Dose Escalation and Expansion of Ziftomenib in Combination With Quizartinib in Acute Myeloid Leukemia

Inclusion Criteria: 1. Age . 18 years. 2. ECOG performance status of \< 2. 3. Relapsed or refractory AML or myeloid mixed-phenotype acute leukemia (MPAL) with NPM1mt, or KMT2Ar, or NUP98r. 4. WBC must be below 25,000/ ƒÊL at time of enrollment. Patients may receive cytoreduction prior to enrollment. 5. Baseline ejection fraction must be \> 40%. 6. Adequate hepatic function (total bilirubin \< 2x upper limit of normal (ULN) unless increase is due leukemic involvement (\<2.5 ULN), unless due to ongoing hemolysis or Gilbert's syndrome and AST and/or 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). 7. Adequate renal function with an estimated glomerular filtration rate . 50 mL/min (using Cockcroft-Gault) unless related to disease. 8. Able to swallow pills. 9. Patient or parent/guardian is willing and able to provide informed consent. 10. 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 longer. Oral hydroxyurea and/or cytarabine (up to 1 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the PI. Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted. 11. Women of childbearing potential must agree to adequate methods of contraception during the study and at least 7 months for females and 4 months for males 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 4 months after the last treatment. Exclusion Criteria: 1. Prior treatment with a menin inhibitor. 2. 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. 3. Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications. 4. Patients with a concurrent active malignancy under treatment. 5. Known active hepatitis B (HBV) or Hepatitis C (HCV) or HIV infection. 6. Female subjects who are pregnant or breast-feeding. 7. Patient has an active uncontrolled infection. 8. 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 including ventricular arrythmias or torsades de pointes, cerebrovascular accident, or transient ischemic attack. 9. History of sustained bradycardia of less than 50 beats per minute unless the subject has a pacemaker. 10. Diagnosis of or suspicion of congenital long QT syndrome (including family history of congenital long QT syndrome). 11. Uncontrolled hypertension with a systolic blood pressure .180 mmHg or diastolic blood pressure .110 mmHg, sustained despite optimal medical management. 12. QTc \>450 msec using the Fridericia Formula. 13. 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. Patients under legal protection measure (guardianship, trusteeship or safeguard of justice) and/or uncontrolled psychiatric comorbidities, ongoing illicit substance abuse, inability, any impairment or unwillingness to comply with the treatments, follow-up, requirements and procedures of this clinical trial. 14. Clinically active central nervous system (CNS) leukemia. 15. Patients with Grade \> 2 active acute GVHD, moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity.