ASCiminib, With or Without Dasatinib Combination, as a 2nd-Line Therapy to ADVANCE the Treatment for Chronic Myelogenous Leukemia in Chronic Phase (ASC2ADVANCE)

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: * 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)): 1. Total abstinence 2. 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. 3. 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. 4. Male sterilization (at least 6 months prior to screening). A vasectomized male partner should be the sole partner for that patient. 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: 1. History of myocardial infarction (MI), coronary artery bypass graft (CABG) surgery, or coronary stent placement within the past six months 2. Uncontrolled angina or uncontrolled congestive heart failure (NYHA class III or IV) within the past six months. 3. Diagnosed congenital long QT syndrome 4. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) 5. Clinically significant, uncontrolled atrial fibrillation or other clinically relevant arrhythmias requiring ongoing intervention. 6. 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 rescreened for QTc. 7. 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: 1. Diagnosed congenital bleeding disorder (e.g., von Willebrand's disease) 2. Diagnosed acquired bleeding disorder within one year (e.g., acquired antifactor VIII antibodies). 3. 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. \-