 
• Adverse events lead to treatment discontinuation 
• Grade 3 and 4 adverse events 
Vital signs 
All vital signs data will be summarized by visit/time. 

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12-lead ECG 
ECGs (12-lead) including PR, QRS, QT, QTcF, and HR intervals will be obtained for each 
subject during the study. ECG data will be read and interpreted locally. 
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.  
All ECG data will be summarized by visit/time. 
Clinical laboratory evaluations 
All laboratory data will be summarized by visit/time. Shift tables using the low/normal/high/ 
(low and high) classification will be used to compare baseline to the worst on-treatment value. 
Grading of laboratory values will be assigned programmatically as per 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 5.0, results will be 
categorized as low/normal/high based on laboratory normal ranges. 
The following listings/summaries will be generated separately for hematology, and 
biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE version 
5.0 if applicable and the classifications relative to the laboratory normal ranges 
For laboratory tests where grades are defined by CTCAE version 5.0 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant will 
be counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE version 5.0 grades to compare baseline to the worst on-treatment 
value 
For laboratory tests where grades are not defined by CTCAE version 5.0: 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline to 
the worst on-treatment value. 
12.5.3 Biomarkers 
Biomarkers will not be part of the secondary endpoints and will be evaluated exploratory only. 
12.5.4 Patient reported outcomes 
The patient reported outcomes objectives are to compare the impact of treatment on patient 
reported outcomes (PRO) including CML-specific symptoms and health related patient quality 

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• Explore the influence of early molecular response levels on long term molecular response 
levels. 
Additional exploratory biomarker analyses may be performed depending on the data. All 
patients with evaluable biomarker measurements in the FAS will be included in the analysis 
and will be reported in a separate biomarker report. 
Optional exploratory biomarker analysis. 
The main aim of this optional exploratory biomarker analysis is to predict which patients will 
be responders at 48 weeks (in MMR) using single cell 
 by mass cytometry. A 
formal power calculation has not been conducted however, based on previous experience, 80 
patients is deemed sufficient.  
The optional exploratory biomarker analysis will be reported in a separate exploratory 
biomarker report that will be done by 
 and provided upon request. This report 
will be independent from the biomarker analysis describe above and from the study CSR. 
Publications that may be done from this research will be provided to sites who contributed. 
12.7 Interim analyses 
No formal interim analysis is planned for this trial. The following analyses are planned as 
detailed below. 
• 48-week primary analysis: Formal testing of the primary endpoint will be performed. 
Analyses of other efficacy endpoints at and by week 48 will also be performed.  
• 96-week analysis: Analyses of efficacy endpoints at and by week 96 will be performed. 
• End of study treatment analysis similar to the 96-week analysis.  
12.8 Sample size calculation 
12.8.1 Primary endpoint(s) 
A sample size of 156 patients (randomized to either asciminib 40 mg b.i.d. or 80 mg q.d.) will 
have 80% power to reject the null proportion of 23% (upper limit of 95% exact binomial CI of 
the MMR rate at Week 48 in Bosutinib arm in ASCEMBL: see below) at 0.025 one-sided level 
of significance if the true rate (under alternative hypothesis) is 33% (considering a clinically 
meaningful difference of 10% or more) using exact test for single proportion (nQuery 7). 
[The MMR rate (95% CI) at Week 48 in Bosutinib arm of ASCEMBL trial (at primary analysis) 
was 11.1 % (4.2% – 22.6%; 54 patients were eligible for this sample size computation]. 
An additional 30 patients (randomized to either asciminib 40 mg b.i.d. or 80 mg q.d.) intolerant 
only to last TKI and in MMR at baseline will also be analyzed.  
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 
CCI
CCI

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local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records 
to Novartis/Sponsor monitors, auditors, Novartis/Sponsor Quality Assurance representatives, 
designated agents of Novartis/Sponsor, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must inform 
Novartis/Sponsor immediately that this request has been made. 
13.3 Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal Standard of Practices, and are performed according to written Novartis 
processes. 
13.5 Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the timepoints indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis/Sponsor. 

