Hydroxychloroquine in Combination with Decitabine-Cedazuridine and Venetoclax for the Treatment of Newly Diagnosed, Relapsed, Refractory and Secondary Acute Myeloid Leukemia

Inclusion Criteria

• Confirmed acute myeloid leukemia per 2022 World Health Organization (WHO) (≥ 20 % blasts or genetically-defined AML)
• Age ≥ 18 years on the date of consent
• Disease status * Phase I: Relapsed/refractory (R/R); or newly-diagnosed, or very high risk defined as p53 mutation or secondary AML after myeloproliferative neoplasm (MPN) or chemotherapy/radiation exposure
• An Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN) (within 14 days of cycle 1 day 1)
• Total bilirubin ≤ 1.5 x ULN (within 14 days of cycle 1 day 1) (unless Gilbert's)
• Creatinine clearance > 60 mL/min (Cockcroft-Gault) (within 14 days of cycle 1 day 1)
• Subjects must have a baseline corrected QT (QTc) interval of greater than 450 milliseconds (> 450 ms)
• White blood cells < 25 x 10^9/L before first dose of hypomethylating agent-debulking with hydroxyurea/leukapheresis or up to 4 doses of cytarabine 100mg-200mg if needed is acceptable
• HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) patients are eligible if viral load is undetectable on stable therapy
• Wash-out from prior therapies should be ≥ 14 days from the last cytotoxic or targeted agent and recovery to ≤ grade 1 non-hematologic toxicity
• Reproductive precautions * Negative serum beta-human chorionic gonadotropin (hCG) for women of childbearing potential (WOCBP) * Agreement to use highly effective contraception during treatment and ≥ 90 days after last dose
• Signed written informed consent and willingness to comply with study procedures

Exclusion Criteria

• Leukemia subtype * Acute promyelocytic leukemia (APL, PML-RARA)
• Central nervous system (CNS) leukemia not cleared (< 5 white blood cell [WBC]/uL & no blasts), or symptomatic CNS involvement
• Recent or uncontrolled transplant-related complications * Allogeneic hematopoietic stem cell transplantation (HSCT) ≤ 90 days before day 1 * Active grade ≥ 2 graft-versus-host disease (GVHD) or systemic immunosuppression > 10 mg/day prednisone-equivalent
• Concurrent malignancies requiring active chemotherapy, except adequately treated in-situ cancers or those not expected to interfere with endpoints
• Active, uncontrolled infection (bacterial, viral, or fungal) despite appropriate antimicrobial therapy
• Cardiac risk, New York Heart Association (NYHA) class III/IV heart failure, unstable angina, recent myocardial infarction (MI) (< 6 months), clinically significant arrhythmia, concomitant use of high-risk QT-prolonging medications that cannot be discontinued, or history of torsades de pointes
• Pregnant or breastfeeding
• Patients with known G6PD deficiency
• Investigational drug or major surgery within 28 days
• Bleeding diathesis/coagulopathy that would preclude required marrow aspirates or lumbar puncture
• Psychiatric or social condition that, in the investigator’s judgment, would impair compliance with protocol-mandated visits/procedures