Advanced Malignant NeoplasmPhase 1/2NCT04067336
First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia
A Phase 1/2 study testing Ziftomenib, Midazolam and Itraconazole in people with Advanced Malignant Neoplasm and Acute Myeloid Leukemia, run by Kura Oncology, Inc. at 43 sites in 7 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Malignant Neoplasm, Acute Myeloid Leukemia, Mixed Lineage Leukemia
- What is being tested?
- Ziftomenib, Midazolam and Itraconazole
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 263 participants
- Where
- 43 sitesin 7 countries
- Study dates
- 12 Sep 2019to 16 Oct 2028
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Show all 16Show fewer
- 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.
- 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.
Who cannot join
- 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.
Show all 21Show fewer
- 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.
- 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.
- Mean QTcF >480 ms on triplicate ECG.
- Major surgery within 4 weeks prior to the first dose of study treatment.
- 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.
- 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.
- For sub-studies 1 and 2: Moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.
Trial locations and contacts
43 sites in 7 countries.
43 sites in 7 countries
United States20 sites
University of Michigan Hospitals
Ann Arbor, Michigan, 48109
University of Maryland Greenebaum Comprehensive Cancer Center
Baltimore, Maryland, 21201
Massachusetts General Hospital
Boston, Massachusetts, 02114
Roswell Park Comprehensive Cancer Center
Buffalo, New York, 14203
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Chicago, Illinois, 60611
Harold C. Simmons Comprehensive Cancer Center - UT Southwestern Medical Center
Dallas, Texas, 75390
Karmanos Cancer Institute
Detroit, Michigan, 48201
Duke Cancer Institute
Durham, North Carolina, 27710
Banner MD Anderson Cancer Center
Gilbert, Arizona, 85234
Hackensack University Medical Center - John Theurer Cancer Center
Hackensack, New Jersey, 07601
MD Anderson Cancer Center
Houston, Texas, 77030
Mayo Clinic
Jacksonville, Florida, 32224
UCLA Ronald Reagan Medical Center
Los Angeles, California, 90095
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, 37232
Weill Cornell Medical College - NY Presbyterian Hospital
New York, New York, 10021
The Mount Sinai Hospital
New York, New York, 10029
Oklahoma University Health - Stephenson Cancer Center
Oklahoma City, Oklahoma, 73117
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
Mayo Clinic
Rochester, Minnesota, 55905
Fred Hutchinson Cancer Research Center
Seattle, Washington, 98109
Spain7 sites
Hospital Universitari Vall d'Hebron
Barcelona, 08035
Universitat de Barcelona
Barcelona, 08035
MD Anderson Cancer Center
Madrid, 28033
Hospital Universitario HM Sanchinarro
Madrid, 28050
Hospital Universitario Central de Asturias
Oviedo, 33011
Hospital Universitario Virgen del Rocio
Seville, 41013
Hospital Universitari i Politecnic La Fe
Valencia, 46026
France6 sites
Centre Hospitalier Universitaire de Lille
Lille, 59037
Centre Hospitalier Universitaire de Nantes
Nantes, 44093
Hopital Saint Louis
Paris, 75475
Magendie Hopital Haut-Leveque
Pessac, 33600
Centre Hospitalier Lyon Sud
Pierre-Bénite, 69310
Institut Gustave Roussy
Villejuif, 94800
Italy4 sites
Institute of Hematology and Medical Oncology "L. and A. Seragnoli"
Bologna, 40138
IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"
Meldola, 47014
UO Ematologia Ospedale di Ravenna
Ravenna, 48121
Institution Fondazione Policlinico Tor Vergata
Roma
Canada3 sites
Queen Elizabeth II Health Sciences Centre
Halifax, Nova Scotia, B3H 1V7
Hopital Maisonneuve-Rosemont
Montreal, Quebec, H1T 2M4
Hopital de l'Enfant-Jesus - Centre Integre en Cancerologie du CHU de Quebec - Universite Laval
Québec, Quebec, G1J 1Z4
Germany2 sites
University Medicine Greifswald
Greifswald, 17475
Medizinische Hochsschule Hannover
Hanover, 30625
About this study
Official title: 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.
Read the detailed description
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.
