Ziftomenib, Venetoclax, and Azacitidine for the Treatment of Pediatric Patients with Relapsed and Refractory Acute Leukemias

Inclusion Criteria

• Age ≥ 2 years to 21 years
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Relapsed/refractory: AML or mixed phenotype acute leukemia (MPAL) patients with KMT2A-r, NPM1-m, NUP98-r or ALL/acute leukemia of ambiguous lineage (ALAL) with KMT2A-r * ≥ 5% leukemic blasts in the bone marrow
• White blood cells (WBC) must be below 25,000/ µL at time of enrollment. Patients may receive cytoreduction prior to enrollment
• Baseline ejection fraction must be > 40%
• Direct bilirubin < 1.5x upper limit of normal (ULN) unless increase is due to Gilbert’s disease or leukemic involvement
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 5x ULN unless considered due to leukemic involvement, in which case direct bilirubin < 3x ULN or AST and/or ALT < 5x ULN will be considered eligible
• Creatinine clearance ≥ 30 mL/min unless related to disease
• In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 14 days for cytotoxic or non-cytotoxic (immunotherapy agent[s]), or an interval of 5 half-lives of the prior therapy (whichever is shorter). Oral hydroxyurea and/or cytarabine (up to 2 g/m^2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the principal investigator (PI). Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted
• Unless surgically or biologically sterile: Women of childbearing potential must agree to adequate methods of contraception during the study and at least 3 months for males, and 6 months for females, after the last treatment

Exclusion Criteria

• Patients who weigh less than 10kg
• Patients with any concurrent uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place the patient at unacceptable risk of study treatment
• The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions (1) intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia. (2) use of hydroxyurea for patients with rapidly proliferative disease or for control of counts during differentiation syndrome. (3) use of steroids for treatment of differentiation syndrome
• Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications
• Patients with a concurrent active malignancy under treatment
• Known active hepatitis B (hepatitis B virus [HBV]) or hepatitis C (hepatitis C virus [HCV]) infection or active/uncontrolled HIV infection, AIDS, or currently taking contraindicated medications for HIV control
• Female subjects who are pregnant or breast-feeding
• Patient has an active uncontrolled infection
• Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack
• Mean corrected QT interval by Fridericia’s formula > 480 ms on 12-lead electrocardiograms
• History of or any concurrent condition, therapy, or laboratory abnormality that in the investigator’s opinion might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate
• Clinically active central nervous system (CNS) leukemia
• The use of topical steroids for cutaneous graft-versus-host disease (GVHD) or stable systemic steroid doses less than or equal to 20 mg of prednisone daily are permitted
• Patients with Grade > 2 active acute GVHD, moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity
• Has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the first dose of venetoclax