Phase II Study Assessing Efficacy and Safety of Asciminib in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase.

Inclusion Criteria:

• Adult participants age ≥18 years.

• Participants must have a diagnosis of Ph-positive or BCR::ABL1 positive CML in earlychronic phase (i.e., time from diagnosis ≤12 months).

• Participants who received prior hydroxyurea, 1 to 2 doses of cytarabine, and/or anFDA approved TKI for <30 days are eligible.

• Participants with additional chromosomal abnormalities at diagnosis (early disease)and no other criteria for accelerated phase will be eligible for this study.

• ECOG performance status ≤2.

• Participants must have adequate end organ function, defined as the following: totalbilirubin ≤1.5x ULN (unless secondary to Gilbert's disease, in which case should be ≤2.5x ULN), SGPT or SGOT ≤3x ULN, creatinine clearance ≥30mL/min calculated usingmodified Cockcroft-Gault.

• Ability to understand and the willingness to sign a written informed consentdocument.

• The effects of asciminib on the developing human fetus are unknown. For this reason,women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry andfor the duration of study participation. (Refer to Pregnancy Assessment Policy MDAnderson Institutional Policy # CLN1114). This includes all female patients, betweenthe onset of menses (as early as 8 years of age) and 55 years unless the participantpresents with an applicable exclusionary factor which may be one of the following:

• Postmenopausal (no menses in greater than or equal to 12 consecutive months).

• History of hysterectomy or bilateral salpingo-oophorectomy.

• Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausalrange, who have received Whole Pelvic Radiation Therapy).

• History of bilateral tubal ligation or another surgical sterilizationprocedure.

• Approved methods of birth control are as follows: Hormonal contraception (i.e. birthcontrol pills, injection, implant, transdermal patch, vaginal ring), Intrauterinedevice (IUD), Tubal Ligation or hysterectomy, Participants/Partner post vasectomy,Implantable or injectable contraceptives, and condoms plus spermicide. Not engagingin sexual activity for the total duration of the trial and the drug washout periodis an acceptable practice; however periodic abstinence, the rhythm method, and thewithdrawal method are not acceptable methods of birth control. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study, she should inform her treating physician immediately.

• Men treated or enrolled on this protocol must also agree to use adequatecontraception prior to the study, for the duration of study participation, and 4months after completion of asciminib administration.

• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

• Participants with a history of hepatitis C virus (HCV) infection must have beentreated and cured. For participants with HCV infection who are currently ontreatment, they are eligible if they have an undetectable HCV viral load.

• Participants with treated brain metastases are eligible if follow-up brain imagingafter central nervous system (CNS)-directed therapy shows no evidence ofprogression.

• Participants with a prior or concurrent malignancy whose natural history ortreatment does not have the potential to interfere with the safety or efficacyassessment of the investigational regimen are eligible for this trial.

• Participants with known history or current symptoms of cardiac disease, or historyof treatment with cardiotoxic agents, should have a clinical risk assessment ofcardiac function using the New York Heart Association Functional Classification. Tobe eligible for this trial, participants should be class 2B or better.

Exclusion Criteria:

• Participants who have received more than 30 days of prior FDA approved TKI or morethan 2 doses of cytarabine.

• Had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas ormitomycin C) prior to entering the study.

• Participants who have not recovered from adverse events due to prior anti-cancertherapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia.

• Participants who are receiving any other investigational agents.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to asciminib or other agents used in study.

• NYHA cardiac class 3-4 heart disease

• Cardiac Symptoms: Participants meeting the following criteria are not eligibleunless cleared by Cardiology:

• Uncontrolled angina within 3 months

• Diagnosed or suspected congenital long QT syndrome

• Any history of clinically significant ventricular arrhythmias (such asventricular tachycardia, ventricular fibrillation, or Torsades de pointes).

• Prolonged QTc interval on pre-entry electrocardiogram (> 460 msec)

• History of significant bleeding disorder unrelated to cancer, including unlesscleared by hematologist or hemato-oncologist:

• Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)

• Diagnosed acquired bleeding disorder within one year (e.g., acquiredanti-factor VIII antibodies)

• Participants with active, uncontrolled psychiatric disorders including psychosis,major depression, and bipolar disorders.

• Participants with cognitive impairment or psychiatric illness/social situations thatwould limit compliance with study requirements.

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial.

• Evidence of other clinically significant uncontrolled condition(s) including, butnot limited to:

• Uncontrolled and/or active systemic infection (viral, bacterial or fungal)

• Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment andhaving detectable virus load. Note: participants with serologic evidence ofprior vaccination to HBV (i.e. hepatitis B surface antigen negative, anti-HBsantibody positive and anti-hepatitis B core antibody negative) or positiveanti-HBc antibody from intravenous immunoglobulins may participate.

• Pregnant women are excluded from this study because asciminib is a BCR::ABL1 TKIwith the potential for teratogenic or abortifacient effects. Because there is anunknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with asciminib, breastfeeding should be discontinued if themother is treated with asciminib. These potential risks may also apply to otheragents used in this study.

• Participants in late chronic phase (i.e., time from diagnosis to treatment >12months), accelerated (except as noted in inclusion criteria 4.1) or blast phase areexcluded. The definitions of CML phases are as follows:

• Early chronic phase: time from diagnosis to therapy ≤12 months Late chronicphase: time from diagnosis to therapy >12 months

• Blastic phase: presence of 30% blasts or more in the peripheral blood or bonemarrow

• Accelerated phase CML: presence of any of the following features: i. Peripheral or marrow blasts 15% or more ii. Peripheral or marrow basophils 20% or more iii. Thrombocytopenia <100 x 109/L unrelated to therapy iv.Documented extramedullary blastic disease outside liver or spleen.