Venetoclax in Combination with ASTX727 for the Treatment of Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia

Inclusion Criteria

• Pediatric patients with relapsed/refractory AML by World Health Organization (WHO) criteria
• Patients must have >= 5% blasts in the bone marrow as assessed by morphology or flow cytometry. However, if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia with >= 5% blasts in the peripheral blood or an AML defining genetic abnormality as specified by the WHO 2022 criteria
• Performance status: Lansky >= 50 for patients who are =< 16 years old and Karnofsky >= 50% for patients who are > 16 years old
• Age >= 2 years of age and =< 18 years of age
• Able to swallow pills
• Total serum bilirubin =< 1.5 x upper limit of normal (ULN) for age. Patients with known Gilbert's syndrome may have a total bilirubin up to =< 5 x ULN for age
• Creatinine clearance (Schwartz-Formula) or radioisotope glomerular filtration rate (GFR) >= 60ml/min/1.73 m^2 or a serum creatinine based on age/sex as follows: Threshold creatinine values for inclusion: * 1 month to < 6 months: ** Maximum serum creatinine mg/dL: male 0.46, female 0.46 ** Maximum serum creatinine μmol/L: male 40, female 40 * 6 months to < 1 year: ** Maximum serum creatinine mg/dL: male 0.58, female 0.58 ** Maximum serum creatinine μmol/L: male 51, female 51 * 1 to < 2 years: ** Maximum serum creatinine mg/dL: male 0.70, female 0.70 ** Maximum serum creatinine μmol/L: male 62, female 62 * 2 to < 6 years: ** Maximum serum creatinine mg/dL: male 0.93, female 0.93 ** Maximum serum creatinine μmol/L: male 82, female 82 * 6 to < 10 years: ** Maximum serum creatinine mg/dL: male 1.16, female 1.16 ** Maximum serum creatinine μmol/L: male 102, female 102 * 10 to < 13 years: ** Maximum serum creatinine mg/dL: male 1.4, female 1.4 ** Maximum serum creatinine μmol/L: male 124, female 124 * 13 to < 16 years: ** Maximum serum creatinine mg/dL: male 1.75, female 1.63 ** Maximum serum creatinine μmol/L: male 154, female 144 * >= 16 years: ** Maximum serum creatinine mg/dL: male 1.98, female 1.63 ** Maximum serum creatinine μmol/L: male 175, female 144
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) =< 3 x ULN; =< 5 x ULN in case of suspected leukemic liver involvement
• Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (β‐HCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 6 months following the last dose of study drug. Effective methods of birth control include: * Birth control pills, skin patches, shots, implants (placed under the skin by a health care provider) * Intrauterine devices (IUDs) * Condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide * Abstinence
• Males, need to inform the doctor right away if the partner becomes pregnant or suspects pregnancy. While in this study and for 3 months after the last treatment the patient should not donate sperm for the purposes of reproduction. He will need to use a condom while in this study and for 3 months after the last treatment
• At least one parents or legally authorized representative (LAR) must provide signature of informed consent and there must be documentation of assent by the subject, as age appropriate, before completing any study-related procedures

Exclusion Criteria

• Concomitant other anti-cancer therapy and/or participation in any other investigational clinical trials except for hydroxyurea. Concurrent hydroxyurea use should be limited to the first 2 cycles of therapy only
• History of another primary invasive malignancy that has not been definitively treated and is in remission. Patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses)
• Presence of clinically significant uncontrolled central nervous system (CNS) pathology such as epilepsy, childhood seizure, paresis, aphasia, stroke, severe brain injuries, organic brain syndrome, or psychosis
• Evidence of active cerebral/meningeal disease. Patients may have history of CNS leukemic involvement if definitively treated with prior therapy and no evidence of active disease at the time of consent with at least 2 consecutive spinal fluid negative assessments for residual leukemia and negative imaging (imaging required only if previously showing evidence of CNS leukemia not otherwise documented by spinal fluid assessment)
• Patients with uncontrolled, active infections (viral, bacterial, or fungal) or other disease expected to interfere with the ability of the principal investigator (PI) to assess the efficacy of the study drug. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines are acceptable
• Known active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive), or hepatitis C (eg, hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected), or chronic hepatitis B or C infection or human immunodeficiency virus (HIV) infection in medical history, with the following exceptions: * Those with a history of hepatitis with a negative polymerase chain reaction (either qualitative or quantitative) OR have documentation of stable disease with aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase < 2.0 x upper limit of normal (ULN) may be eligible for this study. * Subjects with history of HIV who have an undetectable viral load for the prior 3 months, and who agree to maintain antiviral therapy, may be eligible for the study
• Liver cirrhosis or other serious active liver disease or with suspected active alcohol abuse
• Exclude patients with active graft versus host disease (GVHD) and those on immunosuppressive drugs for treatment of GVHD. Require that patients be off calcineurin inhibitors for at least 4 weeks to be eligible
• Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the start of study drugs with the following exception: * To reduce the circulating blast count or palliation: intravenous cytarabine, steroids or hydroxyurea. No washout necessary for these agents
• Females who are pregnant or lactating
• Male or female subjects of childbearing potential, unwilling to use an approved, effective means of contraception
• Other severe, uncontrolled acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the Investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study
• Patients with acute promyelocytic leukemia, juvenile myelomonocytic leukemia, or bone marrow failure syndromes are not eligible
• Known or suspected hypersensitivity to decitabine, cedazuridine, or venetoclax
• Patients on concomitant medications known to be metabolized by cytidine deaminase (CDA) will need review of the medication and assessment of possible impact of avoiding dosing during the 24 hours prior to possible enrollment, at the time of cedazuridine exposure, and 24 hours following the last dose of oral decitabine/cedazuridine
• Patients of adult age (= 18 years of age) who are cognitively impaired will not be eligible for this study