Key Inclusion Criteria (Parts 1a and 1b):

1. 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.

2. ≥ 18 years of age.

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

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

5. Peripheral white blood cell (WBC) counts ≤ 30,000/?L.

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

7. Males with female partners of childbearing potential must agree to use a highly
effective method of contraception throughout the study and for at least 97 days after
the last dose of study treatment.

In Part 1b Dose-Validation /Cohort Expansion, patient must have documented specific genetic
subtypes determined by testing and defined as either KMT2A-r or NPM1-m.

Key Exclusion Criteria (Parts 1a and 1b):

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 (i.e. ANC >1,000 and
platelet count > 100,000).

6. Receiving immunosuppressive therapy post HSCT at the time of screening (must be off
all immunosuppression therapy for at least 2 weeks).

7. Grade ≥ 2 active graft-versus-host disease (GVHD), moderate or severe limited chronic
GVHD, or extensive chronic GVHD of any severity.

8. Received chemotherapy immunotherapy, or radiotherapy or any ancillary therapy that is
considered to be investigational (i.e., used for non-approved indications(s) and in
the context of a research investigation) < 14 days prior to the first dose of
ziftomenib (KO-539) or within 5 drug half-lives (whichever is longer) prior to the
first dose of study drug.

9. Treatment with concomitant drugs that are strong inhibitors or inducers of cytochrome
P450-isozyme 3A4 (CYP3A4) with the exception of antibiotics, antifungals, and
antivirals that are used as standard of care or to prevent or treat infections and
other such drugs that are considered absolutely essential for the care of the patient.

10. Detectable viral load for human immunodeficiency virus, hepatitis C, or hepatitis B
surface antigen indicative of active infection.

11. Active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other
infection.

12. Significant cardiovascular disease including unstable angina pectoris, uncontrolled
hypertension or arrhythmia, history of cerebrovascular accident including transient
ischemic attack within the past 6 months, congestive heart failure (NYHA Class III or
IV) related to primary cardiac disease, ischemic or severe valvular heart disease, or
a myocardial infarction within 6 months prior to the first dose of study treatment.

13. Mean QTcF >480 ms on triplicate ECG.

14. Major surgery within 4 weeks prior to the first dose of study treatment.

15. Women who are pregnant or lactating. All female patients with reproductive potential
must have a negative pregnancy test prior to starting treatment.

Eligibility last updated 7/26/22. Questions regarding updates should be directed to the study team contact.