Efficacy of Ziftomenib Combined with Standard of Care Therapy in Patients with Untreated NPM1-Mutated or KMT2A-Rearranged Acute Myeloid Leukemia
- Trial ID
- 2025-521314-25-00
- Protocol
- KO-MEN-017
- Sponsor
- Kura Oncology Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the therapeutic impact of ziftomenib in combination with different standard of care regimens for patients with untreated acute myeloid leukemia. In the nonintensive therapy arm, the study aims to assess the effect of ziftomenib combined with venetoclax and azacitidine on patient survival in cases of NPM1 mutated disease. In the intensive therapy arm, the study evaluates the effect of ziftomenib combined with 7+3 therapy on event-free survival in patients with untreated NPM1 mutated or KMT2A rearranged disease.
The secondary objectives include:
- Determination of efficacy for ziftomenib in combination with venetoclax and azacitidine in untreated NPM1 mutated disease.
- Assessment of minimal residual disease negativity rates in the nonintensive therapy group.
- Evaluation of complete remission or complete remission with partial hematologic recovery as additional efficacy measures in the nonintensive therapy arm.
- Determination of efficacy for ziftomenib in combination with 7+3 therapy in untreated NPM1 mutated disease.
- Evaluation of the effect of ziftomenib combined with 7+3 therapy on overall survival in patients with untreated NPM1 mutated or KMT2A rearranged disease.
Participants
This study involves 601 participants diagnosed with Acute Myeloid Leukemia. The population includes both male and female patients aged 18 years or older. Eligible participants are those with documented NPM1-m or KMT2A-r mutations according to the 2022 WHO Classification. The study consists of two distinct cohorts: a nonintensive therapy group and an intensive therapy group. The nonintensive cohort includes patients considered ineligible for intensive chemotherapy due to age or specific comorbidities, such as a congestive heart failure history, reduced lung capacity, or renal impairment. The intensive therapy cohort comprises patients fit for intensive treatment with specific requirements regarding FLT3 status and cardiac ejection fraction. Participants must demonstrate adequate hepatic and renal function and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. The study also includes individuals with therapy-related or secondary leukemia. Strict contraception requirements are mandatory for all participants during and after the treatment period.
Plans and Procedures
This Phase 3, randomized, double-blind, placebo-controlled study evaluates the efficacy of ziftomenib in combination with different standard of care regimens for patients with untreated acute myeloid leukemia characterized by NPM1 mutations or KMT2A rearrangements. The research methodology is divided into two distinct study arms: a nonintensive therapy study and an intensive therapy study. In the nonintensive arm, ziftomenib is administered alongside venetoclax and azacitidine to assess overall survival. The intensive arm utilizes ziftomenib in combination with 7+3 therapy, consisting of cytarabine and daunorubicin hydrochloride, to evaluate event-free survival. The clinical trial process begins with a screening visit to confirm diagnosis and eligibility based on genetic profiles and organ function. Following successful screening, participants are randomized to receive either the investigational combination or a placebo. The study involves continuous monitoring through follow-up assessments to track clinical endpoints such as complete remission and minimal residual disease negativity. The estimated period for study recruitment and completion spans from March 2026 to September 2030. Early termination of study participation may occur based on investigator discretion or clinical requirements.
Treatment
Ziftomenib is administered as a hard capsule via the oral route.
Venetoclax is administered via oral use at a dosage of 400 mg.
Azacitidine is administered via intravenous use at a dosage of 75 mg/m2.
Cytarabine is administered via intravenous use at dosages of 200 mg/m2 or 6000 mg/m2.
Daunorubicin hydrochloride is provided as a solution for injection/infusion for intravenous use at a dosage of 60 mg/m2.
A placebo is utilized as a non-experimental comparator.
Efficacy
Efficacy assessment for the nonintensive therapy study is focused on overall survival. Secondary endpoints include the complete remission rate, complete remission with incomplete hematologic recovery rate, and the percentage of patients achieving centrally defined bone marrow measurable residual disease negativity, as determined by ELN 2022 criteria through investigator assessment.
