SNDX-5613 with Decitabine/Cedazuridine, and Venetoclax for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia, SAVE Trial

Inclusion Criteria

• Age >= 12 years with weight >= 40 Kg
• Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
• Newly diagnosed (frontline cohort), who are not eligible for high-intensity induction chemotherapy or relapsed/refractory (R/R cohort) AML or myeloid phenotype mixed phenotype acute leukemia (MPAL) with either KMT2Ar, or NUP98r, or NPM1c
• White blood cell (WBC) must be below 25,000/ uL at time of enrollment. Patients may receive cytoreduction prior to enrollment
• Baseline ejection fraction must be > 40%
• Direct bilirubin < 2 x upper limit of normal (ULN) unless increase is due to Gilbert’s disease or leukemic involvement
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement, in which case direct bilirubin or AST and/or ALT < 5 x ULN will be considered eligible
• Creatinine clearance >= 30 mL/min (unless related to disease)
• 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

• Prior treatment with a menin inhibitor
• 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 (HBV) or hepatitis C (HCV) infection or known human immunodeficiency virus (HIV) infection
• 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) > 470 msec using the Fridericia formula
• History of a complete bundle branch block or high-degree atrioventricular block
• 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 with relapsed or relapsed (R/R) leukemia (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 daily are permitted
• Patients with grade > 2 active acute graft versus host disease (GVHD), moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity