A Phase I Study of Decitabine, Lisaftoclax, and Olverembatinib in Patients With Advanced Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Myeloid Leukemia

Inclusion Criteria:

a) Diagnosis: Age ≥18 years with CML-AP, CML-MBP, or Ph+ AML by WHO 2016 criteria.

• Participants must have been intolerant or resistant to at least one prior BCR::ABL1TKI

2. Performance status ≤3 (ECOG Scale).

3. Adequate liver, cardiac, renal and pancreatic function as defined by thefollowing criteria:

4. Total serum bilirubin < 1.5 x upper limit of normal (ULN), unless due toGilbert's syndrome, hemolysis or the underlying leukemia approved by the PI

5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 3 x ULN,unless due to the underlying leukemia approved by the PI

6. Creatinine clearance ≥30 mL/min

7. Serum amylase or lipase < 1.5 x ULN

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

9. Willingness to use adequate contraception prior to study entry, for theduration of study participation, and for 6 months after completion of studyparticipation. For women of child-bearing potential, adequate methods ofcontraception include: complete abstinence,, hormonal contraception (i.e. birthcontrol pills, injection, implant, transdermal patch, vaginal ring),intrauterine device (IUD), tubal Ligation or hysterectomy, subject/partner postvasectomy, implantable or injectable contraceptives, and condoms plusspermicide.

Exclusion Criteria:

1. Participants who have previously received lisaftoclax or olverembatinib
2. History of acute pancreatitis within 1 year of study or history of chronicpancreatitis
3. Active grade III-V cardiac failure as defined by the New York HeartAssociation Criteria
4. Clinically significant and uncontrolled cardiovascular disease, includingbut not restricted to: i. Myocardial infarction (MI), stroke, revascularization, unstable angina,or transient ischemic attack within 6 months. ii. Left ventricular ejection fraction (LVEF) less than lower limit ofnormal per local institutional standards prior to enrollment. iii. Diagnosed or suspected congenital long QT syndrome. iv. Clinicallysignificant atrial or ventricular arrhythmias (such as uncontrolled,clinically significant atrial fibrillation, ventricular tachycardia,ventricular fibrillation, or Torsades de pointes) as determined by thetreating physician. v. Prolonged QTc interval on pre-entry electrocardiogram (> 480 msec)unless corrected after electrolyte replacement. vi. History of venous thromboembolism including deep venous thrombosis orpulmonary embolism within the past 3 months, excluding line associated DVTof the upper extremity vii. Uncontrolled hypertension (diastolic bloodpressure >100mmHg; and systolic >150mmHg).
5. Active serious infection not controlled by oral or intravenous antibiotics (e.g. persistent fever or lack of improvement despite antimicrobialtreatment).
6. Active central nervous system leukemia
7. Known human immunodeficiency virus (HIV) seropositive, unlesswell-controlled on stable doses of anti-retroviral therapy.
8. Known hepatitis B surface antigen seropositive or known or suspectedactive hepatitis C infection Note: Participants who have isolated positivehepatitis B core antibody (ie, in the setting of negative hepatitis Bsurface antigen and negative hepatitis B surface antibody) must have anundetectable hepatitis B viral load. Participants who have positivehepatitis C antibody may be included if they have an undetectablehepatitis C viral load.
9. Participants with a prior or concurrent malignancy whose natural historyor treatment is not anticipated to interfere with the safety or efficacyassessment of the investigational regimen may be included only afterdiscussion with the PI
10. Consumed strong inducer of CYP3A or p-glycoprotein within 14 days of studyenrollment, or 5 half-lives, whichever is longer. Agents include but arenot limited to: carbamazepine, phenytoin, rifampin, and St. John's wart
11. Treatment with any investigational antileukemic agents or chemotherapyagents in the last 7 days before study entry, unless full recovery fromside effects has occurred or patient has rapidly progressive diseasejudged to be life-threatening by the investigator. Prior recent treatmentwith corticosteroids, hydroxyurea, cytarabine (up to 2 g/m2 given forcytoreduction within the preceding 7 days) and/or an FDA-approvedBCR::ABL1 TKI is permitted.
12. Inability to swallow
13. Pregnant or breastfeeding women will not be eligible
14. History of allergic reactions attributed to compounds of similar chemicalor biologic composition to Decitabine, Lisaftoclax, and Olverembatinib orother agents used in study.
15. Participants with psychiatric illness/social situations that would limitcompliance with study requirements.