Revumenib in Treating Patients with Relapsed or Refractory Leukemia Associated with Upregulation of HOX Genes

Inclusion Criteria

• Age ≥ 12 years with weight ≥ 40Kg
• Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
• Relapsed or refractory acute leukemia, of either myeloid, lymphoid or mixed lineages, with genetic alterations associated with upregulation of HOX, as specified below: * Alteration/Mutation: KMT2A-PTD Cytogenetics: Normal karyotype * Alteration/Mutation: NPM1-MLF1 Cytogenetics: t(3;5)(q25;q34) * Alteration/Mutation: NUP98r Cytogenetics: 11p15 rearrangements * Alteration/Mutation: SET-NUP214 Cytogenetics: t(9;9)(q34;q34) * Alteration/Mutation: RUNX1-EVI1 Cytogenetics: t(3;21)(q26;q22) * Alteration/Mutation: MYST3-CREBBP Cytogenetics: t(8;16)(p11;p13) * Alteration/Mutation: CDX2-ETV6 Cytogenetics: t(12;13)(p13;q12) * Alteration/Mutation: CALM-AF10 Cytogenetics: t(10;11)(p13;q14-21) * Alteration/Mutation: MN1-ETV6 Cytogenetics: t(12;22)(p13;q12) * Alteration/Mutation: UBTF-TD Cytogenetics: Normal karyotype
• White blood cells (WBC) must be below 25,000/ uL at time of enrollment. Patients may receive cytoreduction prior to enrollment
• Baseline ejection fraction must be > 40%
• Adequate hepatic function (direct bilirubin < 1.5x upper limit of normal [ULN] unless increase is due leukemic involvement, and aspartate aminotransferase [AST] and/or alanine transaminase [ALT] < 3x ULN unless considered due to leukemic involvement, in which case direct bilirubin or AST and/or ALT < 5x ULN will be considered eligible)
• Adequate renal function with an estimated glomerular filtration rate >= 60 mL/min based on local institutional practice for age-appropriate determination
• Patient or parent/guardian is willing and able to provide informed consent
• 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. 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
• Women of childbearing potential must agree to adequate methods of contraception during the study and at least 3 months after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study and at least 3 months after the last treatment

Exclusion Criteria

• 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 concurrent active malignancy under treatment
• Known active hepatitis B (HBV) or hepatitis C (HCV) or human immunodeficiency virus (HIV) infections
• 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
• Corrected QT (QTc) > 450 msec for males and QTc > 470 msec for females using the Fridericia formula using an average of the 3 screening electrocardiography (EKGs)
• 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
• Patients on immunosuppressive therapy post-hematopoietic stem cell transplantation (HSCT) at the time of screening (must be off all systemic immunosuppression therapy for at least 2 weeks and calcineurin inhibitors for at least 4 weeks). 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 (or equivalent) daily are permitted
• Patients with grade > 2 active acute GVHD, moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity