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 the bone marrow and who have also failed or are ineligible for any approved standard of care therapies, including HSCT.

1. Phase 1b:

• Patients with a documented lysine[K]-specific methyltransferase 2-rearrangement (KMT2A-r), or

• Patients with a documented nucleophosmin 1 mutation (NPM1-m)

2. Phase 2:

• Patients with a documented nucleophosmin 1 mutation (NPM1-m)

3. Sub-studies:

• Sub-studies 1 and 2: Patients with R/R AML with NPM1-m or other mutationsassociated with MEIS1 overexpression.

• Sub-study 3: Patients with R/R Acute Lymphoblastic Leukemia (ALL) with KMT2A-r.

• Sub-study 4: Patients with R/R AML with mutations associated with MEIS1overexpression.

4. ≥ 18 years of age.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a lifeexpectancy of at least 2 months.

6. Adequate liver and kidney function according to protocol requirements.

7. Peripheral white blood cell (WBC) counts ≤ 30,000/μL. Patients may receivehydroxyurea to control and maintain white blood cell count prior to enrollment.

8. Women of childbearing potential must be willing to use a highly effective method ofcontraception throughout the study and for at least 187 days after the last dose ofstudy treatment.

9. Males with female partners of childbearing potential must agree to use a highlyeffective method of contraception throughout the study and for at least 97 daysafter the 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 limitedchronic GVHD, 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 Criteriafor Adverse Events v5.0) from all acute toxicities or deemed back to a stablebaseline.

10. Treatment with concomitant drugs that are strong inhibitors or inducers ofcytochrome P450-isozyme 3A4 (CYP3A4), as follows:

• Phase 1a, 1b, 2, and sub-studies 3 and 4: with the exception of antibiotics,antifungals, and antivirals that are used as standard of care or to prevent ortreat infections and other such drugs that are considered absolutely essentialfor the care of the patient.

• Sub-studies 1 and 2: No exceptions will be allowed except for the use ofmoderate CYP3A4 antifungal prophylaxis such as fluconazole or isavuconazolewhich is at steady state on Cycle 1 Day 1 and will continue through thecompletion of PKs on Cycle 1 Day 15 (for sub-study 1) or Cycle 1 Day 18 (forsub-study 2).

11. Detectable viral load for human immunodeficiency virus, hepatitis C, or hepatitis Bsurface antigen indicative of active infection. Patients with controlled diseasewill not 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 IIIor IV) related to primary cardiac disease, ischemic or severe valvular heartdisease, or a myocardial infarction within 6 months prior to the first dose of studytreatment.

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 startingtreatment.

18. For sub-studies 1 and 2: Any intake of grapefruit, grapefruit juice, Sevilleoranges, Seville orange marmalade, or other products containing grapefruit orSeville oranges within 7 days of the first administration of ziftomenib until theend of Cycle 1.

19. For sub-studies 1 and 2: Moderate (Child-Pugh class B) or severe (Child-Pugh classC) hepatic impairment.