- Conditions
- Advanced Malignant Neoplasm, Acute Myeloid Leukemia, Mixed Lineage Leukemia, Mixed Lineage Acute Leukemia, Acute Leukemia of Ambiguous Lineage, Mixed Phenotype Acute Leukemia
- Being tested
- Ziftomenib, Midazolam, Itraconazole
- Keywords
- AML, Hematological malignancy, KMT2A, NPM1, Menin, Leukemia, Acute Leukemia, ALL, MLL, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, MEIS1
- Medical subject headings
- Leukemia, Myeloid, Acute, Leukemia, Biphenotypic, Acute, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Hematologic Neoplasms, Leukemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ZiftomenibDrug
Also called KO-539
Oral administration
MidazolamDrug
Also called Seizalam, Hypnovel, Dormicum
Oral administration
ItraconazoleDrug
Also called Sporanox, Onmel, Tolsura
Oral administration
| Study group | Role | What they receive |
|---|---|---|
| Phase 1a - Dose Escalation | Experimental | AML patients will receive multiple doses of ziftomenib Receives: 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 Receives: Drug: Ziftomenib |
| Phase 2 | Experimental | NPM1-m R/R AML patients will receive the recommended phase 2 ziftomenib dose Receives: Drug: Ziftomenib |
| Sub-study 1 | Experimental | R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + midazolam Receives: Drug: Ziftomenib; Drug: Midazolam |
| Sub-study 2 | Experimental | R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + itraconazole Receives: 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 Receives: Drug: Ziftomenib |
| Sub-study 4 | Experimental | R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib Receives: Drug: Ziftomenib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: Timeframe: from Baseline to End of Treatment
Sub-study 3: Time to observed maximum plasma concentration (Tmax) of ziftomenib
Tmax of ziftomenib
Measured: 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
Measured: 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
Measured: 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
Measured: 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)
Assessed by NCI-CTCAE v5.0
Measured: 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
Time to observed maximum plasma concentration of ziftomenib and/or its metabolites
Measured: Cycle 1 and Cycle 2. Each cycle is 28 days.
Phase 1a: AUC(0-t)
Area under the plasma concentration-time curve from time 0 to time t of ziftomenib and/or its metabolites
Measured: Cycle 1 and Cycle 2. Each cycle is 28 days.
Phase 1a: Cmax
Maximum plasma concentration of ziftomenib and/or its metabolites
Measured: 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
To assess the CR/CRh MRD negativity
Measured: For at least 12 months following discontinuation of treatment
Phases 1a, 1b, and 2: Duration of response (DOR)
To assess the DOR, defined as the duration of CR/CRh
Measured: For at least 12 months following discontinuation of treatment
Phases 1a, 1b, and 2: Transfusion independence (TI)
To assess transfusion independence
Measured: For at least 12 months following discontinuation of treatment
Phases 1a, 1b, and 2: Overall response rate (ORR)
To assess the ORR
Measured: For at least 12 months following discontinuation of treatment
Phases 1a, 1b, and 2: Event-free survival (EFS)
To assess event-free survival
Measured: For at least 12 months following end of treatment
Phases 1a, 1b, and 2: Overall survival (OS)
To assess overall survival
Measured: For at least 12 months following end of treatment
Phases 1a, 1b, and 2: Composite complete remission (CRc)
To assess CRc
Measured: For at least 12 months following discontinuation of treatment
Phases 1b and 2: Composite complete remission (CRc) measurable residual disease (MRD) negativity
To assess the CRc MRD negativity
Measured: For at least 12 months following discontinuation of treatment
Phases 1b and 2: Overall response rate (ORR) measurable residual disease (MRD) negativity
To assess the ORR MRD negativity
Measured: For at least 12 months following discontinuation of treatment
Sub-study 2: Corrected QT (QTc) intervals
Assessed by QTc intervals
Measured: During Cycle 1
Sub-study 3: Complete remission (CR) measurable residual disease (MRD) negativity
To assess the CR MRD negativity
Measured: For at least 12 months following discontinuation of treatment
Sub-studies 3 and 4: Composite complete remission (CRc)
To assess CRc
Measured: For at least 12 months following discontinuation of treatment
Sub-study 3: Duration of response (DOR)
To assess the DOR, defined as the duration of CR
Measured: For at least 12 months following discontinuation of treatment
Sub-studies 3 and 4: Overall survival (OS)
To assess overall survival
Measured: For at least 12 months following discontinuation of treatment
Sub-studies 3 and 4: Event-free survival (EFS)
To assess event-free survival
Measured: For at least 12 months following discontinuation of treatment
