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

NCT04067336 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: KO-MEN-001
• Study Type: interventional
• Target: 263
• Locations: 7 countries
• Sites: 43

Brief Summary

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.

Conditions

Acute Myeloid Leukemia; Mixed Lineage Leukemia; Mixed Lineage Acute Leukemia; Acute Leukemia of Ambiguous Lineage; Acute Lymphoblastic Leukemia; Mixed Phenotype Acute Leukemia; Advanced Malignant Neoplasm

Keywords

AML; Hematological malignancy; KMT2A; NPM1; Menin; Leukemia; Acute Leukemia; ALL; MLL; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; MEIS1

Outcome Measures

Primary Outcomes (17)

• Phase 1a: Maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D)

  MTD is defined as the highest dose that is not expected to cause dose limiting toxicity (DLT) in more than 20% of patients.

  Dose Limiting Toxicities (DLTs) will be evaluated during the first 28 days (1 cycle)

• Phase 1b: Number of patients who experience Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Assessed by NCI-CTCAE v5.0

  During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first.

• Phase 1b: Minimum biologically effective dose

  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

  For at least 12 months following end of treatment

• Phase 1a, 1b, and 2: Evidence of anti-leukemia activity

  Assessed by the CR + CRh rate

  For at least 12 months following end of treatment

• Sub-study 1: Time to observed maximum plasma concentration (Tmax) of ziftomenib and midazolam

  Tmax of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam

  Cycle 1 on Days 1 and 15 at predose and postdose

• Sub-study 1: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib and midazolam

  AUC0-t of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam

  Cycle 1 on Days 1 and 15 at predose and postdose

• Sub-study 1: Maximum observed plasma concentration (Cmax) of ziftomenib and midazolam

  Cmax of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam

  Cycle 1 on Days 1 and 15 at predose and postdose

• Sub-study 2: Time to observed maximum plasma concentration (Tmax) of ziftomenib and itraconazole

  Tmax of ziftomenib, its metabolites, and itraconazole

  Cycle 1 on Days 1, 15, and 22 at predose and postdose

• Sub-study 2: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib and itraconazole

  AUC0-t of ziftomenib, its metabolites, and itraconazole

  Cycle 1 on Days 1, 15, and 22 at predose and postdose

• Sub-study 2: Maximum observed plasma concentration (Cmax) of ziftomenib and itraconazole

  Cmax of ziftomenib, its metabolites, and itraconazole

  Cycle 1 on Days 1, 15, and 22 at predose and postdose

• Sub-study 3: Minimum biologically effective dose (MBED) and/or the recommended Phase 2 dose (RP2D)

  Assessed by the number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs) per NCI-CTCAE v5.0

  During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first

• Sub-study 3: Minimum biologically effective dose (MBED) and/or the recommended Phase 2 dose (RP2D)

  Assessed by CR

  For at least 12 months following end of treatment

• Sub-study 3: Change in Eastern Cooperative Oncology Group (ECOG) status

  To assess the change in ECOG status

  Timeframe: from Baseline to End of Treatment

• Sub-study 3: Time to observed maximum plasma concentration (Tmax) of ziftomenib

  Tmax of ziftomenib

  Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards

• Sub-study 3: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib

  AUC0-t of ziftomenib

  Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards

• Sub-study 3: Maximum observed plasma concentration (Cmax) of ziftomenib

  Cmax of ziftomenib

  Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards.

• Sub-study 4: Complete remission (CR) and complete remission with partial hematologic recovery (CRh)

  To assess the CR+CRh rate

  For at least 12 months following end of treatment

Secondary Outcomes (26)

• 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.

• Phase 1a: Tmax

  Cycle 1 and Cycle 2. Each cycle is 28 days.

• Phase 1a: AUC(0-t)

  Cycle 1 and Cycle 2. Each cycle is 28 days.

• Phase 1a: Cmax

  Cycle 1 and Cycle 2. Each cycle is 28 days.

• 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

Study Arms (7)

Phase 1a - Dose Escalation

EXPERIMENTAL

AML patients will receive multiple doses of ziftomenib

Drug: Ziftomenib

Phase 1b - Dose-Validation Expansion

EXPERIMENTAL

Cohort 1: KMT2A-r / NPM1-m R/R AML patients will receive ziftomenib Cohort 2: KMT2A-r / NPM1-m R/R AML patients will receive ziftomenib

Drug: Ziftomenib

Phase 2

EXPERIMENTAL

NPM1-m R/R AML patients will receive the recommended phase 2 ziftomenib dose

Drug: Ziftomenib

Sub-study 1

EXPERIMENTAL

R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + midazolam

Drug: Ziftomenib; Drug: Midazolam

Sub-study 2

EXPERIMENTAL

R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + itraconazole

Drug: Ziftomenib; Drug: Itraconazole

Sub-study 3

EXPERIMENTAL

Part 1a: KMT2A-r R/R ALL patients will receive multiple ziftomenib doses Part 1b: KMT2A-r R/R ALL patients will receive ziftomenib

