This Phase 1/2, first-in-human (FIH), open-label, dose-escalation and dose-validation/expansion study will assess ziftomenib, a menin-MLL(KMT2A) inhibitor, in patients with relapsed or refractory acute myeloid leukemia (AML).
The dose-escalation part of the study (Phase 1a) will determine the maximal tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D).
The dose-validation/expansion part of the study (Phase 1b) will determine the safety, tolerability, and minimal biologically effective dose of ziftomenib in dosing cohorts which have demonstrated early biological activity and have been determined to be safe in the dose-escalation phase.
The Phase 2 portion of the study will determine the safety, tolerability, and anti-leukemia activity of ziftomenib in patients with NPM1-m AML.
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:
1. Patients with a documented lysine[K]-specific methyltransferase 2-rearrangement
(KMT2A-r), or
2. Patients with a documented nucleophosmin 1 mutation (NPM1-m)
2. Phase 2:
a. Patients with a documented nucleophosmin 1 mutation (NPM1-m)
3. ≥ 18 years of age.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a life
expectancy of at least 2 months.
5. Adequate liver and kidney function according to protocol requirements.
6. Peripheral white blood cell (WBC) counts ≤ 30,000/μL. Patients may receive hydroxyurea
to control and maintain white blood cell count prior to enrollment.
7. Women of childbearing potential must be willing to use a highly effective method of
contraception throughout the study and for at least 180 days after the last dose of
study treatment.
8. Males with female partners of childbearing potential must agree to use a highly
effective method of contraception throughout the study and for at least 90 days after
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 limited chronic
GVHD, or extensive chronic GVHD of any severity.
8. Received chemotherapy immunotherapy, 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 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 for
Adverse 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 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.
11. Detectable viral load for human immunodeficiency virus, hepatitis C, or hepatitis B
surface antigen indicative of active infection. Patients with controlled disease will
not be excluded from study enrollment.
12. Pre-existing disorder predisposing the patient to a serious or life-threatening
infection (e.g. cystic fibrosis, congenital or acquired immunodeficiency, bleeding
disorder, or cytopenias not related to AML).
13. Active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other
infection.
14. 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.
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 potential
must have a negative serum pregnancy test within 72 hours prior to starting treatment.