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

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15 References 
Akard LP, Albitar M, Hill CE, et al. (2013) The ‘Hit Hard and Hit Early’ approach to the 
treatment of chronic myeloid leukemia: implications of the updated National Comprehensive 
Cancer Network Clinical Practice Guidelines for routine practice. Clin Adv Hematol Oncol; 
11(7):421-32. 
Baccarani M, Cortes J, Pane F, et al. (2009).European LeukemiaNet. Chronic myeloid 
leukemia: an update of concepts and management recommendations of European 
LeukemiaNet. J Clin Oncology. 27(35):6041-6051 
Baccarani M, Deininger MW, Rosti G et al. (2013). European LeukemiaNet recommendations 
for the management of chronic myeloid leukemia. Blood 2013; 122(6):872-884. 
Baccarani M, Saglio G, Goldman J, et al. (2006). Evolving concepts in the management of 
chronic myeloid leukemia: recommendations from an expert panel on behalf of the European 
LeukemiaNet. Blood. 108(6):1809-1820. 
Cortes JE, Hughes TP, Mauro MJ, et al. Asciminib, a first-in-class STAMP inhibitor, 
provided durable molecular responses in patients with chronic myeloid leukemia harboring 
the T315I mutation. Primary efficacy and safety results from a Phase I trial. 650A: Oral 
presentation at the ASH Annual Meeting & Exposition, held virtually on Dec 5–8, 2020. ASH 
2020 [abstract 650]. 
Cortes JE, Kim DW, Pinilla-Ibarz J, et al. (2013). A phase 2 trial of ponatinib in philadelphia 
chromosome-positive leukemias. N Engl J Med, Nov 2013. 
Cross NCP, Hochhaus A, Müller MC. (2015). Molecular monitoring of chronic myeloid 
leukemia: principles and interlaboratory standardization. Ann Hematol; 94 (2 Suppl):S219-
S225. 
Faderl S, Talpaz M, Estrov Z, et al. (1999). The biology of chronic myeloid leukemia. N Engl 
J Med; 341(3):164-172. 
Geissler J, Sharf G, Bombaci F, et al. (2017). Factors influencing adherence in CML and ways 
to improvement: Results of a patient-driven survey of 2546 patients in 63 countries. J Cancer 
Res Clin Oncol 2017:143:1167-1176 
Garg RJ, Garg RJ, Kantarjian H, O’Brien S et al. (2009). The use of nilotinib or dasatinib 
after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood. 2009; 
114(20):4361-4368 
Giles FJ, Abruzzese E, Rosti G, et al. (2010). Nilotinib is active in chronic and accelerated 
phase chronic myeloid leukemia following failure of imatinib and dasatinib therapy. 
Leukemia. 2010; 24(7):1299–1301. 
Hochhaus A, Baccarini M, Silver RT, et al. (2020a) European LeukemiaNet 2020 
recommendations for treating chronic myeloid leukemia. Leukemia 2020a; 34:966-984. 
Hochhaus A, Breccia M, Saglio G, et al. (2020b). Expert opinion – management of chronic 
myeloid leukemia after resistance to second-generation tyrosine kinas inhibitors. Leukemia 
2020b; 34:1495-1502. 

