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

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.

• Ziftomenib (Drug), also known as KO-539: Oral administration
• Midazolam (Drug), also known as Seizalam, Hypnovel, Dormicum: Oral administration
• Itraconazole (Drug), also known as Sporanox, Onmel, Tolsura: Oral administration

Primary outcomes

• Phase 1a: Maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) [Dose Limiting Toxicities (DLTs) will be evaluated during the first 28 days (1 cycle)]: MTD is defined as the highest dose that is not expected to cause dose limiting toxicity (DLT) in more than 20% of patients.
• Phase 1b: Number of patients who experience Adverse Events (AEs) and Serious Adverse Events (SAEs) [During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first.]: Assessed by NCI-CTCAE v5.0
• Phase 1b: Minimum biologically effective dose [For at least 12 months following end of treatment]: Minimum biologically effective dose in dosing cohorts which have demonstrated biological activity and have been determined to be safe as a part of Part 1a
• Phase 1a, 1b, and 2: Evidence of anti-leukemia activity [For at least 12 months following end of treatment]: Assessed by the CR + CRh rate
• Sub-study 1: Time to observed maximum plasma concentration (Tmax) of ziftomenib and midazolam [Cycle 1 on Days 1 and 15 at predose and postdose]: Tmax of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam
• Sub-study 1: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib and midazolam [Cycle 1 on Days 1 and 15 at predose and postdose]: AUC0-t of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam
• Sub-study 1: Maximum observed plasma concentration (Cmax) of ziftomenib and midazolam [Cycle 1 on Days 1 and 15 at predose and postdose]: Cmax of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam
• Sub-study 2: Time to observed maximum plasma concentration (Tmax) of ziftomenib and itraconazole [Cycle 1 on Days 1, 15, and 22 at predose and postdose]: Tmax of ziftomenib, its metabolites, and itraconazole
• Sub-study 2: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib and itraconazole [Cycle 1 on Days 1, 15, and 22 at predose and postdose]: AUC0-t of ziftomenib, its metabolites, and itraconazole
• Sub-study 2: Maximum observed plasma concentration (Cmax) of ziftomenib and itraconazole [Cycle 1 on Days 1, 15, and 22 at predose and postdose]: Cmax of ziftomenib, its metabolites, and itraconazole
• Sub-study 3: Minimum biologically effective dose (MBED) and/or the recommended Phase 2 dose (RP2D) [During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first]: Assessed by the number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs) per NCI-CTCAE v5.0
• Sub-study 3: Minimum biologically effective dose (MBED) and/or the recommended Phase 2 dose (RP2D) [For at least 12 months following end of treatment]: Assessed by CR
• Sub-study 3: Change in Eastern Cooperative Oncology Group (ECOG) status [Timeframe: from Baseline to End of Treatment]: To assess the change in ECOG status
• Sub-study 3: Time to observed maximum plasma concentration (Tmax) of ziftomenib [Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards]: Tmax of ziftomenib
• Sub-study 3: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib [Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards]: AUC0-t of ziftomenib
• Sub-study 3: Maximum observed plasma concentration (Cmax) of ziftomenib [Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards.]: Cmax of ziftomenib
• Sub-study 4: Complete remission (CR) and complete remission with partial hematologic recovery (CRh) [For at least 12 months following end of treatment]: To assess the CR+CRh rate

