ASCiminib, With or Without Dasatinib Combination, as a 2nd-Line Therapy to ADVANCE the Treatment for Chronic Myelogenous Leukemia in Chronic Phase (ASC2ADVANCE)
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia (CML) in
Sponsor: University Health Network, Toronto

Clinical Protocol No. OZUHN-044 
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CLINICAL STUDY PROTOCOL 
 
Protocol Title: ASCiminib, with or without Dasatinib combination, as a 2nd-Line therapy 
to ADVANCE the Treatment for Chronic Myelogenous Leukemia in chronic phase 
(ASC2ADVANCE) 
 
Clinical Trial Protocol No: 
Ozmosis Study No. OZUHN-044 
Novartis Study Code: CABL001ACA03T 
 
Protocol Version #:  
1.0  
 
Protocol Date: 
10-Feb-2026 
 
Phase of Study:   
II 
 
Sponsor/Principal Investigator:  Dr. Dennis Kim, UHN 
 
 
Investigational Agent: 
 
 
 
 
 
 
 
Asciminib 
Protocol History 
 
Original: 
Version 1.0; dated 10-Feb-2026 
 
 
 

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Sponsor/Principal Investigator:  
Name:  
Dennis Kim 
Address:    
Princess Margaret Cancer Centre 
610 University Avenue  
OPG Rm 6-222 
Toronto, Ontario, M5G 2M9  
Tel: 
 
416-946-4501x2464  
 
Fax:  
416-946-4563  
Email:  
dr.dennis.kim@uhn.ca  
 
Clinical Trial Management Company:  
Name:  
Ozmosis Research Inc. (Ozmosis) 
Address: 
700 University Ave 
Suite 217-2N, Toronto, ON M5G 1Z5 
Main Line:  
416-634-8300 
Fax:   
416-634-8333 
Email:  
ozmclinical@ozmosisresearch.ca 
                                    
 
 

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Sponsor’s Agreement to Protocol Version 1.0, [10-Feb-2026] 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Authorized Personnel  
(Print) 
 
Title of Authorized Personnel  
(Print) 
 
Signature of Authorized 
Personnel: 
 
 
______________________________________ 
 
 
______________________________________ 
 
 
______________________________________ 
 
                    
 
Date of Approval: 
______________________________________ 
 
DD-MMM-YYYY 

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STUDY SYNOPSIS   
Study Title: 
ASCiminib, with or without Dasatinib combination, as a 
2nd-Line therapy to ADVANCE the Treatment for 
Chronic Myelogenous Leukemia in Chronic Phase  
Short Title: 
ASC2ADVANCE 
Brief Summary: 
This study aims to evaluate Asciminib (ASC) +/- 
Dasatinib (DAS) therapy as a second-line treatment 
option for chronic phase chronic myeloid leukemia 
(CML) patients who have failed or met warning criteria 
after front line TKI therapy for resistance (based on the 
ELN 2020 failure/warning criteria). 
Study Design:  
A phase II, open-label, multi-site trial 
Primary Objective: 
To evaluate the effectiveness of ASC as a second-line 
therapy in chronic phase CML patients after 24 weeks 
of treatment. 
Secondary Objectives: 
 
1. To evaluate the effectiveness of ASC as a second-
line therapy in chronic phase CML patients after 
12 and 48 weeks of treatment. 
2. To evaluate the effectiveness of ASC + DAS as a 
second-line therapy in chronic phase CML patients 
with high-risk mutations after 12, 24 and 48 weeks 
of treatment.  
3. To evaluate the safety of ASC +/- DAS when used 
as a second-line therapy 
Study Duration: 
 
Approximately 2.5 years, including 18 months of 
recruitment, and approximately 12 months of treatment 
(12 cycles of 4 weeks each cycle)  
Patient Duration: 
Approximately 13 months including up to 48 weeks of 
treatment, followed by a safety follow up visit one month 
after the last dose. 
Study Sites: 
Approximately 4 sites within Ontario 
Planned Total Sample 
Size: 
Approximately 45 patients will be enrolled 
Investigational Product 
Administration: 
Asciminib (ASC) will be administered PO either as 
monotherapy in patients with a standard mutation 
profile, or in combination with Dasatinib (DAS) (as per 
standard of care (SOC)) for patients with a high-risk 
somatic mutation profile. 
Patients will be given 80 mg ASC PO daily for 28 days 
every 4 weeks (continuously) for a period up to 48 weeks. 

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Patients with a high risk mutation profile will receive 100 
mg DAS PO daily in addition to ASC, starting at C2D1.  
Patient Population: 
Adult patients diagnosed with CML, who have 
experienced treatment failure (i.e. resistance or 
suboptimal response) to first-line TKI therapy. 
Inclusion/Exclusion 
Criteria: 
 
Inclusion Criteria   
1. Patients ≥18 years of age  
2. Diagnosis of CML in chronic phase as per WHO 
criteria based on the presence of BCR::ABL1 
fusion gene by PCR at original diagnosis. 
Confirmation is recommended, if possible, by 
demonstrating the Philadelphia chromosome or 
variants by cytogenetics or FISH (Fluorescence 
In Situ Hybridization) in addition to bone marrow 
morphology confirming CML-CP. Patients with 
additional chromosomal abnormalities in addition 
to the Philadelphia chromosome are eligible. 
NGS testing at initial diagnosis is not required. 
3. Warning or failure to first line of TKI therapy at 
the time of screening due to resistance or 
suboptimal response (based on the ELN 2020 
failure criteria) 
4. BCR::ABL1 transcript type is trackable with 
institutional RQ-PCR (Real-time Quantitative 
Polymerase Chain Reaction) testing for response 
assessment  
5. No prior or concurrent malignancies, except for 
adequately treated non-melanoma skin cancer, 
cervical carcinoma-in-situ, adequately treated 
Stage I or II cancer from which patient is in 
complete remission, or any other cancer from 
which patient has been disease free for a 
minimum of five years 
6. Patients must be ASC naïve 
7. Agree to conduct somatic mutation profile testing 
at enrollment 
8. Adequate organ function defined by:  

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- 
Creatinine clearance level ≥ 30 mL/min as 
calculated using the Cockcroft-Gault formula 
- 
Total bilirubin (TBL) ≤ 3.0 ULN without AST/ALT 
increase; participants with Gilbert's syndrome 
may only be included if TBL ≤ 3.0 x ULN or direct 
bilirubin ≤1.5 x ULN  
- 
Aspartate transaminase (AST) ≤ 5.0 x ULN 
- 
Alanine transaminase (ALT) ≤ 5.0 x ULN 
- 
Alkaline phosphatase (ALP) ≤ 2.5 x ULN 
- 
Serum lipase ≤ 1.5 x ULN. For serum lipase > 
ULN and ≤ 1.5 x ULN, value should be 
considered not clinically significant and not 
associated with risk factors for acute pancreatitis 
9. Women of childbearing potential (defined as all 
women physiologically capable of becoming 
pregnant) and fertile men must agree to use 
adequate contraception from the time of signing 
the informed consent form and for at least 7 days 
following the last dose of study treatment. Women 
are considered post-menopausal and not of 
childbearing potential if they have had 12 months 
of natural (spontaneous) amenorrhea with an 
appropriate clinical profile (i.e., age, history of 
vasomotor symptoms). Acceptable methods of 
contraception include the following (applicable to 
the patient and/or patient’s partner(s)): 
a. Total abstinence 
b. Use of oral, injected or implanted hormonal 
methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine 
system (IUS) or other forms of hormonal 
contraception 
that 
have 
comparable 
efficacy (failure rate <1%), for example 
hormone vaginal ring or transdermal 
hormone contraception. In the case of oral 
contraception use, women should have 
been stable on the same pill for a minimum 
of 3 months before taking study drug. 

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c. 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. 
d. Male sterilization (at least 6 months prior to 
screening). A vasectomized male partner 
should be the sole partner for that patient. 
Note that a negative pregnancy test is required for 
all women of childbearing potential at the time of 
study entry.  
Exclusion Criteria  
1. Failure to provide informed consent 
2. Prior stem cell or bone marrow transplant  
3. Previous diagnosis of CML in accelerated phase 
(AP) or blast crisis (BC) 
4. Known second chronic phase of CML after 
previous progression to AP/BC 
5. ECOG performance status ≥3.  
6. Any one of the following cardiac symptoms: 
a. History of myocardial infarction (MI), 
coronary artery bypass graft (CABG) 
surgery, or coronary stent placement 
within the past six months 
b. Uncontrolled angina or uncontrolled 
congestive heart failure (NYHA class 
III or IV) within the past six months.  
c. Diagnosed congenital long QT 
syndrome  
d. Any history of clinically significant 
ventricular arrhythmias (such as 
ventricular tachycardia, ventricular 
fibrillation, or Torsades de pointes)  

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e. Clinically significant, uncontrolled atrial 
fibrillation or other clinically relevant 
arrhythmias requiring ongoing 
intervention. 
f. Prolonged QTc interval on pre-entry 
electrocardiogram. Specifically, QTcF 
and QTc ≥ 450ms for male patients or 
≥ 460ms for female patients. To be 
reported as the average of three serial 
baseline ECGs (using the QTcF 
formula) as determined by central 
reading. If QTcF ≥ 450 ms and 
electrolytes are not within normal 
ranges, electrolytes should be 
corrected and then the patient re-
screened for QTc.  
g. Subjects with hypokalemia or 
hypomagnesemia if it cannot be 
corrected prior to DAS administration. 
7. Concurrent medical condition, which may 
increase the risk of toxicity including but not 
limited to: Pleural or pericardial effusion of any 
grade and pulmonary arterial hypertension. 
8. History of significant bleeding disorder unrelated 
to cancer, including any of the following:  
a. Diagnosed congenital bleeding disorder 
(e.g., von Willebrand’s disease) 
b. Diagnosed acquired bleeding disorder 
within one year (e.g., acquired antifactor 
VIII antibodies).  
c. Ongoing or recent (≤ 3 months) significant 
gastrointestinal bleeding 
9. Presence of ASC resistant ABL1 KDM 
(Myristolyate site mutation, T315I, M244V, 
V299L, F359) using institutional Sanger 
sequencing test in each center as a SOC (if the 
ABL1 KDM result is available). 
10. History of first line TKI discontinuation (with 
optimal response) due to adverse events 

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including hematologic or non-hematologic 
toxicities 
11. History of recurrent or chronic pancreatitis  
12. Treatment with strong inducers of CYP3A is not 
allowed and should be switched to an alternative 
at least one week prior to the start of study 
treatment  
13. Pregnant or nursing (lactating) women 
14. Participation in a prior investigational study within 
30 days prior to enrolment, or within 5 half-lives 
of the investigational product, whichever is 
longer. 
15. Known central nervous system infiltration (in 
absence of suspicion of CNS involvement, 
lumbar puncture not required). 
16. Known history of chronic Hepatitis B (HBV), or 
chronic Hepatitis C (HCV) infection. Testing for 
Hepatitis B surface antigen (HBs Ag) and 
Hepatitis B core antibody (HBc Ab/anti HBc) will 
be performed at screening. If anti-HBc is 
positive, HBV-DNA evaluation must be carried 
out at screening. Patients having positive HBV-
DNA or positive HBsAg must not be enrolled in 
the study. 
17. Patients with a known hypersensitivity to ASC or 
to any ingredient in the formulation, including any 
non-medicinal ingredient or component of the 
container.  
18. Patients with a known hypersensitivity to DAS or 
to any component of APO-DASATINIB. 
Study Assessments 
Study assessments are depicted in the Study Schedule 
(Appendix I).  
Response Assessment: 
Major Molecular Response (MMR), defined as a 3-log 
reduction or deeper (0.1% International Scale) after 3, 6 
and 12 cycles. 
Statistical Analysis:  
Refer to Section 11 
 
 

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      LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
ABL1 
Abelson murine leukemia viral oncogene homolog 1 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute Neutrophil Count 
AP 
Accelerated Phase 
AS/MTFs 
Activated Signaling and Myeloid Transcription Factors 
ASC 
Asciminib 
AST 
Aspartate transaminase 
BCR 
Breakpoint Cluster Region 
BC 
Blast Crisis 
CBC 
Complete Blood Count 
CCyR 
Complete Cytogenetic Response 
CML 
Chronic Myeloid Leukemia 
CP 
Chronic Phase 
CRF 
Case Report Form 
CT 
Clinical Trial 
DAS 
Dasatinib 
DILI 
Drug-Induced Liver Injury 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ELTS 
EUTOS Long-Term Survival 
EORTC 
European Organization for Research and Treatment of Cancer 
EUTOS 
European Treatment and Outcome Study 
FISH 
Fluorescence In Situ Hybridization 
GCP 
Good Clinical Practice 
HF 
Heart Failure 
ICF 
Informed Consent Form 
KD 
Kinase Domain 
LFTs 
Liver Function Tests 
LLN 
Lower Limit of Normal 
LVEF 
Left Ventricular Ejection Fraction 
MI 
Myocardial Infarction 
MMR 
Major Molecular Response 

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NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NGS 
Next-Generation Sequencing 
Ph 
Philadelphia Chromosome 
PLT 
Platelets 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PO 
By Mouth  
QI 
Qualified Investigator 
QoL 
Quality of Life 
RCT 
Randomized Clinical Trial 
REB 
Research Ethics Board 
RQ-PCR  
Real-time Quantitative Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
STAMP 
Specifically Targets the ABL Myristoyl Pocket. 
SOC 
Standard of Care 
TKI 
Tyrosine Kinase Inhibitor 
TSH 
Thyroid Stimulating Hormone 
UHN 
University Health Network 
ULN 
Upper Limit of Normal 
 
