Venetoclax-Navitoclax With Cladribine-based Salvage Therapy in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Inclusion Criteria: 1. Male or female subjects 18 years or older. 2. Patients must have a diagnosis of morphologically documented AML or secondary AML from prior conditions, such as myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), MDS/MPN, chronic myelomonocytic leukemia (CMML) or therapy-related AML (t-AML), as defined by the World Health Organization (WHO) 2022 criteria. 3. Relapsed or refractory to at least one prior line of therapy. 4. Previous therapy with venetoclax. 5. Eastern Cooperative Oncology Group (ECOG) performance status of: 1. 0-3 for Arm A (i.e., Cladribine-low dose cytarabine backbone arm). 2. 0-2 for Arm B (i.e., CLAG-M backbone arm). 6. Left ventricular ejection fraction (LVEF) of: 1. LVEF ≥35% for Arm A (i.e., Cladribine-low dose cytarabine backbone arm). 2. LVEF ≥45% for Arm B (i.e., CLAG-M backbone arm). 7. Creatinine clearance (CrCl) as calculated by the Cockroft-Gault formula, of: 1. CrCl ≥ 30 mL/min for Arm A (i.e., Cladribine-low dose cytarabine backbone arm). 2. CrCl ≥ 40 mL/min for Arm B (i.e., CLAG-M backbone arm). 8. Clinical laboratory values within the following parameters: 1. Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) unless attributable to underlying leukemia. Patient with total bilirubin \> 1.5 × institutional ULN may enroll if direct bilirubin ≤ 1.5 × institutional ULN of the direct bilirubin. 2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × institutional ULN, unless attributable to underlying leukemia. 3. White blood cell (WBC) count \< 25,000/µL before Cycle 1, Day 1 of therapy (Note: Hydroxyurea, cytarabine or leukapheresis may be used to meet this criterion.) 4. Platelet count of at least 20,000/µL before Cycle 1, Day 1 of therapy (Note: Platelet transfusion can be used to meet this criterion.) 9. Female subjects who: 1. Are postmenopausal for at least one year before the screening visit, OR 2. Are surgically sterile, OR 3. If they are of childbearing potential: i. Agree to practice one highly effective method and one additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through four months after the last dose of study drug (female and male condoms should not be used together), OR ii. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception). 10. Male subjects, even if surgically sterilized (i.e., status post vasectomy), who: 1. Agree to practice effective barrier contraception during the entire study treatment period from the time of signing the informed consent through and through four months after the last dose of study drug (female and male condoms should not be used together), OR 2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods for the female partner\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.) 11. Ability to understand a written informed consent document, and the willingness to sign it. Exclusion Criteria: 1. Acute promyelocytic leukemia. 2. Prior therapy with B-cell lymphoma-extra large (BCL-XL) inhibitor. 3. Treatment with systemic antineoplastic therapy within 14 days or five half-lives from the last dose - whichever is longer - before Cycle 1, Day 1 of therapy. Radiation within 14 days before Cycle 1, Day 1 of therapy. The use of hydroxyurea/cytarabine for leukoreduction is permitted. 4. Hematopoietic stem cell transplantation (HCT) or chimeric antigen receptor T-cell therapy (CAR-T cell) within 60 days of enrollment. (If patients had prior allogeneic HCT, they should have no active graft-versus-host disease and should be off calcineurin inhibitors at least four weeks prior to cycle 1 day 1 of therapy.) 5. Current systemic treatment with strong or moderate Cytochrome P4503A (CYP3A) inducers within 7 days prior to Cycle 1, Day 1 of therapy. 6. Presence of another active malignancy requiring systemic treatment within the last 12 months, except for localized cancers that have been adequately treated. 7. Known HIV positive patients who DO NOT meet the following criteria: 1. Cluster of differentiation (CD) 4 count \> 350 cells/mm\^3. 2. Undetectable viral load. 3. Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents. 4. No history of AIDS-defining opportunistic infections. 8. Known hepatitis B surface antigen seropositive or active hepatitis C infection. Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load. 9. Female subjects who are both lactating and breastfeeding or of childbearing potential who have a positive serum test during screening. 10. Female subjects who intend to donate eggs (ova) during the course of the study or four months after receiving their last dose of the study drug(s). 11. Male subjects who intend to donate sperm during the course of this study or four months after receiving their last dose of the study drug(s). 12. Has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit from three days prior to Cycle 1, Day 1 to throughout the study treatment.