Drug: Ziftomenib

Sub-study 4

EXPERIMENTAL

R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib

Drug: Ziftomenib

Interventions

Ziftomenib DRUG

Oral administration

Also known as: KO-539

Phase 1a - Dose Escalation; Phase 1b - Dose-Validation Expansion; Phase 2; Sub-study 1; Sub-study 2; Sub-study 3; Sub-study 4

Midazolam DRUG

Oral administration

Also known as: Seizalam, Hypnovel, Dormicum

Sub-study 1

Itraconazole DRUG

Oral administration

Also known as: Sporanox, Onmel, Tolsura

Sub-study 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Phase 1b:
• Patients with a documented lysine\[K\]-specific methyltransferase 2-rearrangement (KMT2A-r), or
• Patients with a documented nucleophosmin 1 mutation (NPM1-m)
• Phase 2:
• Patients with a documented nucleophosmin 1 mutation (NPM1-m)
• 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.
• ≥ 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a life expectancy of at least 2 months.
• Adequate liver and kidney function according to protocol requirements.
• Peripheral white blood cell (WBC) counts ≤ 30,000/μL. Patients may receive hydroxyurea to control and maintain white blood cell count prior to enrollment.
• 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.

You may not qualify if:

• Diagnosis of acute promyelocytic leukemia.
• Diagnosis of chronic myelogenous leukemia in blast crisis.
• Donor lymphocyte infusion \< 30 days prior to study entry.
• Clinically active central nervous system (CNS) leukemia.
• Undergone HSCT and have not had adequate hematologic recovery.
• Receiving immunosuppressive therapy post HSCT within 2 weeks of Cycle 1 Day 1.
• Grade ≥ 2 active graft-versus-host disease (GVHD), moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity.
• 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.
• 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.
• 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).
• 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.
• 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).
• Active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection.

Sponsors & Collaborators

• Kura Oncology, Inc.: lead

Study Sites (43)

Banner MD Anderson Cancer Center

Gilbert, Arizona, 85234, United States

Location

UCLA Ronald Reagan Medical Center

Los Angeles, California, 90095, United States

Location

Mayo Clinic

Jacksonville, Florida, 32224, United States

Location

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Maryland Greenebaum Comprehensive Cancer Center

Baltimore, Maryland, 21201, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

University of Michigan Hospitals

Ann Arbor, Michigan, 48109, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Hackensack University Medical Center - John Theurer Cancer Center

Hackensack, New Jersey, 07601, United States

Location

Roswell Park Comprehensive Cancer Center

Buffalo, New York, 14203, United States

Location

Weill Cornell Medical College - NY Presbyterian Hospital

New York, New York, 10021, United States

Location

The Mount Sinai Hospital

New York, New York, 10029, United States

Location

Duke Cancer Institute

Durham, North Carolina, 27710, United States

Location

Oklahoma University Health - Stephenson Cancer Center

Oklahoma City, Oklahoma, 73117, United States

Location

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Harold C. Simmons Comprehensive Cancer Center - UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

AZ Delta - Campus Rumbeke

Roeselare, 8800, Belgium

Location

Queen Elizabeth II Health Sciences Centre

Halifax, Nova Scotia, B3H 1V7, Canada

Location

Hopital Maisonneuve-Rosemont

Montreal, Quebec, H1T 2M4, Canada

Location

Hopital de l'Enfant-Jesus - Centre Integre en Cancerologie du CHU de Quebec - Universite Laval

Québec, Quebec, G1J 1Z4, Canada

Location

Centre Hospitalier Universitaire de Lille

Lille, 59037, France

Location

Centre Hospitalier Universitaire de Nantes

Nantes, 44093, France

Location

Hopital Saint Louis

Paris, 75475, France

Location

Magendie Hopital Haut-Leveque

Pessac, 33600, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69310, France

Location

Institut Gustave Roussy

Villejuif, 94800, France

Location

University Medicine Greifswald

Greifswald, 17475, Germany

Location

Medizinische Hochsschule Hannover

Hanover, 30625, Germany

Location

Institute of Hematology and Medical Oncology "L. and A. Seragnoli"

Bologna, 40138, Italy

Location

IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"

Meldola, 47014, Italy

Location

UO Ematologia Ospedale di Ravenna

Ravenna, 48121, Italy

Location

Institution Fondazione Policlinico Tor Vergata

Roma, Italy

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Universitat de Barcelona

Barcelona, 08035, Spain

Location

MD Anderson Cancer Center

Madrid, 28033, Spain

Location

Hospital Universitario HM Sanchinarro

Madrid, 28050, Spain

Location

Hospital Universitario Central de Asturias

Oviedo, 33011, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, 41013, Spain

Location

Hospital Universitari i Politecnic La Fe

Valencia, 46026, Spain

Location

Related Publications (4)

• 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 DERIVED

• 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 DERIVED

• 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 DERIVED

• 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 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia, Biphenotypic, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematologic Neoplasms; Leukemia

Interventions

Midazolam; Itraconazole

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Piperazines

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: June 25, 2019
• First Posted: August 26, 2019
• Study Start: September 12, 2019
• Primary Completion (Estimated): October 16, 2028
• Study Completion (Estimated): October 16, 2028
• Last Updated: May 13, 2026

Record last verified: 2026-05

Locations

IT (4); US (20); ES (7); BE (1); FR (6); CA (3); DE (2)