 

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TABLE OF CONTENTS 
1.  BACKGROUND and RATIONALE ........................................................................ 15 
1.1. Pathogenesis of chronic myeloid leukemia ......................................................... 15 
1.2. Tyrosine kinase inhibitor therapy in the treatment of CML .................................. 15 
1.3. Asciminib as a novel agent for the treatment of CML .......................................... 16 
1.4. Adverse impact of somatic mutation profiles on treatment outcomes in CML 
patients ...................................................................................................................... 17 
1.5. Promises of combination treatment of Asciminib with other ATP biding pocket 
inhibitors..................................................................................................................... 17 
1.6. Rationale of the present study design ................................................................. 17 
2.  STUDY DESIGN ..................................................................................................... 18 
2.1. Study Schema ..................................................................................................... 18 
2.2. Sample Size ........................................................................................................ 19 
2.3. Study Objectives ................................................................................................. 19 
3. PATIENT SELECTION ........................................................................................... 19 
3.1. Eligibility .............................................................................................................. 19 
3.1.1. Inclusion Criteria ........................................................................................ 20 
3.1.2. 
Exclusion Criteria .................................................................................... 21 
4. PATIENT SCREENING AND ENROLLMENT ........................................................ 23 
5. PRE-TREATMENT EVALUATION ......................................................................... 23 
5.1. Baseline Assessment .......................................................................................... 23 
6. STUDY TREATMENT/ INTERVENTION ................................................................ 24 
6.1. Treatment/Intervention ........................................................................................ 24 
6.2. 
Study Drug Administration .............................................................................. 24 
6.3. 
Packaging and Labelling ................................................................................. 25 
6.4. 
Storage and Stability ....................................................................................... 25 
6.5. 
Accountability and Destruction of Study Drug ................................................. 25 
6.6. 
Drug Supply and Ordering .............................................................................. 26 
6.7. 
Assessment of Subject Compliance ................................................................ 26 
6.8. 
Misuse/Abuse ................................................................................................. 26 

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6.9. 
Modifications to Dose or Schedule .................................................................. 26 
6.10. Concomitant Medications ................................................................................ 33 
7. EVALUATION DURING and AFTER INTERVENTION ......................................... 34 
7.1 Efficacy Assessments .......................................................................................... 34 
7.2 Optional Sub-Study .............................................................................................. 36 
8. DISCONTINUATION OF PROTOCOL ................................................................... 36 
8.1. 
Termination of Protocol ................................................................................... 37 
8.1.2 
 Criteria for Early Permanent Discontinuation of Protocol Treatment 38 
9. SAFETY AND REPORTING REQUIREMENTS ..................................................... 38 
9.1. 
Adverse Event Definitions ............................................................................... 38 
9.2. 
Adverse Event Documentation ........................................................................ 38 
9.3. 
Attribution Definitions ...................................................................................... 39 
9.4. 
Serious Adverse Event ................................................................................... 39 
9.5. 
Adverse Event Reporting Criteria .................................................................... 40 
9.6. 
Adverse Event Reporting Period ..................................................................... 41 
9.7. 
Serious Adverse Event Reporting to Ozmosis ................................................ 41 
9.8. 
Exceptions and Non-Reportable SAEs ........................................................... 42 
9.9. 
Serious Adverse Event Reporting to Health Canada ...................................... 42 
9.10. Reporting SAEs to Local Research Ethics Boards .......................................... 42 
9.11. Reporting of Pregnancy .................................................................................. 42 
9.12. Ozmosis Reporting Responsibility to Pharmaceutical Company ....................... 43 
10. STUDY OUTCOMES .............................................................................................. 43 
10.1. Primary Outcome ............................................................................................ 43 
10.2. Secondary Outcomes ..................................................................................... 43 
10.3. Definitions ....................................................................................................... 44 
10.4. Measuring Response ...................................................................................... 45 
11. STATISTICAL ANALYSIS ..................................................................................... 46 
11.1. General Statistical Considerations .................................................................. 46 
11.2. Sample Size Calculation ................................................................................. 46 
11.3. Evaluation of Study Endpoints ........................................................................ 47 

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11.4. Final Analysis and Reporting .......................................................................... 48 
12. STUDY SIGNIFICANCE ......................................................................................... 48 
13. ETHICS .................................................................................................................. 48 
13.1. Informed Consent ........................................................................................... 48 
13.2. Research Ethics Board (REB) ......................................................................... 48 
14. RESPONSIBILITIES of the INVESTIGATOR ........................................................ 49 
15. DOCUMENTATION, RECORD ACCESS AND MAINTENANCE OF STUDY 
RECORDS .................................................................................................................... 50 
15.1. Documentation of Patient’s Participation ........................................................ 50 
15.2. Regulatory Requirements ............................................................................... 50 
15.3. Patient Confidentiality and Access to Source Data/Documents ...................... 50 
15.4. Confidentiality of the Study ............................................................................. 51 
15.5.   Study Data at the End of Registration of Clinical Trial..................................... 51 
15.6. Data Reporting ................................................................................................ 51 
15.7. Maintenance of Study Records ....................................................................... 51 
16. QUALITY ASSURANCE AND QUALITY CONTROL ............................................ 52 
16.1. Monitoring/Auditing ......................................................................................... 52 
17. ADMINISTRATIVE PROCEDURES ....................................................................... 52 
17.1. Amendments to the Protocol ........................................................................... 52 
17.2. Protocol Deviations and Violations .................................................................. 52 
17.3. Premature Discontinuation of the Study .......................................................... 52 
18. STUDY ORGANIZATION ....................................................................................... 53 
18.1. Steering Committee ........................................................................................ 53 
18.2. Data Safety Monitoring Board ......................................................................... 53 
19. SCIENTIFIC REPORTING and PUBLICATION ..................................................... 53 
20. REFERENCES ....................................................................................................... 54 
Appendix I: Schedule of Study Assessments and Evaluations .................................... 56 
 
 
 
 

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1.  
BACKGROUND and RATIONALE  
1.1. Pathogenesis of chronic myeloid leukemia 
Chronic Myelogenous Leukemia (CML) is a clonal myeloproliferative disorder 
characterized by the overproduction of leukemic myeloid cells with a consequence of 
BCR::ABL1 gene rearrangement. The hallmark of CML is the Philadelphia (Ph) 
chromosome, found in up to 95% of patients1. The Ph chromosome results from a 
reciprocal translocation of chromosomes 9 and 22, i.e. t(9;22)(q34;q11), which fuses a 
portion of the Abelson (ABL1) gene on chromosome 9, with a portion of the breakpoint 
cluster region (BCR) gene on chromosome 22. This translocation creates the BCR-ABL 
fusion protein, a constitutively active cytoplasmic tyrosine kinase that increases signaling 
activity and affects the growth and differentiation of hematopoietic cells, allowing them to 
escape constraints on normal growth and become leukemic 2. 
Most patients are diagnosed in the chronic phase (CP), characterized by anemia, 
splenomegaly, and leukocytosis, generally, with few constitutional symptoms such as 
fatigue, weight loss, malaise, easy satiety, and left upper quadrant fullness or pain. CML 
can progress to the accelerated phase (AP) or blast crisis (BC), often following worsening 
anemia, splenomegaly, and organ infiltration. Without treatment, around 25% of patients 
may transition into BC without a preceding AP 3,4. 
1.2. Tyrosine kinase inhibitor therapy in the treatment of CML 
The introduction of the Tyrosine Kinase Inhibitor (TKI), imatinib (Glivec®), in 2001 
revolutionized the treatment of CML. Subsequently, several second-generation (2G) TKI 
agents, including dasatinib (DAS), nilotinib, and bosutinib, have been approved for first-
line treatment of CML. TKI treatment has significantly improved survival rates for CML 
patients, with optimal responders achieving near-normal life expectancy 5. 
Treatment guidelines recommend selecting the TKI based on individual patient and 
disease characteristics, including risk scores (Sokal, Hasford (Euro), EUTOS, or ELTS), 
preexisting comorbidities, and concomitant medications 6-8.  
Despite advancements in TKI therapy, many patients with CML fail to respond adequately 
to their first-line TKI treatment, either due to resistance or intolerance. There remains an 
unmet need in identifying the optimal strategy for selecting second- or later-line TKI 
therapy. Identifying patients at higher risk of failing second-line treatment, and exploring 
whether this risk can be reduced through combination therapies or dose intensification is 
critical for improving patient outcomes. Current practice suggests that approximately half 
of the patients with CML will have received a second-generation TKI as first-line therapy. 
Moreover, somatic mutations develop in approximately 40% of these patients, highlighting 
the need for more effective and alternative therapeutic agents 9. 

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Selecting the appropriate treatment is critical to achieving early optimal responses, 
reducing the risk of disease progression, maintaining quality of life, and minimizing 
serious side effects. 
1.3. Asciminib as a novel agent for the treatment of CML 
ASC is a novel, oral, potent inhibitor of BCR::ABL1 with a distinct mechanism of action 
that differentiates it from traditional TKIs. Unlike other BCR-ABL targeting TKIs that 
interact with the ATP-site on the SH1 domain in ABL1 protein, ASC specifically targets 
the ABL myristoyl pocket (STAMP) in the ABL1 protein. By occupying this binding site, 
ASC restores the negative regulation of kinase activity on the ABL1 protein. ASC has also 
shown high selectivity against BCR-ABL-positive cell lines compared to other TKIs 10,11. 
Most adverse effects associated with TKIs are due to off-target activity beyond BCR-ABL 
inhibition, which the specificity of ASC has been shown to minimize 12,13. ASC was granted 
accelerated approval by the US FDA in October 2021 for adult patients with Ph+ CML-
CP previously treated with two or more TKIs, and for those with the T315I mutation. It 
was also approved by the Japan Pharmaceuticals and Medical Devices Agency (PMDA) 
in March 2022 for CML treatment resistant or intolerant to previous therapy. 
Overall, ASC has shown a favorable benefit-risk profile. Results from phase I 
(CABL001X2101) and ASCEMBL (CABL001A2301) studies demonstrated its superior 
efficacy in the heavily pretreated patients when compared to bosutinib 6,14. Additionally, 
ASC demonstrated a superior efficacy and a favorable safety profile in newly diagnosed 
chronic-phase CML patients in the ASC4FIRST trial 15. However, ASC has only recently 
been approved for use as a first and second line treatment in Canada. Refer to the ASC 
product monograph for a list of updated risks. 
Specifically, ASC has shown notable advantages when compared to bosutinib, including 
higher rates of major molecular response (MMR; 25.5% vs. 13.2%) and complete 
cytogenetic response (CCyR; 44.4% vs. 20.8%). ASC also has a lower probability of 
discontinuation due to lack of efficacy (24.2% vs. 35.5% at week 96) or adverse events 
(7.0% vs. 25.0%), as well as a higher rate of event-free survival (57.4% vs. 25.2% at week 
96). However, 24.2% of patients on ASC monotherapy still experience lack of efficacy. 
Importantly, 56% of the 39 patients who discontinued ASC due to lack of efficacy had 
new or persistent ABL1 kinase domain mutations, including those at ATP-binding or 
myristoyl pocket site mutations. This indicates that ASC alone may not be sufficient to 
completely overcome TKI resistance, particularly in patients with extensive prior TKI 
exposure 15. 

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1.4. Adverse impact of somatic mutation profiles on treatment outcomes in CML 
patients 
Our research along with that of others 16,17, has highlighted that somatic mutations – 
particularly in activated signaling and myeloid transcription factors (AS/MTFs) – are 
associated with poorer outcomes following TKI therapy. Based on genetic analyses from 
the ASCEMBL study, the adverse impact of somatic mutations does not appear to be 
mitigated by ASC alone when compared to bosutinib 18. 
1.5. Promises of combination treatment of Asciminib with other ATP biding 
pocket inhibitors 
In vitro studies show that different BaF3 cell lines with ABL1 mutations have varying 
sensitivity to ASC 19. Combining ASC with ATP binding pocket inhibitors, such as 
ponatinib or DAS, showed synergistically enhanced cytotoxicity compared to the inhibitors 
alone  19.This suggests a potential for synergistic effects when combining ASC with other 
TKIs, particularly with DAS or ponatinib. 
1.6. Rationale of the present study design 
Despite its promise, several knowledge gaps remain. Specifically, the effectiveness of 
ASC as a second-line therapy and the potential for combination therapy with DAS to 
overcome the adverse impact of somatic mutations are to be further investigated.  
The ASC dose of 80 mg QD for patients with newly diagnosed CML-CP is based on the 
clinical experience in patients with CML-CP in studies CABL001X2101 and 
CABL001A2301 and the PK/Pharmacodynamic (PD) modelling based exposure-
response and exposure-safety analyses. Importantly, ASC 80 mg QD is the dose 
currently approved for patients with CML-CP, making it the most clinically relevant and 
regulatory-supported dose for this trial. 
The treatment period is designed to allow for adequate assessment of both molecular 
and hematologic responses, which may require prolonged therapy given the chronic 
nature of CML and the time-dependent depth of molecular responses observed with TKIs. 
A minimum treatment duration of 12-36 weeks has therefore been chosen to enable a 
robust evaluation of early molecular milestones (e.g., BCR::ABL1 ≤10% at 3 months) and 
sustained responses, while also ensuring sufficient safety data are captured. 
This design will provide critical evidence regarding the potential of ASC in combination 
with DAS to overcome resistance mechanisms, achieve faster and deeper molecular 
responses, and ultimately improve long-term outcomes for patients with CML-CP. 