For the intensive therapy study, efficacy is evaluated using event-free survival, which is defined as the time from randomization to treatment failure, hematologic relapse following complete remission, or death from any cause. Secondary endpoints for this study include overall survival and the percentage of patients achieving complete remission per ELN 2022 criteria with centrally defined bone marrow measurable residual disease negativity.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥18 years at time of signing the informed consent form (ICF).
- Diagnosis of AML per the 2022 WHO Classification of Hematolymphoid Tumors (5th Edition).
- Patients with therapy-related AML (t-AML) or secondary AML (prior myelodysplastic syndrome [MDS] or myeloproliferative neoplasm [MPN]) are eligible. 1. Note: Prior MDS eligibility requires that at the time of MDS diagnosis the patient did not have evidence of either NPM1-m or KMT2A-r (now classified as AML by WHO 5th Edition).
- Patients with prior MDS who have received a single line of treatment with single agent HMA, lenalidomide, luspatercept, or imetelstat are eligible.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
- Adequate liver function defined as: •AST <5×upper limit of normal (ULN), and •ALT <5×ULN, and • Total bilirubin <1.5×ULN (except for patients with known Gilbert’s syndrome or presumed leukemic involvement). Note: If the patient does not meet this criterion but the liver function abnormalities are presumed to be due to AML, this may be discussed with the Medical Monitor to determine eligibility.
- Adequate renal function defined by calculated creatinine clearance ≥30 mL/min (according to the 2021 Chronic Kidney Disease Epidemiology-Collaboration [CKD-EPI] creatinine equation).
- If the patient has comorbid illness, life expectancy attributed to this other condition(s) must be greater than 2 years in the opinion of the Investigator.
- Patient agrees to the following contraception requirements: a. A male patient is eligible to participate if they agree to the following during the study treatment period and for 180 days after the last dose of study treatment: • Refrain from donating sperm. plus, either: • Be abstinent from intercourse where pregnancy can occur (abstinent on a long term and persistent basis) and agree to remain abstinent. or • Agree to use highly effective contraception plus barrier as follows: o Use an external condom (barrier) with female partner of childbearing potential using additional highly effective contraceptive method with a failure rate of <1% per year as described in Appendix 2 when having sexual intercourse with a partner able to give birth who is not currently pregnant. plus o Use an external condom when engaging in any activity that allows for passage of ejaculate to another person. b. A female patient is eligible to participate if not pregnant or breastfeeding, and one of the following conditions applies: • Is of nonchildbearing potential as defined in Appendix 2. or • Is of childbearing potential as defined in Appendix 2 and agrees to the following during the study treatment period and for 180 days after the last dose of study treatment: o Agrees to use a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, as described in Appendix 2 in addition to male partner either using an external condom (barrier) or male partner confirmed azoospermic. plus o Agrees not to donate eggs (ova, oocytes) for the purpose of reproduction. Note: The Investigator should evaluate the potential for contraceptive method failure (eg, noncompliance or recently started) in relationship to the first dose of study treatment.
- Patients must be able to understand and provide informed consent, understand protocol requirements, and be willing to comply with study requirements, in the opinion of the Investigator.
- NONINTENSIVE THERAPY STUDY ONLY (VEN+AZA): a. Documented NPM1-m. b. Patients considered ineligible for IC defined by the following i. Age ≥75, OR ii. Age <75 and unfit for IC. Must meet one of these comorbidity exceptions which prevents them from being treated with IC: 1. ECOG performance status of 2, or 2. Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction of ≤50% or chronic stable angina, or 3. Diffusing capacity of the lungs for carbon monoxide ≤65% or forced expiratory volume in 1 second ≤65%, or 4. Creatinine clearance <45 mL/min and >30 mL/min, or 5.Moderate hepatic impairment with total bilirubin 1.5 to 3.0×ULN, not related to AML involvement or Gilbert’s syndrome, or 6. Other comorbidities that, in the opinion of the Investigator, cause the patient to be incompatible with IC (prior approval by the Medical Monitor is required before enrollment).