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Hochhaus A, Boquimpani C, Rea D, et al. (2019). Efficacy and safety results from 
ASCEMBL, a multicenter, open-label, phase 3 study of asciminib, a first-in-class STAMP 
inhibitor, vs bosutinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) 
previously treated with ≥ tyrosine kinase inhibitors. ASH 2020c Late-breaking abstracts, 
LBA4. 
Hughes T, Mauro MJ, Cortes JE. (2019). Asciminib in chronic myeloid leukemia after ABL 
kinase inhibitor failure. N Engl J Med 2019; 381(24):2315-2326 
Hughes T and Branford S. (2006). Molecular monitoring of BCR–ABL as a guide to clinical 
management in chronic myeloid leukaemia. Blood Reviews. 2006; Vol 20, issue 1: pages 29-
41. 
Ibrahim AR, Eliasson L, Apperley JF et al. (2011). Poor adherence is the main reason for loss 
of CCyR and imatinib failure for chronic myeloid leukemia on long-term therapy. Blood 
2011; 117(14):3733-3736. 
Keläle M, Talvensaari K, Koskenvesa P et al. (2014) Chronic myeloid leukemia patients’ 
adherence to peroral tyrosine kinase inhibitors compared with adherence as estimated by their 
physicians. Patient Preference and Adherence 2014; 8:1619-1627.  
Nowell PC, Hungerford DA. (1960). A minute chromosome in human granulocytic leukemia. 
Science. 1960; 142:1497. 
Manley PW, Stiefl NJ. (2018). Progress in the discovery of BCR-ABL kinase inhibitors for 
the treatment of leukemia. Top Med Chem. 2018; 28:1-38. 
Manley P W, Barys L, Cowan-Jacob S W. (2020). The specificity of asciminib, a potential 
treatment for chronic myeloid leukemia, as a myristate binding ABL inhibitor and analysis of 
its interactions with mutant forms of BCR-ABL1 kinase. Leukemia Research 2020; 
98:106458 
Ongoren S, Eskazan AE, Suzan V, et al. (2017). Third-line treatment with second-generation 
tyrosine kinase inhibitors (dasatinib or nilotinib) in patients with chronic myeloid leukemia 
after two prior TKIs: real-life data on a single center experience along with the review of the 
literature. Hematology. DOI: 10.1080/10245332.2017.13851932017. 
Rowley JD. (1973). A new consistent chromosomal abnormality in chronic myelogenous 
leukaemia identified by quinacrine fluorescence and Giemsa staining [letter]. Nature 1973; 
243:290-293. 
Sawyers CL. (1999). Chronic Myeloid Leukemia. N Engl J Med; 340(17):1330-1340. 
Steegmann JL, Baccarani M, Breccia M, et al. (2016). European LeukemiaNet 
recommendations for the management and avoidance of adverse events of treatment in 
chronic myeloid leukemia. Leukemia 2016; 30:1648-1671. 
Soverini S, et al. (2014). Implications of BCR-ABL1 kinase domain-mediated resistance in 
chronic myeloid leukemia. Leukemia research 38 (2014) 10-20. 
Soverini S, et al. (2016). Best practices in Chronic Myeloid Leukemia Monitoring and 
Management. The Oncologist 2016; 21:626-633. 

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Wylie AA, Schoepfer J, Jahnke W, et al. (2017). The allosteric inhibitor ABL001 enables dual 
targeting of BCR-ABL1. Nature 2017; 543:733-737 

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16 Appendices 
16.1 List of concomitant medications for patients on asciminib 
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited in Section 6.2.2 for patients on 
asciminib. 
The following lists are based on the internal [Pharmacokinetic Sciences memorandum on Drug- 
Drug Interaction] (release date: January 2018), which was compiled from the Indiana University 
School of Medicine’s “Clinically Relevant” Table and supplemented with the 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). This list is not comprehensive and is only 
meant to be used as a guide. Please contact the medical monitor with any questions.  
Table 16-1 Concomitant medications to be used with caution for patients on asciminib 
Category 
Drug Names 
Strong inducers of 
CYP3A4 
carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, rifabutin, 
rifampicin, St. John’s wort (Hypericum perforatum) 
Narrow Therapeutic 
index substrates of 
CYP2C9 
phenytoin, warfarin (also sensitive) 
Narrow Therapeutic 
index substrates of 
CYP3A 
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus, terfanadine, 
Torsade de Pointes 
(TdP) TdP/QT risk : 
Known 
amiodarone, anagrelide, arsenic trioxide, astemizole (off us mkt), azithromycin, bepridil 
(off us mkt), chloroquine, chlorpromazine, cilostazol, cisapride (off us mkt), citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone (not on us mkt), donepezil,