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2.  
STUDY DESIGN  
This study is designed as a prospective study, focusing on a cohort of patients diagnosed 
with CML, who have experienced treatment failure (i.e. resistance or suboptimal 
response) to first-line TKI therapy. Eligible patients who provide consent will initiate 
treatment with ASC at 80 mg daily as a second-line therapy. Upon enrollment, somatic 
mutation profiling will be performed through the central lab for next-generation 
sequencing (NGS) test. Patients with a high-risk mutation profile who tolerate ASC for 4 
weeks, will receive, in addition to ASC, DAS 100 mg daily, administered as per standard 
of care (SOC). Patients will continue on ASC 80 mg daily (with or without DAS), with 
potential dose adjustments based on adverse events. 
1) Patients without a high-risk mutation profile will receive ASC monotherapy at a dose 
of 80 mg daily, in 28-day cycles, administered every 4 weeks.  
2) Patients with a high-risk mutation profile will receive ASC 80 mg daily for the first 4 
weeks (Cycle 1), followed by a combination of ASC 80 mg + DAS 100 mg daily 
starting from Cycle 2 onward. 
To assess response, a minimum of 3 and a maximum of 12 cycles (up to 48 weeks) will 
be given for both groups. 
2.1. Study Schema 
 
Figure 1. Summary of study concept for high-risk mutation profile-based stratification of 
treatment arms into ASC 80 mg daily monotherapy vs combination of ASC 80 mg daily 
with DAS 100 mg daily. Each cycle is 28 days in length, administered every 4 weeks, for 
a maximum total duration of 48 weeks. 

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2.2. Sample Size 
Approximately 45 adult patients will be enrolled in this study. 
2.3. Study Objectives 
Table 1: Study objectives and endpoints 
Primary Objective 
Primary Endpoint 
To evaluate the effectiveness of ASC as a 
second-line therapy in chronic phase 
CML patients after 24 weeks of treatment. 
The proportion of patients achieving 
Major Molecular Response (MMR), 
defined as a 3-log reduction or deeper 
(0.1% International Scale), after 24 weeks 
(6 cycles) of treatment with ASC as a 
second-line therapy. 
Secondary Objectives 
Secondary Endpoints 
To evaluate the effectiveness of ASC as a 
second-line therapy in chronic phase 
CML patients after 12 and 48 weeks of 
treatment. 
The proportion of patients achieving 
MMR, defined as a 3-log reduction or 
deeper (0.1% International Scale), after 
12 and 48 weeks (3 and 12 cycles) of 
treatment with ASC as a second-line 
therapy. 
To evaluate the effectiveness of ASC + 
DAS as a second-line therapy in chronic 
phase CML patients with high-risk 
mutations after 12, 24 and 48 weeks of 
treatment.  
The proportion of patients achieving MMR 
with ASC + DAS, defined as a 3-log 
reduction or deeper (0.1% International 
Scale), after 12, 24 and 48 weeks (3, 6 
and 12 cycles) of treatment  
To evaluate the safety of ASC +/- DAS 
when used as a second-line therapy 
1. Rate of discontinuation of 
treatment due to adverse events 
2. Rate of patients requiring dose 
adjustments due to adverse events 
3. Rate of grade 3 or 4 AEs in all 
patients 
4. Type, frequency and severity of all 
adverse events  
3. 
PATIENT SELECTION  
3.1. Eligibility 
This trial will be conducted in compliance with the protocol, GCP and applicable 
regulations. Eligibility status must be confirmed by a Qualified Investigator (QI) or 
designate prior to enrollment.  It is important that no exception is to be made to the 
eligibility criteria. Questions related to eligibility requirements must be discussed with 
Ozmosis and/or QI prior to enrollment.  

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3.1.1. Inclusion Criteria   
For inclusion in this study, patients must fulfill all the following criteria: 
1. Patients ≥18 years of age  
2. Diagnosis of CML in chronic phase as per WHO criteria based on the presence 
of BCR::ABL1 fusion gene by PCR at original diagnosis. Confirmation is 
recommended, if possible, by demonstrating the Philadelphia chromosome or 
variants by cytogenetics or FISH (Fluorescence In Situ Hybridization) in addition 
to bone marrow morphology confirming CML-CP. Patients with additional 
chromosomal abnormalities in addition to the Philadelphia chromosome are 
eligible. NGS testing at initial diagnosis is not required. 
3. Warning or failure to first line of TKI therapy at the time of screening due to 
resistance or suboptimal response (based on the ELN 2020 failure criteria) 
4. BCR::ABL1 transcript type is trackable with institutional RQ-PCR (Real-time 
Quantitative Polymerase Chain Reaction) testing for response assessment  
5. No prior or concurrent malignancies, except for adequately treated non-
melanoma skin cancer, cervical carcinoma-in-situ, adequately treated Stage I or 
II cancer from which patient is in complete remission, or any other cancer from 
which patient has been disease free for a minimum of five years 
6. Patients must be ASC naïve 
7. Agree to conduct somatic mutation profile testing at enrollment 
8. Adequate organ function defined by:  
- 
Creatinine clearance level ≥ 30 mL/min as calculated using the Cockcroft-Gault 
formula 
- 
Total bilirubin (TBL) ≤ 3.0 ULN without AST/ALT increase; participants with 
Gilbert's syndrome may only be included if TBL ≤ 3.0 x ULN or direct bilirubin 
≤1.5 x ULN  
- 
Aspartate transaminase (AST) ≤ 5.0 x ULN 
- 
Alanine transaminase (ALT) ≤ 5.0 x ULN 
- 
Alkaline phosphatase (ALP) ≤ 2.5 x ULN 
- 
Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN and ≤ 1.5 x ULN, value 
should be considered not clinically significant and not associated with risk factors 
for acute pancreatitis 
9. Women of childbearing potential (defined as all women physiologically capable of 
becoming pregnant) and fertile men must agree to use adequate contraception 
from the time of signing the informed consent form and for at least 7 days following 
the last dose of study treatment. Women are considered post-menopausal and not 
of childbearing potential if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (i.e., age, history of vasomotor 

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symptoms). Acceptable methods of contraception include the following (applicable 
to the patient and/or patient’s partner(s)): 
a. Total abstinence 
b. Use of oral, injected or implanted hormonal methods of contraception or 
placement of an intrauterine device (IUD) or intrauterine system (IUS) or 
other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception. In the case of oral contraception use, women 
should have been stable on the same pill for a minimum of 3 months before 
taking study drug. 
c. 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. 
d. Male sterilization (at least 6 months prior to screening). A vasectomized 
male partner should be the sole partner for that patient. 
Note that a negative pregnancy test is required for all women of childbearing 
potential at the time of study entry.  
3.1.2. Exclusion Criteria  
1. Failure to provide informed consent 
2. Prior stem cell or bone marrow transplant  
3. Previous diagnosis of CML in accelerated phase (AP) or blast crisis (BC) 
4. Known second chronic phase of CML after previous progression to AP/BC 
5. ECOG performance status ≥3.  
6. Any one of the following cardiac symptoms: 
a. History of myocardial infarction (MI), coronary artery bypass graft (CABG) 
surgery, or coronary stent placement within the past six months 
b. Uncontrolled angina or uncontrolled congestive heart failure (NYHA class III 
or IV) within the past six months.  
c. Diagnosed congenital long QT syndrome  
d. Any history of clinically significant ventricular arrhythmias (such as 
ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)  
e. Clinically significant, uncontrolled atrial fibrillation or other clinically relevant 
arrhythmias requiring ongoing intervention. 
f. Prolonged QTc interval on pre-entry electrocardiogram. Specifically, QTcF 
and QTc ≥ 450ms for male patients or ≥ 460ms for female patients. To be 
reported as the average of three serial baseline ECGs (using the QTcF 

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formula) as determined by central reading. If QTcF ≥ 450 ms and 
electrolytes are not within normal ranges, electrolytes should be corrected 
and then the patient re-screened for QTc.  
g. Subjects with hypokalemia or hypomagnesemia if it cannot be corrected 
prior to DAS administration. 
7. Concurrent medical condition, which may increase the risk of toxicity including 
but not limited to: Pleural or pericardial effusion of any grade and pulmonary 
arterial hypertension. 
8. History of significant bleeding disorder unrelated to cancer, including any of the 
following:  
a. Diagnosed congenital bleeding disorder (e.g., von Willebrand’s disease) 
b. Diagnosed acquired bleeding disorder within one year (e.g., acquired 
antifactor VIII antibodies).  
c. Ongoing or recent (≤ 3 months) significant gastrointestinal bleeding 
9. Presence of ASC resistant ABL1 KDM (Myristolyate site mutation, T315I, M244V, 
V299L, F359) using institutional Sanger sequencing test in each center as a SOC 
(if the ABL1 KDM result is available). 
10. History of first line TKI discontinuation (with optimal response) due to adverse 
events including hematologic or non-hematologic toxicities 
11. History of recurrent or chronic pancreatitis  
12. Treatment with strong inducers of CYP3A is not allowed and should be switched 
to an alternative at least one week prior to the start of study treatment  
13. Pregnant or nursing (lactating) women 
14. Participation in a prior investigational study within 30 days prior to enrolment, or 
within 5 half-lives of the investigational product, whichever is longer. 
15. Known central nervous system infiltration (in absence of suspicion of CNS 
involvement, lumbar puncture not required). 
16. Known history of chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) 
infection. Testing for Hepatitis B surface antigen (HBs Ag) and Hepatitis B core 
antibody (HBc Ab/anti HBc) will be performed at screening. If anti-HBc is positive, 
HBV-DNA evaluation must be carried out at screening. Patients having positive 
HBV-DNA or positive HBsAg must not be enrolled in the study. 
17. Patients with a known hypersensitivity to ASC or to any ingredient in the 
formulation, including any non-medicinal ingredient or component of the 
container.  
18. Patients with a known hypersensitivity to DAS or to any component of APO-
DASATINIB. 

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4. 
PATIENT SCREENING AND ENROLLMENT   
Prior to screening patients, each site must have submitted all necessary regulatory 
documentation to Ozmosis and the site must have been activated by Ozmosis. Access to 
the electronic case report forms (eCRFs) will only be granted once this has been received.   
All patients will be screened and confirmed to be eligible by a site QI, and consenting will 
occur according to the site’s ethics board approved process, prior to the patient’s 
enrollment into this study.  
No patient can receive protocol treatment until eligibility has been confirmed and the 
Patient Enrollment Form has been submitted to Ozmosis. The Patient Enrollment Form 
must be completed, and signed by a QI prior to enrollment. There are 2 sections to the 
Patient Enrollment Form: 
 SCREENING (top section): This section is completed by the site and should be e-
mailed to ozmclinical@ozmosisresearch.ca or faxed to 416-634-8333 at the time 
of screening. 
 
 ENROLLMENT (bottom section): This section is completed by the site at the time 
of enrollment. The site will submit the signed and completed Patient Enrollment 
Form to Ozmosis by e-mailing to ozmclinical@ozmosisresearch.ca or fax to 416-
634-8333. Only after this has been submitted to Ozmosis can the patient receive 
investigational product(s)/treatment. 
 
The protocol treatment is to be given within 5 working days of patient enrollment. 
5. 
PRE-TREATMENT EVALUATION   
Refer to Appendix I: Schedule of Study Assessments and Evaluations 
5.1. Baseline Assessment   
At baseline, a comprehensive clinical history and physical examination will be conducted. 
Clinical history will involve recording the date of CML diagnosis, phase at presentation, 
Sokal and ELTS (EUTOS Long-Term Survival) risk score (if available), and any additional 
chromosomal abnormalities identified on the diagnostic karyotype. If NGS test was 
performed at the time of initial diagnosis, this result will be also captured. All prior 
treatments, including the type of tyrosine kinase inhibitor (TKI), dosage, treatment 
response, toxicity and any treatment interruptions lasting longer than two weeks, will also 
be documented. 
Acquired ABL1 kinase domain mutations and additional chromosomal abnormalities 
occurring prior to enrollment will be recorded along with the corresponding dates, if 
available. 

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6. 
STUDY TREATMENT/ INTERVENTION   
Refer to Appendix I: Schedule of Study Assessments and Evaluations 
6.1. Treatment/Intervention   
All eligible patients who provide consent will initiate treatment with ASC at 80 mg daily for 
up to 12 cycles. Each cycle consists of 28 days (i.e., 4 weeks).  
Upon enrollment, somatic mutation profiling will be performed through the central lab at 
Toronto General Hospital for next-generation sequencing (NGS) test. Based on the 
results of this assessment, patients will be stratified into two groups; those with a high-
risk mutation profile and those without a high-risk mutation profile. Standard NGS testing 
will be performed on peripheral blood (PB) samples. Risk stratification will be centrally 
assessed based on the presence of genetic mutations and additional high-risk 
cytogenetic abnormalities. 
Patients with a high-risk somatic mutation profile will also initiate standard of care 
treatment with DAS in addition to ASC 80 mg daily on Cycle 2 Day 1. Patients will initiate 
SOC DAS treatment at a starting dose of 100 mg, as indicated in the product monograph. 
Patients will continue on ASC 80 mg daily (with or without DAS) for maximum 12 cycles 
of 28 days each (i.e. total of 48 weeks), with potential dose modifications based on the 
development of adverse events and its severity (refer to tables 2a). Monitoring of 
BCR::ABL1 transcript levels by PCR will occur every three cycles using local PCR test 
per SOC.  
The two treatment strategies are summarized below: 
1. Patients without a high-risk mutation profile will receive ASC 80 mg daily. 
2. Patients with a high-risk mutation profile will receive ASC 80 mg daily in 
combination with SOC DAS (i.e.,100 mg) daily. 
Patients who experience serious adverse events (more than 2 episodes, at least possibly 
related to study drug) without any clinical response, require discontinuation of the 
treatment for more than 28 days, or withdraw consent, will be discontinued from the trial. 
Additionally, the treating investigator holds the authority to discontinue a patient from 
treatment at any time if they deem it is not in the patient’s best interest to continue 
receiving treatment.  
6.2. 
Study Drug Administration 
Product 
Dose 
Route Of Administration 
Schedule 
ASC 
80 mg 
Oral (PO) 
Daily 

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All patients will receive open label investigational product. ASC should be taken once 
daily approximately 24 hours apart and should not be taken with food. No food should be 
consumed for 2 hours before the dose is taken and no additional oral intake other than 
water should be consumed for at least one hour after the dose is taken. Patients should 
be instructed to swallow tablets whole with a full 8 oz. glass of water, and not to chew 
them. Vomited doses should not be repeated. 
6.3. 
Packaging and Labelling   
For this protocol, ASC will be supplied to participating sites as 40 mg film coated tablets. 
Tablets are supplied in blister pack (10 blisters/card, 6 cards/carton). 
The study drug will be labeled consistent with the regulatory requirements and local site 
guidelines.  
6.4. 
Storage and Stability   
All medication must be stored in a secure area under the proper storage requirements 
with access restricted to the site staff pharmacist or designee(s). The storage conditions 
for investigational product will be provided on the medication label. 
Do not store ASC above 25o C. Store in the original package to protect from moisture. 
Patients should ensure study drug is kept out of the reach and sight of children when 
storing at home.  
6.5. 
Accountability and Destruction of Study Drug 
The QI or designee at each participating site must maintain a careful record of the 
inventory of the study drug received using a drug accountability form. Study drug 
accountability records will be available for review by the study monitor, as applicable, 
according to the monitoring plan. The local site pharmacies will follow the appropriate 
GCP for the storage and dispensing of the medication to the study patient. 
The study drug should not be used for any purpose outside the scope of this protocol, nor 
can it be transferred or licensed to any party not participating in the clinical study.  
Upon completion or termination of the study, the Sponsor shall follow Novartis’ 
instructions regarding the return or disposal of all unused study drug. The Sponsor shall 
be responsible for compliance with all laws and regulations applicable to any destruction 
or disposal of study drug at participating sites. The Sponsor will follow the instructions of 
Novartis in case Novartis determines that a recall of the study drug is required and in 
addition, the Sponsor will inform Novartis should the Sponsor determine that a recall of 
the study drug is required. 

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The Sponsor should ensure that the site has acceptable drug destruction policies in place. 
Documentation of study drug destruction should be maintained by the site, filed in the trial 
master file and provided to Ozmosis upon request.  
6.6. 
Drug Supply and Ordering 
Study drug for the trial will be provided by Novartis.  Sites must request study drug by 
submitting an order form to the drug depot, copying Ozmosis, in order for the study drug 
to be shipped to the site pharmacy.  The QI (or designee) will verify and acknowledge 
receipt of all study drug shipments by signing and returning all required forms. 
6.7. 
Assessment of Subject Compliance   
Compliance to study medication will be ascertained by use of patient diaries and pill 
counting. Patients will record the date, time and number of pills consumed in the diary on 
a daily basis. The QI or designee will account for the number of tablets dispensed against 
those returned by the patient. Any deviations and missed doses will be recorded in the 
CRF and drug accountability logs for verification with the reasons. The QI/designee will 
try to ensure complete compliance with the dosing schedule by providing timely 
instructions to the patients. 
6.8. 
Misuse/Abuse 
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.  
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
All sites must report any misuse and abuse of ASC to Ozmosis, who will report this to 
Novartis. 
6.9. 
Modifications to Dose or Schedule   
For patients who do not tolerate the protocol-specified dosing schedule, dose 
interruptions and/or reductions are either recommended or mandated in order to allow the 
patient to continue the study treatment. The dose modifications for ASC are summarized 
in Table 2. Dose modifications for DAS should be managed per standard of care. The 
dose reductions indicated as “recommendations” are provided to assist investigators in 
the event the patient experiences toxicity. All dose modifications should be based on the 
worst preceding toxicity. 
Re-escalation is permitted if a change in the patient’s individual benefit/risk assessment 
at the lower dose level is seen. Re-escalation will be allowed only once. Permanent 
treatment discontinuation is mandatory for specific events indicated as such in Table 2. 
Any dose changes must be recorded in the Dose Administration eCRF. A patient must be 

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discontinued from treatment with either ASC or DAS if, after treatment is resumed at a 
lower dose, the toxicity recurs with the same or worse severity (See Table 2). If a patient 
requires a dose interruption of > 28 days, then the patient must be discontinued from the 
study treatment. Patients who discontinue the study treatment for an adverse event 
suspected to be related to study drug or an abnormal laboratory value suspected to be 
related to study drug must be followed.  
Table 2. Dose modifications for patients on ASC treatment 
Severity (CTCAE v5.0) 
Guidance 
Neutropenia 
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: Maintain dose level  
If resolved in >14 days: Reduce dose 1 dose level 
Grade 4 (ANC < 0.5 x 10⁹/L) 
Mandatory: Hold dose until resolved to ≤ Grade 2 
(recheck CBC 2x/week), then:  
If resolved in ≤14 days: Maintain dose level  
If resolved in >14 days: Reduce dose 1 dose level 
Febrile neutropenia (ANC < 
1.0 x 10⁹/L, fever ≥ 38.5°C) 
Mandatory: Hold dose until resolved then reduce 
dose 1 dose level 
Thrombocytopenia 
Grade 1 (PLT < LLN – 75 x 
10⁹/L) 
Recommendation: Maintain dose level 
Grade 2 (PLT < 75 – 50 x 
10⁹/L) 
Recommendation: Maintain dose level 
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: Maintain dose level  
If resolved in >14 days: 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: Maintain dose level  
If resolved in >14 days: Reduce dose 1 dose level 
Recurrence of all cytopenias 
Recommendation: For recurrent Grade 3-4 
cytopenias: 
If resolved to ≤ Grade 2 in ≤ 14 days, maintain dose 
level  
If resolved in >14 days, then reduce dose 1 dose 
level 
Non-Hematologic Adverse Reactions 

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Grade 1 
Recommendation: Maintain dose level 
Grade 2 
Recommendation: Hold dose until resolved to ≤ 
Grade 1, then maintain dose level 
Grade 3 
Mandatory: Hold dose until resolved to ≤ Grade 1, 
then reduce dose 1 dose level 
Grade 4 
Mandatory: Permanently discontinue from treatment 
Serum Creatinine (Renal Impairment) 
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 from treatment 
Grade 4 (>6.0 x ULN) 
Mandatory: Permanently discontinue from treatment 
Isolated Total Bilirubin Elevation 
> ULN – 1.5 × ULN 
Recommendation: Maintain dose level 
> 1.5 – 3.0 × ULN 
Recommendation: Omit dose; repeat LFTs within 48-
72 hours, then monitor weekly, or more frequently if 
clinically indicated, until resolved to ≤ 1.5 x ULN or 
baseline: 
If resolved in ≤14 days: maintain dose. If >14 days: 
Reduce dose, 1 dose level 
> 3.0 – 10.0 × ULN 
Mandatory: Omit dose; repeat LFTs within 48-72 
hours, then monitor weekly, or more frequently if 
clinically indicated, until resolved to ≤ 1.5 x ULN or 
baseline: 
If resolved in ≤ 14 days, then reduce dose 1 dose 
level 
If resolved in > 14 days, then discontinue patient 
from study drug treatment. The patient should be 
monitored weekly (including LFTs), or more 
frequently if clinically indicated, until total bilirubin 
have resolved to baseline or stabilization over 4 
weeks 
> 10.0 × ULN 
Mandatory: Permanently discontinue patient from 
treatment; monitor LFTs weekly (or more frequently if 
clinically indicated) until return to baseline or 
stabilization over 4 weeks 
Isolated AST/ALT Elevation 
> ULN – 3.0 × ULN 
Recommendation: Maintain dose level 
> 3.0 – 5.0 × ULN 
Recommendation: Maintain dose level. Repeat LFTs 
as soon as possible, ideally within 48–72h; if 
abnormal values are confirmed upon the repeat test, 
monitor LFTs weekly (or more frequently if clinically 
indicated) until ≤ 3.0 × ULN 
> 5.0 – 10.0 × ULN 
Mandatory: Omit dose. Repeat LFTs as soon as 
possible, ideally within 48–72h. Monitor LFTs weekly 

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or more frequently if clinically indicated, until 
resolved to ≤ 3.0 × ULN. Then: 
If resolved in ≤ 14 days, resume dosing at prior dose 
level 
If resolved in > 14 days, resume with 1 dose level 
reduction 
> 10.0 – 20.0 × ULN 
Mandatory: Omit dose. Repeat LFTs as soon as 
possible, ideally within 48–72h. Monitor LFTs weekly 
or frequently if clinically indicated, until ≤ resolved to 
≤ 3.0 × ULN. Then resume with 1 dose level 
reduction 
> 20.0 × ULN 
Mandatory: Permanently discontinue study treatment 
Elevated baseline (> Baseline 
– 3 × Baseline AND < 5 × 
ULN) 
Maintain dose level 
Elevated baseline (> 3 × 
Baseline AND > 5 × ULN, 
duration < 2 weeks) 
Mandatory: Maintain dose level. Repeat LFTs as 
soon as possible, preferably within 48–72 hours; if 
abnormal values are confirmed, monitor LFTs weekly 
or more frequently until resolved to ≤ ULN or 
baseline. Resume with same dose once resolved. 
Elevated baseline (> 3 × 
Baseline AND > 5 × ULN, 
duration > 2 weeks) 
Mandatory: Omit dose. Repeat LFTs as soon as 
possible, preferably within 48–72 hours; if abnormal 
values are confirmed, monitor LFTs weekly or more 
frequently until resolved to ≤ ULN or baseline. 
Resume with same dose once resolved. 
Elevated baseline (> 5 × 
Baseline AND > 8 × ULN, any 
duration) 
Mandatory: Omit dose. Repeat LFTs as soon as 
possible, preferably within 48–72 hours; if abnormal 
values are confirmed, monitor LFTs weekly or more 
frequently until resolved to ≤ ULN or baseline. If 
resolved, resume with 1 dose level reduction 
> 20 × ULN 
Permanently discontinue study treatment. 
Combined elevations of AST or ALT and total bilirubin 
For patients with normal 
baseline ALT and AST and 
total bilirubin value: 
 
AST or ALT > 3.0 x ULN 
combined with total bilirubin > 
2.0 x ULN without evidence of 
cholestasis  
 
For patients with elevated 
baseline AST or ALT or 
total bilirubin value  
 
Mandatory: Interrupt treatment and adjudicate for 
drug include liver injury (DILI). 
Repeat as soon as possible, preferably within 48 
hours from awareness of the abnormal results, then 
with weekly monitoring of LFTs, or more frequently if 
clinically indicated, until AST, ALT, or bilirubin have 
resolved to baseline or stabilization over 4 weeks.  
 