Sub-study 4: Transfusion independence (TI)
To assess transfusion independence
Measured: For at least 12 months following discontinuation of treatment
Sub-studies 3 and 4: Overall response rate (ORR) measurable residual disease (MRD) negativity
To assess the ORR MRD negativity
Measured: For at least 12 months following discontinuation of treatment
Sub-study 4: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs)
Assessed by NCI-CTCAE v5.0
Measured: 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 4: Duration of response (DOR)
To assess the DOR, defined as the duration of CR/CRh
Measured: For at least 12 months following discontinuation of treatment
Sub-study 4: Time to observed maximum plasma concentration (Tmax) of ziftomenib
Tmax of ziftomenib and its metabolites
Measured: Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards
Sub-study 4: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib
AUC0-t of ziftomenib and its metabolites
Measured: Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards
Sub-study 4: Maximum plasma concentration (Cmax) of ziftomenib
Cmax of ziftomenib and its metabolites
Measured: Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Aug 2019
- Study start12 Sep 2019
- Primary completion16 Oct 2028 (estimated)
- Study completion16 Oct 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Advanced Malignant NeoplasmStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 263 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Kura Oncology, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04067336
- Sponsor's protocol ID
- KO-MEN-001
- Status last verified
- May 2026
- First submitted
- 25 Jun 2019
- Last updated
- 13 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
- Expanded access
- Available
Publications
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.
PubMed 40997296Wang 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.
PubMed 39362248Sasca 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.
PubMed 34267079Jimenez 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.
PubMed 33741715
Study at a glance
From the registry record, last updated by the sponsor on 13 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT04067336
- Acronym / sponsor ID
- KO-MEN-001
- Conditions
- Advanced Malignant Neoplasm, Acute Myeloid Leukemia, Mixed Lineage Leukemia, Mixed Lineage Acute Leukemia, Acute Leukemia of Ambiguous Lineage, Mixed Phenotype Acute Leukemia
- Keywords
- AML, Hematological malignancy, KMT2A, NPM1, Menin, Leukemia, Acute Leukemia, ALL
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 263 participants (estimated)
- Lead sponsor
- Kura Oncology, Inc.Industry (pharma, biotech, devices)
- Study start
- 12 Sep 2019 (actual)
- Primary completion
- 16 Oct 2028 (estimated)
- Study completion
- 16 Oct 2028 (estimated)
- First posted
- 26 Aug 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| Phase 1a - Dose Escalation | Experimental | Drug: ZiftomenibAML patients will receive multiple doses of ziftomenib |
| Phase 1b - Dose-Validation Expansion | Experimental | Drug: ZiftomenibCohort 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 | Experimental | Drug: ZiftomenibNPM1-m R/R AML patients will receive the recommended phase 2 ziftomenib dose |
| Sub-study 1 | Experimental | Drug: Ziftomenib, Drug: MidazolamR/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + midazolam |
| Sub-study 2 | Experimental | Drug: Ziftomenib, Drug: ItraconazoleR/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + itraconazole |
| Sub-study 3 | Experimental | Drug: ZiftomenibPart 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 | Experimental | Drug: ZiftomenibR/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- 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:
- Phase 2:
- Sub-studies:
- ≥ 18 years of age.
Key exclusion criteria (21 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ZiftomenibAlso: KO-539Oral administration | Drug | Phase 1a - Dose Escalation, Phase 1b - Dose-Validation Expansion, Phase 2, Sub-study 1, Sub-study 2, Sub-study 3, Sub-study 4 |
| MidazolamAlso: Seizalam, Hypnovel, DormicumOral administration | Drug | Sub-study 1 |
| ItraconazoleAlso: Sporanox, Onmel, TolsuraOral administration | Drug | Sub-study 2 |
Primary outcome
Phase 1a: Maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D)
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: For at least 12 months following end of treatment
Assessed by CR
Sub-study 3: Change in Eastern Cooperative Oncology Group (ECOG) status
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: For at least 12 months following end of treatment
To assess the CR+CRh rate
26 secondary outcomes
Phase 1a and 2: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: 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
Time frame: Cycle 1 and Cycle 2. Each cycle is 28 days.
Phase 1a: AUC(0-t)
Time frame: Cycle 1 and Cycle 2. Each cycle is 28 days.
