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

A Phase 1/2 First in Human Study of the Menin-MLL(KMT2A) Inhibitor KO-539 in Patients With Relapsed or Refractory Acute Myeloid Leukemia

In this trial, ziftomenib, a menin-MLL(KMT2A) inhibitor, will be tested in patients for the first time. The trial includes a Main Study and four sub-studies. In the Main Study (including Phase 1a, Phase 1b, and Phase 2 portions), ziftomenib will be evaluated in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). The main study has completed enrollment.

In Sub-studies 1 and 2, the effects of taking ziftomenib and other common drugs at the same time will be investigated in AML patients. In Sub-study 3, ziftomenib will be evaluated in patients with R/R acute lymphoblastic leukemia (ALL). In Sub-study 4, ziftomenib will be evaluated in patients with R/R AML with certain genetic mutations.

This first-in-human (FIH), open-label study will assess ziftomenib, a menin-MLL(KMT2A) inhibitor, in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). The trial includes a Main Study and four sub-studies.

The Main Study is a Phase 1/2 dose-escalation and dose-validation/expansion study to assess ziftomenib in patients with R/R AML. The dose-escalation part of the study (Phase 1a) will determine the maximum 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 (MBED) of ziftomenib in biomarker-specific dosing cohorts from among doses that demonstrated early biological activity and are 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 nucleophosmin 1-mutant (NPM1-m) AML.

In Sub-study 1, the effects of co-administration of ziftomenib on the pharmacokinetics (PK) of midazolam will be studied in patients with R/R AML with certain genetic mutations.

In Sub-study 2, the effects of co-administration of itraconazole on the PK of ziftomenib will be studied in patients with R/R AML with certain genetic mutations.

In Sub-study 3, the safety, tolerability, and MBED/RP2D of ziftomenib will be studied in patients with R/R KMT2A-rearranged (KMT2A-r) ALL (Phase 1a dose escalation). These parameters will be investigated further for the RP2D in a Phase 1b dose-validation/cohort expansion part of the sub-study.

In Sub-study 4, the clinical activity of ziftomenib will be studied in patients with R/R AML with certain genetic mutations.

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 mutations associated 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 MEIS1 overexpression.

4. ≥ 18 years of age.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a life expectancy 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 receive hydroxyurea 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 of contraception throughout the study and for at least 187 days after the last dose of study treatment.

9. 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.

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), 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 or treat infections and other such drugs that are considered absolutely essential for the care of the patient.
    • Sub-studies 1 and 2: No exceptions will be allowed except for the use of moderate CYP3A4 antifungal prophylaxis such as fluconazole or isavuconazole which is at steady state on Cycle 1 Day 1 and will continue through the completion of PKs on Cycle 1 Day 15 (for sub-study 1) or Cycle 1 Day 18 (for sub-study 2).

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.

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

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