8-Chloroadenosine in Combination with Decitabine and Venetoclax for the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia

Inclusion Criteria

• Documented informed consent of the participant and/or legally authorized representative.
• Age: >= 18 years.
• Eastern Cooperative Oncology Group (ECOG) =< 2.
• Life expectancy > 3 months.
• Patients with histologically confirmed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)/AML, according to World Health Organization (WHO) criteria, with relapsed/refractory disease and risk stratification by 2022 European LeukemiaNet (ELN) criteria.
• Patients must have any one of the following treatment history criteria: * Relapsed AML ** Failed at least 1 line of salvage therapy or ** Untreated relapse and are not candidates for allogeneic hematopoietic stem cell transplantation (alloHCT) * De novo AML ** have not achieved complete response (CR) after 2 lines of therapy or ** refractory to frontline therapy and not eligible for alloHCT * AML or MDS/AML evolving from MDS or myeloproliferative disorder who have failed hypomethylating agents (HMA) or induction chemotherapy * Patients who have relapsed after allo-HCT are eligible if they are at least 3 months after HCT, do not have active graft versus host disease (GVHD) and are off immunosuppression except for maintenance dose of steroids (prednisone 10 mg/day or less).
• Male subjects must agree to not donate sperm while taking protocol therapy through at least 90 days after the last dose.
• White blood cell (WBC) =< 25 x 10^9/L prior to initiation of venetoclax. Cytoreduction with hydroxyurea prior to treatment and/or during cycle 1 may be required.
• Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert’s disease).
• Aspartate aminotransferase (AST) =< 2.5 x ULN.
• Alanine aminotransferase (ALT) =< 2.5 x ULN.
• Creatinine clearance of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula.
• Left ventricular ejection fraction (LVEF) >= 50%. Note: Echocardiogram to be performed within 28 days prior to Day 1 of protocol therapy
• Fridericia’s formula–corrected QT interval (QTcF) =< 450 ms (repeated triplicate).
• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Agreement by females and males of childbearing potential* to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months (females) and 3 months (males) after the last dose of protocol therapy. * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only).

Exclusion Criteria

• Current or planned use of other investigational agents, antineoplastic, biological, chemotherapy, or radiation therapy during the study treatment period, or within 2 weeks or 5 half-lives, whichever is shorter, prior to day 1 of protocol therapy, with the following exception: * Hydroxyurea which may be continued through cycle 1.
• Expected to undergo HCT within 120 days of enrollment.
• Current or planned use of agents that prolong or suspected to prolong corrected QT interval (QTc) within 5 half-lives plus 7 days prior to Day 1 of protocol therapy. For drugs with a black box warning of QTc elongation, washout must be at least 5 half-lives plus 7 days.
• Received strong or moderate CYP3A inducers or St. John's wort within 7 days prior to Day 1 of protocol therapy. * Certain strong CYP3A inhibitors are not allowed throughout the study, and some are excluded during cycle 1 and cautionary thereafter with required dose modification of venetoclax. Moderate CYP3A inhibitors are allowed and cautionary throughout and require dose modification of venetoclax.
• Consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to day 1 of protocol therapy.
• Toxicities (grade > 1) unresolved from prior treatment (including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, or surgery) that is not attributable to active disease
• Must not have received or planning to receive live vaccine while being on study or 4 weeks before and after completion of treatment
• Acute promyelocytic leukemia.
• Active central nervous system (CNS) leukemia.
• Active fungal infection or bacterial sepsis.
• Class III/IV cardiovascular disability according to the New York Heart Association classification
• Participants with clinically significant structural heart disease as assessed by complete echocardiogram with Doppler.
• Participants with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of enrollment. Subjects with controlled, asymptomatic atrial fibrillation can enroll
• History of acute cardiovascular ischemic event, i.e., myocardial infarction or unstable angina within 6 months of enrollment.
• History of unexplained syncope, significant histories of coronary artery disease (CAD) (requiring revascularization by percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]), cardiomyopathy (ejection fraction [EF] < 50%).
• A history of additional risk factors for arrhythmia torsades de pointes (TdP) (e.g., congenital syndromes associated with long QT interval)
• Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy).
• Unable to swallow capsules, has a partial or small bowel obstruction, or has a gastrointestinal condition resulting in a malabsorptive syndrome (e.g. small bowel resection with malabsorption).
• Active peptic ulcer disease.
• Other active malignancy except for localized skin cancer, bladder, prostate, breast or cervical carcinoma in situ.
• Females only: Pregnant or breastfeeding.
• Any other condition that would, in the investigator’s judgment, contraindicate the patient’s participation in the clinical study due to safety concerns with clinical study procedures.
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).