Mandatory: If causality assessment indicates DILI is 
probable, permanently discontinue patient from study 
treatment 

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AST or ALT > 3 x baseline OR 
[> 8.0 x ULN], whichever is 
lower, combined with total 
bilirubin > 2x baseline AND 
>2.0 x ULN 
 
**Note: For patients with 
Gilbert's syndrome, at least 2-
fold increase in direct bilirubin 
If not DILI: Treat the identified cause according to 
institutional guidelines. Once resolved, reduce by 
one dose level if cause is treatment related. 
Asymptomatic amylase/lipase elevation 
Grade 1 (> ULN – 1.5 × ULN) 
Recommendation: Maintain dose level; monitor 
2x/week 
Grade 2 (> 1.5 – 5.0 × ULN) 
Recommendation: Maintain dose level; monitor 
2x/week 
Grade 3 (> 5.0 × ULN) 
Mandatory: Hold dose until resolved to Grade ≤ 1 
(1.5 × ULN) or baseline;  
If resolved in ≤7 days: Reduce dose 1 dose level 
If resolved in >7 days: Discontinue treatment and 
obtain appropriate imaging (i.e., MRI, CT scan or 
ultrasound) 
Grade 4 (> 5.0 × ULN with 
symptoms) 
Mandatory: Permanently discontinue study treatment 
and obtain appropriate imaging 
Hypertension 
Grade 2 (Systolic 140-159 
mmHg or Diastolic 90-99 
mmgHg) 
Recommendation: Maintain dose level. Initiate 
antihypertensive drug/increase the dose of existing 
antihypertensive drug or change treatment plan as 
per the Investigator’s assessment 
Grade 3 (Systolic ≥160 mmHg 
or Diastolic ≥100 mmHg) 
Mandatory: Omit dose until resolved to ≤ Grade 
1/baseline; then reduce dose, 1 dose level. Initiate 
antihypertensive drug/increase the dose of existing 
antihypertensive drug or change treatment plan as 
per the Investigator’s assessment 
Grade 4 
Mandatory: Permanently discontinue from study 
treatment 
Pancreatitis 
Grade 2 
(enzyme elevations with 
radiologic findings for 
pancreatitis as per CTCAE 
v5.0. For isolated increased 
enzymes please see table for 
asymptomatic amylase and/or 
lipase elevation) 
Mandatory: If radiologic pancreatitis, hold treatment 
until revocery of the radiologic findings. If treatment 
delay is ≤ 21 days, then reduce dose by 1 dose level. 
If treatment delay is > 21 days, discontinue treatment 
and keep monitoring with appropriate imaging (i.e., 
MRI, CT scan or ultrasound) 
Grade ≥3 
Mandatory: Permanently discontinue study treatment 
and obtain appropriate imaging 

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Cardiac Adverse Events 
LVEF < 45% 
Recommended: For Grade 2 (asymptomatic, resting 
LVEF < 50 - 40%), close monitoring with a follow-up 
ECHO within 4 weeks is recommended.  
Mandatory: For Grade 3 events (symptomatic HF 
responsive to intervention; LVEF < 40 - 20%) follow 
guidance for cardiac “other” described below. For 
Grade 4 (refractory HF or poorly controlled; LVEF < 
20%) Permanently discontinue patient 
from study drug treatment 
QTcF prolongation 
Mandatory: If QTcF >500 msec or QTcF prolongation 
>60 msec from baseline is observed at any point 
during study treatment, and confirmed, the below 
guidance must be followed:  
1. Assess the quality of the ECG recording and 
the QT value and repeat if needed 
2. Interrupt study treatment until confirmed 
resolution of QTcF and as per dose reduction 
guidelines for non-hematological AEs.  
3. Determine the serum electrolyte levels (in 
particular hypokalemia, hypomagnesemia). If 
abnormal, replace it and correct abnormalities 
before resuming study drug treatment.  
4. Review concomitant medication use for other 
causes for QT prolongation (refer to 
qtdrugs.org for known QT prolonging drugs), 
and for drugs with the potential to increase the 
risk of drug exposure related QT prolongation 
(e.g., concomitant use of CYP3A4 inhibitors, if 
the study drug is a CYP3A4 substrate)  
5. Check study drug dosing schedule and 
treatment compliance  
6. Increased ECG safety monitoring is 
recommended during or in-between 
subsequent visits. 
Cardiac “other” 
Grade 2: Omit dose until ≤ Grade 1, then Reduce 
dose, 1 dose level; Grade ≥3: Permanently 
discontinue & imaging 
Pleural or Pericardial Effusion 
All grades 
Mandatory: Both ASC and DAS should be held.  
An echocardiogram can be performed to assess 
pulmonary hypertension, if suspected. Once the 

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effusion has fully resolved, ASC can be resumed, 
with chest X-ray assessments. DAS should be 
permanently discontinued if recurs 
Diarrhea 
Grade 1 
Recommendation: Maintain dose level; start anti-
diarrhea medication 
Grade 2 
Recommendation: Hold dose until resolved (initiate 
anti-diarrhea treatment) to ≤ Grade 1, then maintain 
dose level. If diarrhea returns as ≥ Grade 2, then 
hold dose until resolved to ≤ Grade 1, then reduce 
dose by 1 dose level 
Grade 3 
Recommendation: Hold dose, initiate anti-diarrhea 
treatment and discontinue patient from study drug 
treatment 
Grade 4 
Mandatory: Initiate anti- diarrhea treatment and 
permanently discontinue patient from study drug 
treatment 
Skin/Subcutaneous Disorders 
Grade 1 
Recommendation: Maintain dose level. Consider 
initiating skin toxicity therapy (e.g., antihistamines, 
topical or low-dose systemic corticosteroids) 
Grade 2 
Recommendation: Maintain dose level. 
Intensify/initiate appropriate skin toxicity therapy 
Grade 3, despite skin toxicity 
therapy 
Recommendation: Hold dose until resolved to Grade 
≤ 1, then: 
If resolved in ≤ 7 days, reduce dose by 1 dose level  
If resolved in > 7 days (despite appropriate skin 
toxicity therapy), then discontinue patient from study 
drug treatment 
Grade 4, despite skin toxicity 
therapy 
Mandatory: Permanently discontinue from study 
treatment 
Fatigue / Asthenia 
Grade 1–2 
Recommendation: Maintain dose level 
Grade 3 
Recommendation: Omit dose until ≤ Grade 1; if ≤7 
days: maintain dose; if >7 days: Reduce dose, 1 
dose level 
Hypersensitivity Reactions: 
Grade 1–2 
Recommendation: Interrupt until symptoms resolve 
to Grade ≤1 
Initiate appropriate medical management (e.g., 
antihistamines ± corticosteroids)  
Resume at the same or reduced dose, based on 
clinical judgment 
Grade 3 
Recommendation: Interrupt immediately 
 

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Initiate appropriate medical treatment (e.g., systemic 
corticosteroids, supportive care) 
Rechallenge: 
May resume at a reduced dose only if symptoms fully 
resolve and the benefit–risk assessment supports 
rechallenge 
Permanent discontinuation should be considered if 
reaction recurs 
Other AEs 
Grade 1–2 
Recommendation: Maintain dose level 
Grade 3 
Mandatory: Hold dose; if resolved ≤ 28 days: 
Resume dosing at 1 dose level reduction 
Grade 4 
Mandatory: Omit dose until ≤ Grade 1; if ≤7 days: 
maintain dose; if >7 days: Reduce dose, 1 dose level 
 
For patients receiving combination therapy of ASC and DAS, if treatment is temporarily 
discontinued, resume ASC alone for 7–14 days, once the criteria for resumption are met. 
If no recurrence occurs, resume DAS. If ASC and/or DAS are held for more than 28 days, 
therapy will be permanently discontinued. 
Follow-up for toxicities in patients whose treatment is permanently discontinued due to a 
study drug related adverse event or clinically significant laboratory value, should be 
performed once a week or every 2 weeks for 4 weeks, depending on severity. Follow up 
should be continued until resolution or stabilization of the event, whichever comes first. 
Appropriate clinical experts such should be consulted as deemed necessary.  
Table 3. Dose Reduction Steps  
Drug 
Starting Dose 
(Level 0) 
Dose 
Level -1 
Dose Level -2 
Minimum 
Allowed Dose 
Tablet 
Dispensed 
ASC 
80 mg QD 
40 mg QD 
Not allowed 
40 mg/day 
40 mg 
tablets 
6.10. Concomitant Medications 
Details of any concomitant medications (including herbal or alternative medicines) taken 
by the patient at study entry and during protocol therapy must be recorded on the 
appropriate eCRFs. See Table 4 below for a list of concomitant medications and their 
associated guidance/restrictions.  
 
 
 

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Table 4. Concomitant medication guide  
Drug/Class 
Guidance / 
Restrictions 
Notes / Monitoring 
Anti-emetics 
Allowed; initiate 
prophylactically only 
after nausea/vomiting 
Prefer drugs without QT 
prolongation; monitor for TdP 
risk 
Hormonal contraceptives 
Allowed 
Standard contraceptive 
guidance applies 
Anticoagulants / Anti-
platelet agents 
Allowed under 
Investigator discretion 
Warfarin: monitor closely due 
to CYP2C9 interactions; Anti-
PLT pro-drugs: careful 
monitoring; DTIs and Factor 
Xa inhibitors allowed; LMWH 
acceptable alternative 
Acid-reducing agents 
Allowed 
No effect on ASC absorption 
CYP3A4/5 substrates 
(narrow therapeutic index) 
Use with caution 
Dose adjustment per 
prescribing information 
CYP2C9 substrates 
(narrow therapeutic index) 
Use with caution 
Monitor for interactions, adjust 
dose as needed 
Strong CYP3A4 inducers 
Not allowed 
May reduce ASC exposure 
OATP1B/BCRP substrates 
Use with caution 
Adjust dose or avoid co-
administration; e.g., statins 
(rosuvastatin, simvastatin, 
atorvastatin, pitavastatin) 
Drugs with 
Known/Possible/Conditional 
TdP risk 
Avoid if possible 
If necessary, continue under 
close ECG monitoring 
Investigator-selected TKI 
Follow local label 
Adhere to concomitant therapy 
restrictions 
Bisphosphonates 
Allowed 
No restrictions 
7. 
EVALUATION DURING and AFTER INTERVENTION   
Appendix I: Schedule of Study Assessments and Evaluations 
7.1 Efficacy Assessments 
Complete Hematologic Response (CHR): 
CHR is defined as meeting all of the following criteria present for > 4 weeks: 
 
WBC count < 10 × 10⁹/L or within the upper limit of normal (ULN) per local 
laboratory 
 
No immature granulocytes present in peripheral blood 
 
Basophils < 5% 
 
Platelet count < 450 × 10⁹/L 

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 
Non-palpable spleen 
Molecular Response: 
Molecular response will be assessed in all patients. Levels of BCR::ABL1 transcripts will 
be determined by real-time quantitative polymerase chain reaction (RQ-PCR) on 
peripheral blood samples, analyzed at each treating center. 
Results will be expressed as: 
 
Log reduction in BCR::ABL1 transcript levels from standardized baseline values, 
or 
 
Percent ratio of BCR::ABL1 to control gene (ABL1) transcripts, converted to the 
International Scale (IS). 
Definitions: 
 
Major Molecular Response (MMR): BCR::ABL1 (IS) ≤ 0.1% 
 
MR4: BCR::ABL1 (IS) ≤ 0.01% 
 
MR4.5: BCR::ABL1 (IS) ≤ 0.0032% 
 
MR5: BCR::ABL1 (IS) ≤ 0.001% 
Loss of MMR 
Defined as: 
 
Increase of BCR::ABL1/ABL1 > 0.1% (IS), and 
 
≥ 5-fold rise in BCR::ABL1 from the lowest value achieved on study treatment, 
 
Confirmed by repeat testing of the same sample, and verified by a subsequent 
sample within 4–6 weeks. 
Loss of MMR can also be confirmed if associated with: 
 
Loss of CHR, or 
 
Loss of complete cytogenetic response (CCyR), or 
 
Progression to accelerated phase, blast phase, or CML-related death. 
Progression to Advanced Disease 
Progression is defined as development of: 
 
Accelerated phase: presence of 15–29% blasts in bone marrow or peripheral 
blood, ≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow 
aspirate, ≥20% basophils in the peripheral blood 
 
Blast phase (BP): ≥30% blasts in bone marrow or peripheral blood, or 
extramedullary blast proliferation (proven by biopsy)  
 
Acquisition of new additional cytogenetic mutations  

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Any value of AP or BC within the first 4 weeks of study treatment is not considered as 
progression to AP/BC unless the patient discontinues study treatment due to progression 
or unsatisfactory therapeutic effect within the first 8 weeks. 
Treatment Failure 
Treatment failure is defined as any of the following: 
 
Failure to achieve CHR within 3 months of treatment initiation 
 
BCR-ABLI transcript level > 10% IS at 3 months if confirmed within the next 1-3 
months 
 
BCR-ABLI transcript level > 10% IS at 6 months 
 
BCR-ABLI transcript level > 1% IS at 12 months 
 
Evidence of disease progression (i.e. increased blasts above 15% in the marrow 
or peripheral blood) 
 
Acquisition of new additional cytogenetic abnormalities 
 
Acquisition of ABL KM mutation  
 
7.2 Optional Sub-Study 
All patients who agree to participate in this study, will also be presented with the option 
to have their blood samples stored for future research. Study samples will be sent to the 
Advanced Molecular Diagnostics Laboratory in Toronto, Canada for genetic testing for 
the purpose of the main study. If is the patient consents to the long term storage and use 
of samples for future research, they will be stored at this location for up to 10 years. If the 
patient declines consent to the optional study, the samples will be destroyed following the 
genetic testing. Access to samples in long term storage (for patents who consented) will 
be restricted to representatives delegated by the PI. Samples will be de-identified by using 
a unique patient number. Refer to laboratory manual for details or correlative sample 
storage.  
8. 
DISCONTINUATION OF PROTOCOL  
Patients may voluntarily discontinue from the study treatment for any reason at any time. 
If a patient decides to discontinue from the study treatment, the investigator should make 
a reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for 
this decision and record this information in the patient’s chart and on the appropriate 
eCRF pages. They may be considered withdrawn if they state an intention to withdraw, 
fail to return for visits, or become lost to follow-up for any other reason. In addition, the QI 
may decide to withdraw the patient from the study if he/she feels that it is in the best 
interest of the patient’s health and safety. Patients who discontinue study treatment 
should undergo an end of treatment (EOT) visit. For patients who discontinue treatment 
for reasons other than death, lost to follow-up, or withdrawal of consent, the 30-day safety 

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follow-up visit should be performed. Patients who discontinue the study treatment due to 
an adverse event or abnormal laboratory value suspected to be related to study drug, 
must be followed until resolution. Note that the EOT visit is not required to be performed 
in patients who complete the treatment duration period (i.e., perform the C12D28 visit). 
This is because the C12D28 visit will be the date of the last dose administered, and 
assessments performed on this day will not need to be repeated within 7 days. The EOT 
visit will only be applicable for patients who come off treatment due to progression, 
treatment failure or intolerance. 
 