Secondary outcomes

• Phase 1a and 2: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs) [During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first.]: Assessed by NCI-CTCAE v5.0
• Phase 1a: Tmax [Cycle 1 and Cycle 2. Each cycle is 28 days.]: Time to observed maximum plasma concentration of ziftomenib and/or its metabolites
• Phase 1a: AUC(0-t) [Cycle 1 and Cycle 2. Each cycle is 28 days.]: Area under the plasma concentration-time curve from time 0 to time t of ziftomenib and/or its metabolites
• Phase 1a: Cmax [Cycle 1 and Cycle 2. Each cycle is 28 days.]: Maximum plasma concentration of ziftomenib and/or its metabolites
• Phases 1a, 1b, and 2: Complete remission (CR) and complete remission with partial hematologic recovery (CRh) measurable residual disease (MRD) negativity [For at least 12 months following discontinuation of treatment]: To assess the CR/CRh MRD negativity
• Phases 1a, 1b, and 2: Duration of response (DOR) [For at least 12 months following discontinuation of treatment]: To assess the DOR, defined as the duration of CR/CRh
• Phases 1a, 1b, and 2: Transfusion independence (TI) [For at least 12 months following discontinuation of treatment]: To assess transfusion independence
• Phases 1a, 1b, and 2: Overall response rate (ORR) [For at least 12 months following discontinuation of treatment]: To assess the ORR
• Phases 1a, 1b, and 2: Event-free survival (EFS) [For at least 12 months following end of treatment]: To assess event-free survival
• Phases 1a, 1b, and 2: Overall survival (OS) [For at least 12 months following end of treatment]: To assess overall survival
• Phases 1a, 1b, and 2: Composite complete remission (CRc) [For at least 12 months following discontinuation of treatment]: To assess CRc
• Phases 1b and 2: Composite complete remission (CRc) measurable residual disease (MRD) negativity [For at least 12 months following discontinuation of treatment]: To assess the CRc MRD negativity
• Phases 1b and 2: Overall response rate (ORR) measurable residual disease (MRD) negativity [For at least 12 months following discontinuation of treatment]: To assess the ORR MRD negativity
• Sub-study 2: Corrected QT (QTc) intervals [During Cycle 1]: Assessed by QTc intervals
• Sub-study 3: Complete remission (CR) measurable residual disease (MRD) negativity [For at least 12 months following discontinuation of treatment]: To assess the CR MRD negativity
• Sub-studies 3 and 4: Composite complete remission (CRc) [For at least 12 months following discontinuation of treatment]: To assess CRc
• Sub-study 3: Duration of response (DOR) [For at least 12 months following discontinuation of treatment]: To assess the DOR, defined as the duration of CR
• Sub-studies 3 and 4: Overall survival (OS) [For at least 12 months following discontinuation of treatment]: To assess overall survival
• Sub-studies 3 and 4: Event-free survival (EFS) [For at least 12 months following discontinuation of treatment]: To assess event-free survival
• Sub-study 4: Transfusion independence (TI) [For at least 12 months following discontinuation of treatment]: To assess transfusion independence
• Sub-studies 3 and 4: Overall response rate (ORR) measurable residual disease (MRD) negativity [For at least 12 months following discontinuation of treatment]: To assess the ORR MRD negativity
• Sub-study 4: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs) [During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first.]: Assessed by NCI-CTCAE v5.0
• Sub-study 4: Duration of response (DOR) [For at least 12 months following discontinuation of treatment]: To assess the DOR, defined as the duration of CR/CRh
• Sub-study 4: Time to observed maximum plasma concentration (Tmax) of ziftomenib [Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards]: Tmax of ziftomenib and its metabolites
• Sub-study 4: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib [Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards]: AUC0-t of ziftomenib and its metabolites
• Sub-study 4: Maximum plasma concentration (Cmax) of ziftomenib [Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards]: Cmax of ziftomenib and its metabolites

Sex: All, ages: 18 Years to any

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.

• Results publication: Wang ES, Montesinos P, Foran J, Erba H, Rodriguez-Arboli E, Fedorov K, Heiblig M, Heidel FH, Altman JK, Baer MR, Ades L, Pettit K, Peterlin P, Papayannidis C, Berthon C, Walter RB, Shah MV, Balasubramanian S, Khawandanah M, Salamero Garcia O, Bergeron J, Madanat YF, Roboz GJ, Ulrickson M, Redner RL, McCloskey J, Pigneux A, de la Fuente Burguera A, Mitra A, Soifer HS, Tabachri M, Zhang Z, Riches M, Corum D, Leoni M, Issa GC, Fathi AT; KOMET-001. Ziftomenib in Relapsed or Refractory NPM1-Mutated AML. J Clin Oncol. 2025 Nov;43(31):3381-3390. doi: 10.1200/JCO-25-01694. Epub 2025 Sep 25. PMID 40997296
• Results publication: Wang ES, Issa GC, Erba HP, Altman JK, Montesinos P, DeBotton S, Walter RB, Pettit K, Savona MR, Shah MV, Kremyanskaya M, Baer MR, Foran JM, Schiller G, Ades L, Heiblig M, Berthon C, Peterlin P, Rodriguez-Arboli E, Salamero O, Patnaik MM, Papayannidis C, Grembecka J, Cierpicki T, Clegg B, Ray J, Linhares BM, Nie K, Mitra A, Ahsan JM, Tabachri M, Soifer HS, Corum D, Leoni M, Dale S, Fathi AT. Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial. Lancet Oncol. 2024 Oct;25(10):1310-1324. doi: 10.1016/S1470-2045(24)00386-3. PMID 39362248
• Results publication: Sasca D, Guezguez B, Kuhn MWM. Next generation epigenetic modulators to target myeloid neoplasms. Curr Opin Hematol. 2021 Sep 1;28(5):356-363. doi: 10.1097/MOH.0000000000000673. PMID 34267079
• Results publication: Jimenez JA, Apfelbaum AA, Hawkins AG, Svoboda LK, Kumar A, Ruiz RO, Garcia AX, Haarer E, Nwosu ZC, Bradin J, Purohit T, Chen D, Cierpicki T, Grembecka J, Lyssiotis CA, Lawlor ER. EWS-FLI1 and Menin Converge to Regulate ATF4 Activity in Ewing Sarcoma. Mol Cancer Res. 2021 Jul;19(7):1182-1195. doi: 10.1158/1541-7786.MCR-20-0679. Epub 2021 Mar 19. PMID 33741715