Phase 1a: Cmax
Time frame: 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
Time frame: For at least 12 months following discontinuation of treatment
Phases 1a, 1b, and 2: Duration of response (DOR)
Time frame: For at least 12 months following discontinuation of treatment
Phases 1a, 1b, and 2: Transfusion independence (TI)
Time frame: For at least 12 months following discontinuation of treatment
Phases 1a, 1b, and 2: Overall response rate (ORR)
Time frame: For at least 12 months following discontinuation of treatment
Phases 1a, 1b, and 2: Event-free survival (EFS)
Time frame: For at least 12 months following end of treatment
Phases 1a, 1b, and 2: Overall survival (OS)
Time frame: For at least 12 months following end of treatment
Phases 1a, 1b, and 2: Composite complete remission (CRc)
Time frame: For at least 12 months following discontinuation of treatment
Phases 1b and 2: Composite complete remission (CRc) measurable residual disease (MRD) negativity
Time frame: For at least 12 months following discontinuation of treatment
Phases 1b and 2: Overall response rate (ORR) measurable residual disease (MRD) negativity
Time frame: For at least 12 months following discontinuation of treatment
Sub-study 2: Corrected QT (QTc) intervals
Time frame: During Cycle 1
Sub-study 3: Complete remission (CR) measurable residual disease (MRD) negativity
Time frame: For at least 12 months following discontinuation of treatment
Sub-studies 3 and 4: Composite complete remission (CRc)
Time frame: For at least 12 months following discontinuation of treatment
Sub-study 3: Duration of response (DOR)
Time frame: For at least 12 months following discontinuation of treatment
Sub-studies 3 and 4: Overall survival (OS)
Time frame: For at least 12 months following discontinuation of treatment
Sub-studies 3 and 4: Event-free survival (EFS)
Time frame: For at least 12 months following discontinuation of treatment
Sub-study 4: Transfusion independence (TI)
Time frame: For at least 12 months following discontinuation of treatment
Sub-studies 3 and 4: Overall response rate (ORR) measurable residual disease (MRD) negativity
Time frame: For at least 12 months following discontinuation of treatment
Sub-study 4: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: 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 4: Duration of response (DOR)
Time frame: For at least 12 months following discontinuation of treatment
Sub-study 4: Time to observed maximum plasma concentration (Tmax) of ziftomenib
Time frame: Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards
Sub-study 4: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib
Time frame: Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards
Sub-study 4: Maximum plasma concentration (Cmax) of ziftomenib
Time frame: Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 May 2026.
- Derived from this study: PubMed 40997296Wang 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.
- Derived from this study: PubMed 39362248Wang 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.
- Derived from this study: PubMed 34267079Sasca 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.
- Derived from this study: PubMed 33741715Jimenez 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.
- Individual participant dataSharing planned: Undecided
Related trials for Advanced Malignant Neoplasm
RecruitingPhase 1/2
A Study of Neladalkib (NVL-655) in Patients With Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1)
Locally Advanced Solid Tumor, Metastatic Solid Tumor
RecruitingPhase 1
Modified FOLFIRINOX and Pentamidine in Advanced and Metastatic Pancreatic Cancer
Pancreatic Ductal Adenocarcinoma (PDAC)
Active, not recruitingPhase 2
Testing AZD5363 as a Potential Targeted Treatment in Cancers With AKT Genetic Changes (MATCH-Subprotocol Y)
Advanced Lymphoma, Advanced Malignant Solid Neoplasm
RecruitingPhase 1/2
Phase 1/2 Study of DS010 in Advanced Cancer Patients With Cachexia
Cancer, Cachexia
Not yet recruitingPhase 1
A Study to Assess the Pharmacokinetics and Safety of Revumenib in Participants With Advanced Cancer and Hepatic or Renal Impairment
Relapsed/Refractory (R/R) Hematologic Malignancies, Acute Leukemia
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
43 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Ziftomenib, Midazolam and Itraconazole in people with Advanced Malignant Neoplasm and Acute Myeloid Leukemia, run by Kura Oncology, Inc. at 43 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 13 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 43 sites in United States, Spain, France, Italy, Canada and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase 1a: Maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) (time frame: Dose Limiting Toxicities (DLTs) will be evaluated during the first 28 days (1 cycle)). The study lists 17 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04067336, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 May 2026.