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
1 other identifier
interventional
263
9 countries
56
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Sep 2019
Longer than P75 for phase_1
56 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
June 25, 2019
CompletedFirst Posted
Study publicly available on registry
August 26, 2019
CompletedStudy Start
First participant enrolled
September 12, 2019
CompletedPrimary Completion
Last participant's last visit for primary outcome
October 16, 2028
ExpectedStudy Completion
Last participant's last visit for all outcomes
October 16, 2028
April 21, 2026
April 1, 2026
9.1 years
June 25, 2019
April 17, 2026
Conditions
Keywords
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
- +21 more secondary outcomes
Study Arms (7)
Phase 1a - Dose Escalation
EXPERIMENTALAML patients will receive multiple doses of ziftomenib
Phase 1b - Dose-Validation Expansion
EXPERIMENTALCohort 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
Phase 2
EXPERIMENTALNPM1-m R/R AML patients will receive the recommended phase 2 ziftomenib dose
Sub-study 1
EXPERIMENTALR/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + midazolam
Sub-study 2
EXPERIMENTALR/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + itraconazole
Sub-study 3
EXPERIMENTALPart 1a: KMT2A-r R/R ALL patients will receive multiple ziftomenib doses Part 1b: KMT2A-r R/R ALL patients will receive ziftomenib
Sub-study 4
EXPERIMENTALR/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib
Interventions
Oral administration
Eligibility Criteria
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.
- +1 more criteria
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.
- +6 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (56)
Banner MD Anderson Cancer Center
Gilbert, Arizona, 85234, United States
Mayo Clinic
Phoenix, Arizona, 85054, United States
University of Southern California
Los Angeles, California, 90033, United States
UCLA Ronald Reagan Medical Center
Los Angeles, California, 90095, United States
Mayo Clinic
Jacksonville, Florida, 32224, United States
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Chicago, Illinois, 60611, United States
Indiana University Melvin and Bren Simon Comprehensive Cancer Center
Indianapolis, Indiana, 46202, United States
University of Maryland Greenebaum Comprehensive Cancer Center
Baltimore, Maryland, 21201, United States
Massachusetts General Hospital
Boston, Massachusetts, 02114, United States
University of Michigan Hospitals
Ann Arbor, Michigan, 48109, United States
Karmanos Cancer Institute
Detroit, Michigan, 48201, United States
Mayo Clinic
Rochester, Minnesota, 55905, United States
Hackensack University Medical Center - John Theurer Cancer Center
Hackensack, New Jersey, 07601, United States
Roswell Park Comprehensive Cancer Center
Buffalo, New York, 14203, United States
Weill Cornell Medical College - NY Presbyterian Hospital
New York, New York, 10021, United States
The Mount Sinai Hospital
New York, New York, 10029, United States
Duke Cancer Institute
Durham, North Carolina, 27710, United States
Oklahoma University Health - Stephenson Cancer Center
Oklahoma City, Oklahoma, 73117, United States
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232, United States
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, 37232, United States
Harold C. Simmons Comprehensive Cancer Center - UT Southwestern Medical Center
Dallas, Texas, 75390, United States
MD Anderson Cancer Center
Houston, Texas, 77030, United States
Fred Hutchinson Cancer Research Center
Seattle, Washington, 98109, United States
UZ Brussel
Jette, 1090, Belgium
AZ Delta - Campus Rumbeke
Roeselare, 8800, Belgium
CHU UCL Namur
Yvoir, 5530, Belgium
Queen Elizabeth II Health Sciences Centre
Halifax, Nova Scotia, B3H 1V7, Canada
McMaster University Juravinski Cancer Centre
Hamilton, Ontario, L8V 5C2, Canada
Hopital Maisonneuve-Rosemont
Montreal, Quebec, H1T 2M4, Canada
Hopital de l'Enfant-Jesus - Centre Integre en Cancerologie du CHU de Quebec - Universite Laval
Québec, Quebec, G1J 1Z4, Canada
Centre Hospitalier Universitaire de Lille
Lille, 59037, France
Centre Hospitalier Universitaire de Nantes
Nantes, 44093, France
Hopital Saint Louis
Paris, 75475, France
Magendie Hopital Haut-Leveque
Pessac, 33600, France
Centre Hospitalier Lyon Sud
Pierre-Bénite, 69310, France
Institut Gustave Roussy
Villejuif, 94800, France
Charitè-Campus Benjamin Franklin
Berlin, 12203, Germany
University Medicine Greifswald
Greifswald, 17475, Germany
Medizinische Hochsschule Hannover
Hanover, 30625, Germany
Johannes Gutenberg - University Mainz
Mainz, 55131, Germany
Institute of Hematology and Medical Oncology "L. and A. Seragnoli"
Bologna, 40138, Italy
IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"
Meldola, 47014, Italy
UO Ematologia Ospedale di Ravenna
Ravenna, 48121, Italy
Institution Fondazione Policlinico Tor Vergata
Roma, Italy
Nasz Lekarz Przychodnie Medyczne
Torun, 87-100, Poland
Hospital Universitari Vall d'Hebron
Barcelona, 08035, Spain
Universitat de Barcelona
Barcelona, 08035, Spain
MD Anderson Cancer Center
Madrid, 28033, Spain
Hospital Universitario HM Sanchinarro
Madrid, 28050, Spain
Hospital Universitario Central de Asturias
Oviedo, 33011, Spain
Hospital Universitario Virgen del Rocio
Seville, 41013, Spain
Hospital Universitari i Politecnic La Fe
Valencia, 46026, Spain
Cardiff and Vale University
Cardiff, CF14 4XW, United Kingdom
Beatson West of Scotland Cancer Centre
Glasgow, G12 0YN, United Kingdom
Barts Health NHS Trust
London, EC1A 7BE, United Kingdom
St. George's Hospital
London, SW17 0QT, United Kingdom
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: 40997296DERIVEDWang 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. Erratum In: Lancet Oncol. 2024 Nov;25(11):e542. doi: 10.1016/S1470-2045(24)00584-9.
PMID: 39362248DERIVEDSasca 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: 34267079DERIVEDJimenez 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: 33741715DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Central Study Contacts
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
April 21, 2026
Record last verified: 2026-04