First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia
NCT ID: NCT04067336
Last Updated: 2025-11-10
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE1/PHASE2
263 participants
INTERVENTIONAL
2019-09-12
2028-10-16
Brief Summary
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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.
Detailed Description
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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.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Phase 2
NPM1-m R/R AML patients will receive the recommended phase 2 ziftomenib dose
Ziftomenib
Oral administration
Sub-study 1
R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + midazolam
Ziftomenib
Oral administration
Midazolam
Oral administration
Sub-study 2
R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + itraconazole
Ziftomenib
Oral administration
Itraconazole
Oral administration
Sub-study 3
Part 1a: KMT2A-r R/R ALL patients will receive multiple ziftomenib doses
Part 1b: KMT2A-r R/R ALL patients will receive ziftomenib
Ziftomenib
Oral administration
Sub-study 4
R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib
Ziftomenib
Oral administration
Phase 1a - Dose Escalation
AML patients will receive multiple doses of ziftomenib
Ziftomenib
Oral administration
Phase 1b - Dose-Validation Expansion
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
Ziftomenib
Oral administration
Interventions
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Ziftomenib
Oral administration
Midazolam
Oral administration
Itraconazole
Oral administration
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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.
Exclusion Criteria
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.
18 Years
ALL
No
Sponsors
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Kura Oncology, Inc.
INDUSTRY
Responsible Party
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Locations
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Banner MD Anderson Cancer Center
Gilbert, Arizona, United States
Mayo Clinic
Phoenix, Arizona, United States
University of Southern California
Los Angeles, California, United States
UCLA Ronald Reagan Medical Center
Los Angeles, California, United States
Mayo Clinic
Jacksonville, Florida, United States
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Chicago, Illinois, United States
Indiana University Melvin and Bren Simon Comprehensive Cancer Center
Indianapolis, Indiana, United States
University of Maryland Greenebaum Comprehensive Cancer Center
Baltimore, Maryland, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
University of Michigan Hospitals
Ann Arbor, Michigan, United States
Karmanos Cancer Institute
Detroit, Michigan, United States
Mayo Clinic
Rochester, Minnesota, United States
Hackensack University Medical Center - John Theurer Cancer Center
Hackensack, New Jersey, United States
Roswell Park Comprehensive Cancer Center
Buffalo, New York, United States
Weill Cornell Medical College - NY Presbyterian Hospital
New York, New York, United States
The Mount Sinai Hospital
New York, New York, United States
Duke Cancer Institute
Durham, North Carolina, United States
Oklahoma University Health - Stephenson Cancer Center
Oklahoma City, Oklahoma, United States
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States
Harold C. Simmons Comprehensive Cancer Center - UT Southwestern Medical Center
Dallas, Texas, United States
MD Anderson Cancer Center
Houston, Texas, United States
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States
UZ Brussel
Jette, , Belgium
AZ Delta - Campus Rumbeke
Roeselare, , Belgium
CHU UCL Namur
Yvoir, , Belgium
Queen Elizabeth II Health Sciences Centre
Halifax, Nova Scotia, Canada
McMaster University Juravinski Cancer Centre
Hamilton, Ontario, Canada
Hopital Maisonneuve-Rosemont
Montreal, Quebec, Canada
Hopital de l'Enfant-Jesus - Centre Integre en Cancerologie du CHU de Quebec - Universite Laval
Québec, Quebec, Canada
Centre Hospitalier Universitaire de Lille
Lille, , France
Centre Hospitalier Universitaire de Nantes
Nantes, , France
Hopital Saint Louis
Paris, , France
Magendie Hopital Haut-Leveque
Pessac, , France
Centre Hospitalier Lyon Sud
Pierre-Bénite, , France
Institut Gustave Roussy
Villejuif, , France
Charitè-Campus Benjamin Franklin
Berlin, , Germany
University Medicine Greifswald
Greifswald, , Germany
Medizinische Hochsschule Hannover
Hanover, , Germany
Johannes Gutenberg - University Mainz
Mainz, , Germany
Institute of Hematology and Medical Oncology "L. and A. Seragnoli"
Bologna, , Italy
IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"
Meldola, , Italy
UO Ematologia Ospedale di Ravenna
Ravenna, , Italy
Institution Fondazione Policlinico Tor Vergata
Roma, , Italy
Nasz Lekarz Przychodnie Medyczne
Torun, , Poland
Hospital Universitari Vall d'Hebron
Barcelona, , Spain
Universitat de Barcelona
Barcelona, , Spain
MD Anderson Cancer Center
Madrid, , Spain
Hospital Universitario HM Sanchinarro
Madrid, , Spain
Hospital Universitario Central de Asturias
Oviedo, , Spain
Hospital Universitario Virgen del Rocio
Seville, , Spain
Hospital Universitari i Politecnic La Fe
Valencia, , Spain
Cardiff and Vale University
Cardiff, , United Kingdom
Beatson West of Scotland Cancer Centre
Glasgow, , United Kingdom
Barts Health NHS Trust
London, , United Kingdom
St. George's Hospital
London, , United Kingdom
Countries
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Central Contacts
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Facility Contacts
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Role: primary
Bruck Habtemariam
Role: primary
Role: primary
Larissa Sanglard, MD
Role: primary
Christine Connolly
Role: primary
Role: primary
Emily Tolksdorf
Role: primary
Celina Joco Melendez
Role: primary
Role: primary
Tina Czaplinska
Role: primary
Silas Day
Role: primary
Felicia Kass
Role: primary
Yasmeen Akhtar, MBBS,MS,CCRP
Role: primary
Rachel Abramowicz
Role: primary
Kaysey Orlowski
Role: primary
References
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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.
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.
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.
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.
Other Identifiers
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KO-MEN-001
Identifier Type: -
Identifier Source: org_study_id