Phase II Study Assessing the Efficacy and Toxicity of Olverembatinib Monotherapy in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase

Eligibility Criteria:

• Adult participants age ≥18 years.

• Participants must have a diagnosis of Ph-positive or BCR::ABL1 positive CML in earlychronic phase.

• 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 olverembatinib on the developing human fetus are unknown. For thisreason,women of child-bearing potential and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry, for the duration of study participation, and 4 months after completionof olverembatinib administration. This includes all female participants, between theonset of menses (as early as 8 years of age) and 55 years unless the participantspresents 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, Participant 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 4 months after completion of olverembatinib administration.

• For participants with evidence of chronic hepatitis B virus (HBV) infection,the HBV viral 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 on treatment, 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 2 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 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 olverembatinib 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 cardiologist

• 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 includingpsychosis, major depression, and bipolar disorders.

• Participants with cognitive impairment or psychiatric illness/socialsituations that would limit compliance with study requirements.

• Human immunodeficiency virus (HIV)-infected patients on effectiveanti-retroviral therapy with undetectable viral load within 6 months areeligible for this trial.

• Evidence of other clinically significant uncontrolled condition(s)including, but not 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: subjects with serologic evidence of priorvaccination to HBV (i.e. hepatitis B surface antigen negative, anti-HBsantibody positive and antihepatitis B core antibody negative) or positiveanti-HBc antibody from intravenous immunoglobulins may participate.

• Pregnant women are excluded from this study because olverembatinib is aBCR::ABL1 TKI with the potential for teratogenic or abortifacient effects.Because there is an unknown but potential risk for adverse events innursing infants secondary to treatment of the mother with olverembatinib,breastfeeding should be discontinued if the mother is treated witholverembatinib. These potential risks may also apply to other agents usedin this study.

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

• Early chronic phase: time from diagnosis to therapy ≤ 12 months.

• Late chronic phase: 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.