First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia

Key Inclusion Criteria: Patients with refractory or relapsed AML defined as the reappearance of ≥ 5% blasts in thebone marrow and who have also failed or are ineligible for any approved standard of caretherapies, including HSCT.

1. Phase 1b:
2. Patients with a documented lysine[K]-specific methyltransferase 2-rearrangement (KMT2A-r), or
3. Patients with a documented nucleophosmin 1 mutation (NPM1-m)
4. Phase 2: a. Patients with a documented nucleophosmin 1 mutation (NPM1-m)
5. ≥ 18 years of age.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a lifeexpectancy of at least 2 months.
7. Adequate liver and kidney function according to protocol requirements.
8. Peripheral white blood cell (WBC) counts ≤ 30,000/μL. Patients may receive hydroxyureato control and maintain white blood cell count prior to enrollment.
9. Women of childbearing potential must be willing to use a highly effective method ofcontraception throughout the study and for at least 180 days after the last dose ofstudy treatment.
10. Males with female partners of childbearing potential must agree to use a highlyeffective method of contraception throughout the study and for at least 90 days afterthe last dose of study treatment.

Key Exclusion Criteria:

1. Diagnosis of acute promyelocytic leukemia.
2. Diagnosis of chronic myelogenous leukemia in blast crisis.
3. Donor lymphocyte infusion < 30 days prior to study entry.
4. Clinically active central nervous system (CNS) leukemia.
5. Undergone HSCT and have not had adequate hematologic recovery.
6. Receiving immunosuppressive therapy post HSCT within 2 weeks of Cycle 1 Day 1.
7. Grade ≥ 2 active graft-versus-host disease (GVHD), moderate or severe limited chronicGVHD, or extensive chronic GVHD of any severity.
8. Received chemotherapy immunotherapy, radiotherapy, or any ancillary therapy that isconsidered to be investigational (i.e., used for non-approved indications(s) and inthe context of a research investigation) < 14 days prior to the first dose ofziftomenib or within 5 drug half-lives prior to the first dose of study drug.
9. Not recovered to < Grade 2 (National Cancer Institute Common Terminology Criteria forAdverse Events v5.0) from all acute toxicities or deemed back to a stable baseline.
10. Treatment with concomitant drugs that are strong inhibitors or inducers of cytochromeP450-isozyme 3A4 (CYP3A4) with the exception of antibiotics, antifungals, andantivirals that are used as standard of care or to prevent or treat infections andother such drugs that are considered absolutely essential for the care of the patient.
11. Detectable viral load for human immunodeficiency virus, hepatitis C, or hepatitis Bsurface antigen indicative of active infection. Patients with controlled disease willnot be excluded from study enrollment.
12. Pre-existing disorder predisposing the patient to a serious or life-threateninginfection (e.g. cystic fibrosis, congenital or acquired immunodeficiency, bleedingdisorder, or cytopenias not related to AML).
13. Active uncontrolled acute or chronic systemic fungal, bacterial, viral, or otherinfection.
14. Significant cardiovascular disease including unstable angina pectoris, uncontrolledhypertension or arrhythmia, history of cerebrovascular accident including transientischemic attack within the past 6 months, congestive heart failure (NYHA Class III orIV) related to primary cardiac disease, ischemic or severe valvular heart disease, ora myocardial infarction within 6 months prior to the first dose of study treatment.
15. Mean QTcF >480 ms on triplicate ECG.
16. Major surgery within 4 weeks prior to the first dose of study treatment.
17. Women who are pregnant or lactating. All female patients with reproductive potentialmust have a negative serum pregnancy test within 72 hours prior to starting treatment.