Patients who experience serious adverse events (more than 2 episodes, at least possibly 
related to study drug) without any clinical response, require discontinuation of the 
treatment for more than 28 days, or withdraw consent, will be discontinued from the trial. 
Additionally, the treating investigator holds the authority to discontinue a patient from 
treatment at any time if they deem it is not in the patient’s best interest to continue 
receiving treatment.  
 
Patients may also be discontinued from the study treatment if any of the following 
occurs: 
 Disease progression 
 Discovery of patient ineligibility 
 Errors in treatment compliance [study treatment, other prescribed or non-
prescribed medications]  
 Missed/unscheduled/off schedule/incomplete/incorrect assessments  
 Major protocol deviation  
 Pregnancy during treatment phase  
 Intercurrent illness that interferes with study assessments 
 Other treatments become available 
 Any other protocol deviation that results in a significant risk to the patient’s safety 
8.1. 
Termination of Protocol 
The study can be terminated at any time for any reason by the sponsor. Should this be 
necessary, the patients should be contacted as soon as possible and instructed to stop 
taking study medication. The end of treatment visit should be scheduled and the same 
assessments should be performed. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the patient’s interests. The investigator will be responsible for informing 
REBs of the early termination of the trial. As directed by the Sponsor, all study materials 
must be collected and all eCRFs completed to the greatest extent possible. 

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8.1.2  Criteria for Early Permanent Discontinuation of Protocol Treatment   
Reasons for permanent discontinuation of protocol treatment due to adverse events are 
outlined under the section "Modifications to Dose or Schedule." Patients may continue 
therapy for up to 48 weeks as long as they derive clinical benefit and no adverse event 
warrants permanent discontinuation. Upon completion of the clinical trial, patients will 
transition to a commercially available TKI. It would be the responsibility of the study 
investigator to assess the best available treatment option for the patients. 
9. 
SAFETY AND REPORTING REQUIREMENTS  
This study will be conducted in accordance with Health Canada regulatory requirements 
and ICH Good Clinical Practice Guidelines.  Adverse Events (AEs) and Serious Adverse 
Events (SAEs) data will be reported and collected.   
9.1. 
Adverse Event Definitions 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical 
investigation patient who is administered a drug or biologic (medicinal product) or using 
a medical device; the event does not necessarily have to have a causal relationship with 
this treatment or usage.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not considered related to 
the medicinal (investigational) product.  Each AE is to be classified by the investigator as 
serious or non-serious. 
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to the 
use of the product are not considered AEs after administration of the study product unless 
they reoccur after the patient has recovered from the pre-existing condition or they 
represent an exacerbation in intensity or frequency.  
A laboratory test abnormality considered clinically relevant (e.g. causing the patient to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations) 
or judged relevant by the QI should be reported as an AE. 
9.2. 
Adverse Event Documentation 
AEs will use the descriptions and grading scales found in the revised NCI CTCAE. This 
study will utilize the CTCAE Version 5.0 for AE reporting.  
All AEs must be recorded in the eCRFs. Documentation must be supported by an entry 
in the patient’s file. Each event should be described in detail along with start and stop 
dates, severity, relationship to investigational product as judged by the QI, action taken 
and outcome. 

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9.3. 
Attribution Definitions 
For all AEs, relationship to investigational product will be reported on the appropriate AE 
CRF page. The PI must judge whether the investigational product caused or contributed 
to the AE in which case it is considered to be an adverse drug reaction (ADR), and 
report it as either: 
Related (definitely, probably or possibly): there is a reasonable possibility that the 
investigational product caused or contributed to the AE; this conclusion may be supported 
by the following observations, though these are not required for the determination of 
relatedness: 
 There is a plausible time sequence between onset of the AE and investigational 
product administration; 
 There is a plausible biological mechanism through which investigational 
product may have caused or contributed to the AE. 
Not related (unrelated, unlikely related): It is highly unlikely or impossible that the 
investigational product caused or contributed to the AE; this conclusion may be supported 
by the following observations, though these are not required for a determination of not 
related: 
 Another cause of the AE is evident and most plausible; the temporal sequence 
is inconsistent between the onset of the AE and investigational product 
administration; a causal relationship is considered biologically implausible. 
9.4. 
Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose:  
 
Results in death 
 
Is life-threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly / birth defect 
 
Is an important medical event that may not be immediately life threatening or 
result in death or hospitalization, but may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed above 
(example: intensive treatment in an emergency room or at home for 
bronchospasm, convulsions that do not result in hospitalization). Medical and 
scientific judgment should be exercised in deciding whether some events should 
be considered as serious because their quick reporting to the Sponsor may be 
of interest for the overall conduct of the study. 

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Life-threatening: The term “life-threatening” in the definition of “serious” refers to an 
adverse event in which the patient was at risk of death at the time of the event. It does 
not refer to an adverse event that hypothetically might have caused death if it were more 
severe. 
Hospitalization: Any AE leading to hospitalization or prolongation of hospitalization will 
be considered as Serious, UNLESS at least one of the following exceptions are met: 
 
The admission results in a hospital stay of less than 12 hours. 
  
 
OR 
 
The admission is pre-planned (i.e., elective or scheduled surgery arranged prior 
to the start of the study or for prophylactic insertion of a gastric feeding tube).  
     OR 
 
The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care). 
However, it should be noted that invasive treatment during any hospitalization may fulfil 
the criteria of ‘medically important’ and as such may be reportable as an SAE dependant 
on clinical judgement. In addition, where local regulatory authorities specifically require a 
more stringent definition, the local regulation takes precedent. 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
Important medical event: Any adverse event may be considered serious because it may 
jeopardize the patient and may require intervention to prevent another serious condition.  
Any death (regardless of cause) that occurs from the time of administration of the first 
dose of study therapy until 30 days after the final administration of the investigational 
product, and any death occurring after this time that is judged at least possibly related to 
prior treatment with the investigational product, will be promptly reported. 
An AE is unexpected when the nature or severity of the AE is not consistent with the 
applicable product information (i.e. investigator’s brochure for an unapproved 
investigational product or package insert/summary of product characteristics for an 
approved product).  An AE is considered to be associated with the use of the drug if the 
attribution is classified as “possible”, “probable” or “very likely”. 
9.5. 
Adverse Event Reporting Criteria     
AEs are to be recorded within the CRF.  Whenever possible, symptoms should be 
grouped as a single syndrome or diagnosis.  The investigator should specify the date of 
onset, grade, action taken with respect to the investigational product, corrective treatment 

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or therapy given, outcome and his/her opinion as to whether there is a reasonable 
possibility that the AE was related to the investigational product.   
The severity of all AEs will be graded according to the NCI CTCAE, version 5.0.  For each 
event, the highest severity grade attained since the last assessment period will be 
reported. 
9.6. 
Adverse Event Reporting Period   
The AE reporting period begins at the time the patient receives their first dose of study 
treatment.  All AEs and SAEs must be followed until resolution or 30 days following the 
last dose of study treatment, whichever comes first.  
Patients withdrawn from the study due to an AE will be followed until the AE has resolved.  
In the case of an SAE, the patient will be followed until clinical recovery or until 
progression has been stabilized or judged to be chronic. After discontinuation from 
protocol treatment, all patients will be followed for any ongoing or late toxicities. Patients 
will be seen 30 ± 7 days after discontinuing treatment. Safety Follow up procedures will 
be completed as indicated in the Study Calendar. 
9.7. 
Serious Adverse Event Reporting to Ozmosis 
All SAEs defined as per section Error! Reference source not found.3 must be recorded 
on case report forms. In addition, they must be reported to Ozmosis according to the 
following instructions:  
1. Within 24 hours of becoming aware of the event, report initial information (on trial 
specific SAE report form) by fax or e-mail to: 
Ozmosis Research Inc.  
Fax: 416-634-8333 
 
E-mail: ozmsafety@ozmosisresearch.ca 
 The initial information should always contain:  
- 
Name of reporter/Site Investigator,  
- 
Patient identification,  
 
- 
AE Term and grade,  
- 
Investigational product dose and start/stop dates 
 
2. On the next working day if the initial report in step #1 did not contain complete 
information: Fax completed trial-specific SAE form  
3. Follow-up SAE reports should be submitted to Ozmosis as soon as possible. 
All SAEs must be followed until resolved, become chronic, or stable unless the patient is 
lost to follow up. Resolution status of such an event should be documented on the eCRF. 

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9.8. 
Exceptions and Non-Reportable SAEs 
Progressive disease and death due to progressive disease will not be reportable as an 
SAE in this study. Progression of the underlying malignancy is not reported as an adverse 
event if it is clearly consistent with the suspected progression of the underlying cancer. 
Clinical symptoms of progression may be reported as an AE if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy or does 
not fit the expected pattern of progression for the disease under study. If there is any 
uncertainty of an AE being due only to cancer it should be reported as an AE or SAE. 
Elective procedures requiring hospitalization will not be considered SAE’s if they were 
pre-planned prior to signing consent; however, other events may occur during this 
hospitalization that may be considered serious or non-serious adverse events and will 
need to be captured according to the protocol SAE reporting period if hospitalization is 
prolonged. 
9.9. 
Serious Adverse Event Reporting to Health Canada   
Ozmosis, acting on behalf of Sponsor, will be responsible for notifying Health Canada in 
an expedited manner of adverse events which are considered serious and unexpected 
and related to the protocol treatment (or for which a causal relationship with the protocol 
treatment cannot be ruled out).   Follow-up of SAEs as documented and submitted by the 
clinical site on the Ozmosis. SAE form will be forwarded to Health Canada by Ozmosis, 
where applicable.    
9.10. Reporting SAEs to Local Research Ethics Boards   
SAEs occurring within a site should also be reported to local ethics boards according to 
their local policies. 
Ozmosis will notify all Principal Investigators of all SAEs that are reportable to regulatory 
authorities from this trial or from other clinical trials as reported to the Sponsor. Principal 
Investigators (or their designee) must notify their ethics boards and file the report with 
their Investigator Site File.  
Documentation that SAEs have been reported to ethics boards must be provided by the 
site to Ozmosis, and kept on file at the site and Ozmosis.   
9.11. Reporting of Pregnancy   
Pregnancies occurring in study patients/sexual partner(s) will be treated procedurally as 
SAEs. Pregnancies occurring in study patients or their sexual partner(s) after 
investigational product treatment should be reported separately on the Pregnancy Report 
Form to Ozmosis and the patient must discontinue the trial medication. 

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The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and 
documented even if the patient has discontinued from the study. 
Pregnancy in itself, occurring in female patients, and female partners of male patients is 
not regarded as an AE unless there is a suspicion that the IP under study may have 
interfered with the effectiveness of a contraceptive medication. 
The QIs are required to report to Ozmosis any pregnancy occurring in female patients, 
and female partners of male patients. Women of childbearing potential will be instructed 
to contact the investigator or study staff immediately if they suspect they might be 
pregnant (e.g. missed or late menstrual period) at any time during study participation.  
The investigator must immediately notify Ozmosis if a study subject becomes pregnant 
and discontinue trial. Any drug exposures during pregnancy must immediately be 
reported to Ozmosis. Ozmosis will then report this to Novartis within 15 days of receipt.  
9.12. Ozmosis Reporting Responsibility to Pharmaceutical Company    
Ozmosis, acting on behalf of the Sponsor, will notify Novartis of all SAEs, any 
misuse/abuse of ASC, or any ASC exposure during pregnancy within 15 days of receipt 
of reports from the sites.   
10. 
STUDY OUTCOMES   
10.1. Primary Outcome   
The primary outcome will be the proportion of patients achieving MMR, defined as a 3-
log reduction or deeper (0.1% International Scale), after 24 weeks (6 cycles) of treatment 
with ASC as a second-line therapy. 
10.2. Secondary Outcomes   
The secondary outcomes will be: 
1. The proportion of patients achieving MMR, defined as a 3-log reduction or deeper 
(0.1% International Scale), after 12 and 48 weeks (3 and 12 cycles) of treatment 
with ASC as a second-line therapy 
2. The proportion of patients achieving MMR, defined as a 3-log reduction or deeper 
(0.1% International Scale), after 12, 24 and 48 weeks (3, 6 and 12 cycles) of 
second-line therapy treatment. 
3. The safety of ASC +/- DAS when used as a second-line therapy as assessed by 
the: 
A. Adverse Events (AEs):  
 

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1. Incidence, severity (NCI CTCAE v5.0), and relationship to study drug 
2. Tabulation by system organ class (SOC) and preferred term (PT) 
3. Specific analyses will include:  
i. Incidence of Grade ≥3 AEs 
ii. Incidence of Serious AEs (SAEs) 
iii. AEs leading to discontinuation, dose reduction, or interruption 
iv. AEs of special interest: pleural effusion, pulmonary hypertension, 
pancreatitis, cardiac events, QT prolongation 
 
B. Laboratory Parameters:  
 
1. Shift tables (baseline to worst post-baseline grade) 
2. Descriptive statistics for hematology, serum chemistry, and lipase 
parameters 
3. Incidence of CTCAE Grade 3/4 abnormalities 
 
C. Vital Signs and ECG:  
 
1. Descriptive summary of changes from baseline 
2. Incidence of QTcF >500 ms or increase >60 ms 
 
D. Physical Examination and ECOG Status:  
 
1. Summary of changes 
 
E. Dose Intensity and Modifications:  
 
1. Percentage of planned dose received (dose intensity) 
2. Frequency and reasons for dose reduction, interruption or discontinuations 
 
10.3. Definitions   
Evaluable for adverse events. All patients will be evaluable for adverse event evaluation 
from the time of their first dose. 
Evaluable for response. All patients who have their CML evaluated after 3, 6 and / or 
12 cycles, will be considered evaluable for response (exceptions will be those who exhibit 
objective disease progression prior to the end of their treatment period).  

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10.4. Measuring Response 
Peripheral blood samples for RQ-PCR will be collected and processed locally to assess 
molecular response. Molecular response will be assessed in all participants at predefined 
time points (weeks 12, 24, and 48 of treatment). 
 
The response criteria used in this study are those previously defined: A major molecular 
response (MMR) is defined as a BCR/ABL transcript level 0.1%IS, and a molecular 
response with 2 log reduction and 4.5 log reduction or deeper will be defined as a 
BCR/ABL transcript level of 1%IS or 0.0032%IS, respectively.  
 
Time to treatment failure is defined as the interval between the initiation of treatment and 
the occurrence of events that indicated possible treatment failure, including primary 
hematologic resistance, cytogenetic resistance, loss of MR2, development of tyrosine 
kinase domain mutation, clonal evolution and progression to accelerated phase, or blast 
crisis. Time to progression free survival (PFS) is defined as the interval between initiation 
of treatment and confirmed progression to accelerated AP or BC or death from any cause, 
whereas OS is calculated from initiation of treatment until the date of death from any 
cause or until last follow-up. Event will be captured including discontinuation of treatment 
due to adverse events, treatment failure (primary hematologic resistance, cytogenetic 
resistance, loss of MR2, development of tyrosine kinase domain mutation, clonal 
evolution and progression to AP/BC. 
 
To further elucidate the dynamic nature of somatic mutations in response to therapeutic 
interventions, NGS-based somatic mutation profiling will be repeated at the end of the 
treatment. This follow-up assessment is essential for evaluating mutational changes or 
evolutionary dynamics that may occur during the treatment period, such as the 
emergence of new mutations, clonal expansion, or reduction in variant allele frequencies. 
By comparing the baseline mutational profile obtained at enrollment with the end-of-
treatment results, we can correlate these alterations with key clinical outcomes, including 
molecular response rates, disease progression, or treatment resistance. This exploratory 
analysis will provide valuable insights into the mechanisms underlying therapeutic 
efficacy or failure of ASC-based second line therapy, potentially informing future risk 
stratification models and personalized treatment strategies, while ensuring the study's 
preliminary findings contribute to a deeper understanding of CML biology without 
imposing undue burden on participants. 

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11. 
STATISTICAL ANALYSIS 
The final analysis will be performed once all participants have either completed at least 
48 weeks of treatment or discontinued study treatment prior to Week 48. Data from all 
participating centers will be pooled to ensure an adequate sample size for analysis.  
Demographic and baseline disease characteristics will be summarized descriptively. 
Categorical variables will be presented as frequencies and percentages, and continuous 
variables as mean, SD, median, minimum, and maximum; for selected parameters, the 
25th and 75th percentiles will also be provided. 
The number of participants with dose modifications (reductions, interruptions, or 
permanent discontinuations) and the corresponding reasons will be summarized. All 
dosing data will be listed. Categorical variables will be summarized as frequencies and 
percentages, while continuous variables will be summarized using mean, SD, median, 
25th and 75th percentiles, minimum, and maximum. 
The primary endpoint is the binary outcome (Yes/No) of whether a participant achieves 
MMR at Week 24. The proportion of patients achieving MMR and corresponding 95% CIs 
will be estimated. Participants who discontinue treatment for any reason (e.g., intolerance, 
death) or who meet treatment failure criteria prior to the scheduled assessment will be 
counted as not achieving MMR at that time point. 
Molecular response (MR2, MMR and MR2.5) as the binary outcome (Yes/No) at 12, 24, 
and 48 weeks will also be assessed. The proportion of patients achieving MMR and 
corresponding 95% CIs will be estimated. 
There are no planned interim analyses for this study.  
11.1. General Statistical Considerations 
Demographic and baseline characteristics (including, but not limited to, age, sex, mutation 
profile, and baseline ECOG Performance Status) will be summarized by treatment group 
for all patients. Continuous variables will be summarized using descriptive statistics (i.e., 
number of patients, mean, median, standard deviation, minimum, and maximum). 
Categorical variables will be summarized by frequency and its corresponding percentage. 
Graphical summaries of the data may also be presented.  
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless 
otherwise stated. Additional exploratory analyses of the data will be conducted as 
deemed appropriate. 
11.2. Sample Size Calculation   
The calculation assumes that 40% of enrolled patients will have a somatic mutation 
profile, while 60% will not. The primary endpoint is the MMR rate, with the null hypothesis 

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positing an MMR rate of 40% for the non-mutated group and 20% for the mutated group, 
and the alternative hypothesis expecting an MMR rate of 60% for the non-mutated group 
and 55% for the mutated group. A one-sided exact binomial test will be used to evaluate 
the primary endpoint in each arm, with α = 0.01, and a statistical power of 80% . The 
calculation indicates that 45 evaluable patients are required to detect these differences.  
11.3. Evaluation of Study Endpoints 
All endpoint analyses will be performed using the intention to treat (ITT) population, 
unless otherwise specified. This will consist of all enrolled patients, with patients grouped 
according to their assigned treatment or pre-specified characteristics. 
11.3.1 Evaluation of the Primary Endpoint 
The first primary outcome, which is the proportion of evaluable patients who achieve MMR 
after 6 cycles (24 weeks) will be tested using a one-sided, one-sample test of proportions. 
11.3.1 Evaluation of the Secondary Endpoints 
The proportion of the evaluable patients achieving MMR, MR2, and MR4.5 will be 
calculated at 3, 6 and 12 cycles time points with intent-to-treat basis. The cumulative 
incidences of MMR, MR2 and MR4.5 will be estimated using the cumulative incidence 
method considering the competing risks of treatment discontinuation and death. The 
probabilities of freedom from treatment failure, event free (EFS), progression-free (PFS), 
and OS will be calculated using the Kaplan-Meier method. The start of follow-up and 
censor date of these outcomes are clarified in Table 5. 
 
Table 5. Summary of Secondary Endpoints  
 
Endpoint 
Start of 
Follow-Up Event Definition 
Censoring 
EFS (Event-Free 
Survival) 
Cycle 1 
Day 1 
Progression to AP/BC, loss of 
MMR (confirmed), or death from 
any cause 
Last contact with 
confirmed MMR and no 
progression 
PFS (Progression-
Free Survival) 
Cycle 1 
Day 1 
Progression to AP/BC or death 
from any cause 
Last contact without 
progression 
OS (Overall 
Survival) 
Cycle 1 
Day 1 
Death from any cause 
Last known alive date 
 
All time-to-event analyses use Kaplan-Meier estimation. 
 
Follow-up continues up to 48 weeks of treatment + 30-day safety follow-up, then 
long-term follow-up every 3 months until study closure or withdrawal. 

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 
Censoring occurs at the last assessment date where the patient was known to be 
event-free/alive. 
 
11.4. Final Analysis and Reporting  
The final analysis will be conducted when the accrual target has been met, and all patients 
have completed their final study visit. Any deviation from the original statistical plan will 
be described in the final report. 
12. 
STUDY SIGNIFICANCE   
Despite significant advancements in the treatment of CML with TKIs, many patients do 
not respond adequately to first-line therapy. 
According to the ASCEMBL trial results and follow-up analyses, ASC is effective in 
achieving an MMR rate of 57% following the completion of 3, 6, and 12 cycles of treatment 
when used as a second-line treatment. It has been hypothesized that when combined 
with DAS, patients can overcome the poor outcomes associated with frequently mutated 
somatic mutations. This novel, mutation-oriented approach could potentially offer a form 
of precision medicine for CML patients, tailoring treatments to their specific genetic 
profiles and improving overall treatment outcomes. 
13. 
ETHICS    
13.1. Informed Consent   
Patient/Legally acceptable representative (LAR) consent must be obtained according to 
local site and/or ethics board requirements prior to any study-specific screening 
procedures. It will be the responsibility of the QI to obtain the necessary clearance, and 
to indicate in writing to Ozmosis that such clearance has been obtained, before the trial 
can commence at that site. Sample English consent forms for the trial will be provided. A 
copy of the initial full board ethics board approval and approved consent form must be 
sent to Ozmosis. The patient/LAR must sign consent prior to registration/enrollment.  
13.2. Research Ethics Board (REB) 
Each participating site will have on file with Ozmosis, a list indicating the composition of 
its ethics board consistent with regulatory guidelines. This list will be updated as 
appropriate.  
For Canadian sites, a Health Canada REB Attestation Form must be completed and 
signed by the REB representative. Alternatively, an attestation may be included in the 

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signed local ethics approval document. This documentation must be received by Ozmosis 
before the site can be locally activated. 
Initial approval: All study sites are required to obtain full board ethics approval of the 
protocol and consent form by the appropriate ethics board prior to commencement of the 
clinical trial at each site. 
Continuing approval: Annual (or as required by the ethics board) re-approval may be 
required for as long as patients are being followed on protocol. It will be the Principal 
Investigator’s responsibility to apply for and obtain the re-approval. 
Amendment: Any amendments or modifications to the study protocol and/or ICF 
document, as issued by Ozmosis, must be submitted to and approved by Novartis. All 
protocol amendments will be confirmed in writing and submitted, as appropriate, for 
review by the ethics board and health authorities. Amendments will be reviewed and 
approved by applicable regulatory authorities prior to central implementation of the 
amendment, and by ethics boards prior to local implementation, EXCEPT when the 
amendment eliminates an immediate hazard to clinical trial patients or when the 
change(s) involve(s) only logistical or administrative aspects of the trial. 
Ethics board refusals: If an ethics board refuses to approve this protocol (or an 
amendment/revision to this protocol), Ozmosis must be notified immediately of the date 
of refusal and the reason(s) for the refusal. Notification will then be made to the regulatory 
authorities. 
SAEs, safety updates and investigator brochure updates: During the course of the study 
SAEs, safety updates or investigator brochure updates may be sent to sites for reporting 
to their ethics board. If/when this occurs documentation of ethics board submission must 
be forwarded to Ozmosis. 
14. 
RESPONSIBILITIES of the INVESTIGATOR   
One QI will oversee the trial at each clinical site.  The QI performs the study in accordance 
with this clinical trial protocol, ICH Guidelines for Good Clinical Practice and the applicable 
Health Canada regulations and local REB requirements. 
The QI may appoint other individuals as he/she deems appropriate to assist in the study's 
conduct.  All appointed designates will be listed and provided to Ozmosis.  The appointed 
designates will be supervised by and under the QI's responsibility.  
For ensuring compliance with the clinical trial protocol, ICH GCP and applicable 
regulatory requirements, the QI agrees to permit study monitoring/auditing by or on the 
behalf of Ozmosis and inspection by applicable regulatory authorities.  The investigator 

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agrees to allow the auditors/inspectors to have direct access to his/her study records, 
including source data/documents. 
15. 
DOCUMENTATION, RECORD ACCESS AND MAINTENANCE OF STUDY 
RECORDS 
15.1. Documentation of Patient’s Participation 
A statement acknowledging the participation of a patient in this clinical trial must be 
documented in the patient's medical records along with the signed ICF. 
15.2. Regulatory Requirements  
The following documents are required: 
 All Principal Investigators must complete and sign the Health Canada Qualified 
Investigator Undertaking form. The completed forms must be returned to Ozmosis 
prior to any drug shipment. 
 Ozmosis will submit a completed Health Canada Clinical Trial Site Information 
Form to Health Canada after local activation of each participating Canadian site. 
 All applicable regulatory documents as listed in the Site Activation Checklist 
provided by Ozmosis to the sites. 
 A copy of the initial full board approval letter from the ethics board. Continuing 
approval (full board) will be obtained at least yearly until follow-up on patients is 
completed and no further data is being obtained for research purpose. 
15.3. Patient Confidentiality and Access to Source Data/Documents 
Any research information obtained about the patient in this study will be kept confidential. 
A patient will not be identified by name. The patient’s name or any identifying information 
will not appear in any reports published as a result of this study. 
However, information obtained from the patient’s participation in the study may be 
disclosed with their consent to the health care providers for the purpose of obtaining 
appropriate medical care. The patient’s medical records/charts, tests will be made 
available to Ozmosis, the Sponsor’s partners, the Canadian regulatory authority Health 
Canada, the ethics boards and any other regulatory authorities. This is for the purpose of 
verifying information obtained for this study. Confidentiality will be maintained throughout 
the study within the limits of the law.   
A patient’s name will not be given to anyone except the researchers conducting the study, 
who have pledged an oath of confidentiality. All identifying information will be kept behind 

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locked doors, under the supervision of the study Principal Investigator and will not be 
transferred outside of the hospital.  
A patient may take away their permission to collect, use and share information about them 
at any time. If this situation occurs, the patient will not be able to remain in the study. No 
new information that identifies the patient will be gathered after that date. However, the 
information about the patient that has already been gathered and transferred may still be 
used and given to others as described above in order to preserve the scientific integrity 
and quality of the study. 
15.4. Confidentiality of the Study 
Data generated as a result of this study are to be available for inspection on request by 
local health authority auditors, the Sponsor’s Study Monitors and other personnel (as 
appropriate) and by the ethics board. The Principal Investigator shall permit the Sponsor, 
authorized agents of the Sponsor, CRO and regulatory agency employees to enter and 
inspect any site where the drug or records pertaining to the drug are held, and to inspect 
all source documents. The protocol and other study documents contain confidential 
information and should not be shared or distributed without the prior written permission 
of the Sponsor.   
15.5.   Study Data at the End of Registration of Clinical Trial 
Prior to the first patient being enrolled into this study, the Sponsor will be responsible for 
ensuring that the clinical trial is registered (e.g. clinicaltrials.gov) appropriately to remain 
eligible for publication in any major peer-reviewed journal, adhering to the guidelines put 
forth by the International Committee of Medical Journal Editors (ICMJE). 
15.6. Data Reporting 
The data will be collected in electronic CRFs using a Medidata database. 
Please see the study specific eCRF Completion Guidelines for additional details. The 
timelines and details for completion of eCRFs are included in these guidelines. 
15.7. Maintenance of Study Records 
To enable evaluations and/or audits from regulatory authorities, Ozmosis or the Sponsor, 
the Principal Investigator agrees to keep records, including the identity of all participating 
patients (sufficient information to link records, eCRFs and hospital records), all original 
signed informed consent forms, copies of all source documents, and detailed records of 
treatment disposition. The PI should retain these records for 15 years after study close-
out as required by Canadian regulations or as specified in the Clinical Trial Agreement, 
whichever is longer.   
 

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If the PI relocates, retires, or for any reason withdraws from the study, then the Sponsor 
should be prospectively notified. The study records must be transferred to an acceptable 
designee, such as another QI, another institution, or to the Sponsor. The PI must obtain 
the Sponsor’s written permission before disposing of any records. 
 16. 
QUALITY ASSURANCE AND QUALITY CONTROL 
As per the Guidelines of Good Clinical Practice (CPMP/ICH/135/95), the Sponsor will be 
responsible for implementing and maintaining quality assurance and quality control 
systems.  
16.1. Monitoring/Auditing 
Ozmosis will organize monitoring to be conducted as per the Monitoring Plan. 
As this trial is conducted under a CTA with Health Canada, your site may be subject to 
an inspection by the Health Products and Food Branch Inspectorate. Other audits may 
be conducted by the Sponsor, Novartis, Ozmosis, and/or other regulatory authorities. 
17. 
ADMINISTRATIVE PROCEDURES   
17.1. Amendments to the Protocol   
Modifications of the signed protocol are only possible by approved protocol amendments 
authorized by the Sponsor. All protocol amendments will be approved by the ethics board 
prior to implementation. QIs must not implement any deviation from, or change to the 
protocol, except where it is necessary to eliminate an immediate hazard to trial patient or 
when the change(s) involves only logistical or administrative aspects of the trial. 
An amendment may require a change to the ICF.  The investigator must receive REB 
approval/favorable opinion of the revised ICF before implementing the change. 
17.2. Protocol Deviations and Violations  
All violations or deviations are to be reported to the site’s ethics board (as per ethics board 
guidelines). All ethics board correspondence is to be forwarded to Ozmosis. The site must 
notify Ozmosis and/or the Sponsor immediately of any protocol violations.  
17.3. Premature Discontinuation of the Study 
The Sponsor reserves the right to discontinue the trial for any reason but intends only to 
exercise this right for valid scientific or administrative reasons.  After such a decision, the 
QIs must contact all participating patients immediately after notification is provided by the 
Sponsor. Standard therapy and follow-up for patients will be assured and, where required 
by the applicable regulatory requirement(s), the relevant regulatory authority(ies) will be 
informed. 

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The ethics board will be informed promptly by the site and will be provided with a detailed 
written explanation for the termination or suspension. 
As directed by the Sponsor, all study materials must be collected and all eCRFs 
completed to the greatest extent possible. 
18. 
STUDY ORGANIZATION  
18.1. Steering Committee 
The Steering Committee is responsible for the trial's overall conduct, including the design, 
execution, analyses and reporting.  In addition, the Steering Committee is also 
responsible for the assignment of responsibilities to other study committees.  The 
Steering Committee will hold the primary responsibility for the publication of the study 
results.  This Committee will convene on a regular basis by teleconference or face-to-face 
meetings at least every six months to address policy issues, to monitor study progress, 
execution and management and to review the reports from the DSMC.  A list of the 
Steering Committee members is maintained by Ozmosis. 
18.2. Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) has been established. The DSMB 
will comprise of clinical trial experts in hematology and clinical trial methodology, 
independent of the study. A list of the DSMB members can be found in the DSMB charter.     
The DSMB will monitor the safety aspects of the trial including review of all SAEs and 
accumulating safety data during the Safety Review Meeting as per the timelines in the 
DSMB Charter. Additional meetings may be scheduled as necessary.  Please refer to the 
DSMB Charter. 
19. 
SCIENTIFIC REPORTING and PUBLICATION   
This clinical trial protocol was developed by the principal investigators with the assistance 
of Ozmosis. 
The Steering Committee is responsible for the scientific reporting, publishing and/or 
presentation of the study results. Authorship will be determined by the Steering 
Committee and guided by the extent of participation in the protocol's development, 
accrual of patients to the study, involvement in the study analysis and the final manuscript 
drafting.  Results of the study will be disseminated through publications and presentations 
at international meetings.  Any other publication or presentation related to the study and 
the results by any investigator or patient must receive prior approval from the Steering 
Committee.  No other publication or presentation is permitted before the primary 
publication or presentation by the Steering Committee.   

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The information developed during the conduct of this clinical study is considered 
confidential. 
 
 
20. 
REFERENCES   
1. 
Seong D, Kantarjian HM, Albitar M, et al. Analysis of Philadelphia chromosome-
negative BCR-ABL-positive chronic myelogenous leukemia by hypermetaphase 
fluorescence in situ hybridization. Ann Oncol 1999; 10(8): 955-9. 
2. 
Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999; 340(17): 1330-40. 
3. 
Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: 
biology and therapy. Ann Intern Med 1999; 131(3): 207-19. 
4. 
Savage DG, Szydlo RM, Goldman JM. Clinical features at diagnosis in 430 
patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period. 
Br J Haematol 1997; 96(1): 111-6. 
5. 
Garcia-Gutierrez V, Hernandez-Boluda JC. Tyrosine Kinase Inhibitors Available 
for Chronic Myeloid Leukemia: Efficacy and Safety. Front Oncol 2019; 9: 603. 
6. 
Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 
recommendations for treating chronic myeloid leukemia. Leukemia 2020; 34(4): 966-84. 
7. 
Saglio G, Jabbour E. First-line therapy for chronic phase CML: selecting the 
optimal BCR-ABL1-targeted TKI. Leuk Lymphoma 2018; 59(7): 1523-38. 
8. 
Shah NP, Bhatia R, Altman JK, et al. Chronic Myeloid Leukemia, Version 2.2024, 
NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2024; 22(1): 
43-69. 
9. 
Soverini S, Branford S, Nicolini FE, et al. Implications of BCR-ABL1 kinase 
domain-mediated resistance in chronic myeloid leukemia. Leuk Res 2014; 38(1): 10-20. 
10. 
Manley PW, Barys L, Cowan-Jacob SW. The specificity of asciminib, a potential 
treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and 
analysis of its interactions with mutant forms of BCR-ABL1 kinase. Leuk Res 2020; 98: 
106458. 
11. 
Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables 
dual targeting of BCR-ABL1. Nature 2017; 543(7647): 733-7. 
12. 
Hantschel O. Chronic myeloid leukemia. Hemasphere 2019; 3(Suppl): 47. 
13. 
Steegmann JL, Cervantes F, le Coutre P, Porkka K, Saglio G. Off-target effects 
of BCR-ABL1 inhibitors and their potential long-term implications in patients with chronic 
myeloid leukemia. Leuk Lymphoma 2012; 53(12): 2351-61. 
14. 
Rea D, Mauro MJ, Boquimpani C, et al. A phase 3, open-label, randomized study 
of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood 
2021; 138(21): 2031-41. 
15. 
Hochhaus A, Wang J, Kim DW, et al. Asciminib in Newly Diagnosed Chronic 
Myeloid Leukemia. N Engl J Med 2024; 391(10): 885-98. 

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16. 
Perusini MA, Zackova D, Kim T, et al. Mutations in myeloid transcription factors 
and activated signaling genes predict chronic myeloid leukemia outcomes. Blood Adv 
2024; 8(10): 2361-72. 
17. 
Shanmuganathan N, Wadham C, Shahrin N, et al. Impact of additional genetic 
abnormalities at diagnosis of chronic myeloid leukemia for first-line imatinib-treated 
patients receiving proactive treatment intervention. Haematologica 2023; 108(9): 2380-
95. 
18. 
Susan Branford ea. Longitudinal Clonal Tracking Reveals That Early and 
Sensitive Detection of Blood Cancer-Related Gene Variants in Patients with Chronic 
Myeloid Leukemia Predicts Treatment Failure. Blood (2024) 144 (Supplement 1): 996 
2024. 
19. 
Han HJ, Kim JJ, Pyne D, et al. In vitro evidence of synergistic efficacy with 
asciminib combined with reduced dose of ATP-binding pocket tyrosine kinase inhibitors 
according to the ABL1 kinase domain mutation profile. Leukemia 2024; 38(2): 412-5. 
 
 

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Appendix I: Schedule of Study Assessments and Evaluations 
  
Screening 
Treatment 
End of Treatment   
and Follow Up  
Visit Name 
Screening 
 
C1 
D1 
C1 
D15 
C2 
D1 
C2 
D812 
C2 
D1512 
C3 
D1 
C4 
D1 
C7 
D1 
C10 
D1 
C12 
D28 
EOT 
Visit13 
30 Day 
Safety FU 
Window 
-21 days 
+/- 7 days +/- 5 days +/- 5 days +/- 5 days +/- 5 days +/- 5 days +/- 7 days +/- 7 days +/- 7 days +/- 7 days +/- 7 days +/- 7 days 
PROCEDURES 
Informed Consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Sokal & ELTS risk calculation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ASC administration2 
 
X+ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
DAS administration2 
 
 
 
X+ 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical assessment4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance 
status assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology bloodwork5 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
 
X* 
Biochemistry bloodwork6 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
 
X* 
Serum amylase 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
  Serum lipase 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
Hepatitis screening 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation7 
X* 
 
 
 
 
 
 
 
 
 
 
 
X* 
HbA1C 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine)8 
X 
As clinically indicated 
 
Thyroid function (TSH only) 
X* 
 
 
X* 
 
 
 
X* 
X* 
X* 
X* 
 
X* 
EKG 
X* 
As clinically indicated 
 
 
Adverse events9 
 
(Continuous) 
Concomitant medications 
(Continuous) 
MOLECULAR ASSESSMENTS 

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Bone Marrow Aspirate 
X* 
If clinically indicated 
X* 
X* 
 
Peripheral Blood RQ-PCR for 
BCR/ABL transcript10  
X* 
  
  
  
 
  
  
X* 
X* 
X* 
X* 
 
  
  
NGS testing 
 
X11 
 
 
 
 
 
 
 
 
 
X* 
 
1 Consent should be done prior to any screening assessments and according to site institutional guidelines. Site should follow their institutional guidelines for consenting window 
(timeframe for prior to enrollment/protocol treatment). Subject enrollment with Ozmosis Research Inc. is required. Please refer to Section 4. 
2 Refer to protocol section 6.0 for dosing information. There are no windows for treatment dosing aside from C1D1 for ASC and C2D1 for DAS.  
3 Vital signs: Pulse rate, blood pressure, temperature, and respiratory rate. Vitals will be measured prior to dosing.  
4 Clinical assessment will include assessment of height, weight, and extramedullary involvement (spleen, liver, and lymph nodes). A focused abdominal physical examination will 
be performed at scheduled visits to assess for clinical signs and symptoms of pancreatic toxicity, including abdominal tenderness, epigastric pain, guarding, nausea, or vomiting, 
to rule out pancreatitis. Physical examination will also include assessment for clinical signs of hypersensitivity, such as rash, urticaria, facial or oropharyngeal swelling, respiratory 
distress, hypotension, or other systemic allergic reactions. Patients will also be instructed to report any such symptoms between visits.. Height will be measured at screening only. 
5 Hematology includes complete blood count (CBC) + differential 
6 Blood chemistry includes sodium, potassium, chloride, bicarbonate, calcium, phosphate, magnesium, serum creatinine, urea, ALT, AST, ALP, LDH, and bilirubin 
7 Coagulation bloodwork includes INR and aPTT 
8 Only for women of reproductive potential (including women of reproductive potential whose partners are sterilized). Required at baseline, as clinically indicated thereafter. 
9 Adverse Events will be coded as per CTCAE version 5.0. The AE reporting period begins at the time the patient receives their first dose of study treatment.  All AEs and SAEs 
must be followed until resolution or 30 days following the last dose of study treatment, whichever comes first 
10 BCR::ABL1 transcript level analysis will be performed using local PCR test in each study center’s laboratory 
11 To be performed at the central lab at Toronto General Hospital. Please see Lab Manual for further instructions.  
12 Only required for combination arm ASC + DAS 
13 EOT either due to progression, treatment failure or intolerance. Note that the EOT visit does not need to be performed for patients who attend the C12D28 visit.  
* To be performed per standard of care 
+ Window to administer drug is +/- 3 days