- INTENSIVE THERAPY STUDY ONLY (7+3): a. Documented NPM1-m or KMT2A-r (patients with a partial tandem duplication [PTD] are not eligible). b. Documented FLT3 wild-type or ITD ratio <0.05 OR ineligible to receive FLT3 targeted therapy (medically ineligible or mutation in which FLT3 inhibition is not SOC). Lack of access to an FLT3 inhibitor is not considered “ineligible” for FLT3 targeted therapy. c. Ejection fraction of >50% by transthoracic echocardiogram (ECHO) or multigated acquisition scan (MUGA). d. Fit for IC per Investigator opinion.
Exclusion Criteria
- Diagnosis of either acute promyelocytic leukemia (APL), blast phase chronic myeloid leukemia, or isolated myeloid sarcoma. Note: Patients with myeloid sarcoma in addition to BM disease are eligible.
- Known history of BCR-ABL mutation.
- History of other active concurrent malignancies prior to study entry except: • Basal cell skin cancer or localized squamous cell cancer of the skin • Previous malignancy confined and locally resected (or treated with other modalities) with curative intent • Prostate or breast cancer receiving adjuvant hormonal therapy (see Section 7.5.1 for permitted medications)
- Active central nervous system (CNS) involvement by AML. Note: Those patients with evidence of CNS AML involvement at baseline/screening now controlled (cerebrospinal fluid [CSF] cleared and no symptoms) with intrathecal chemotherapy or those who are at high risk of developing CNS disease (including KMT2A-r, high white blood cells [WBC], high lactate dehydrogenase [LDH], presence of extramedullary disease [EMD]) may continue to receive intrathecal chemotherapy as treatment or prophylaxis, respectively, as per institutional practice.
- Clinical signs/symptoms of leukostasis or WBC >25×109/L prior to start of ziftomenib/placebo. Note: Hydroxyurea and/or leukapheresis are permitted to meet this criterion. Cytotoxic therapy in addition to the SOC protocol backbones (7+3 or ven+aza) is not permitted to manage leukocytosis.
- Prior therapy for AML (except hydroxyurea or leukapheresis for WBC control). Patients may have received ATRA if there is an early suspicion of APL. Patients with a confirmed diagnosis of APL are not eligible.
- Prior ven+HMA therapy, isocitrate dehydrogenase 1 inhibitor, or intensive chemotherapy for MDS. Note: Prior MDS treatment with either single agent HMA, lenalidomide, luspatercept, or imetelstat is allowed. Any of these agents for prior MDS treatment must have been discontinued ≥14 days prior to Cycle 1 Day 1.
- Known uncontrolled HIV infection or known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Viral serologies for HIV, HBV, HCV are not required. However, for patients with a known medical history of HIV/HBV/HCV infection, an undetectable viral load must be confirmed. Patients with serologic evidence of prior vaccination to HBV (HBV surface antigen negative and anti-HBV surface antibody positive) may participate.
- Any other significant ongoing medical condition, including psychiatric illness or laboratory abnormality, that would preclude the patient from participating in the study or would confound the interpretation of the results of the study in the opinion of the Investigator.
- Diagnosis with any of the following per Investigator opinion: uncontrolled intercurrent illness including but not limited: • Symptomatic CHF • Unstable angina pectoris • Serious cardiac arrhythmia • Myocardial infarction with evidence of residual abnormalities within 6 months prior to enrollment (troponin leak alone not included if no residual dysfunction) • New York Heart Association Class III or IV heart failure • Severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia • Mean QTcF >480 ms on triplicate ECGs Note: If a patient has bundle branch block or QRS >120 ms, the QTcF must be either calculated by cardiology, calculated using a QTc calculator (eg, the Mayo Clinic QTc calculator [https://www.mayoclinic.org/medical-professionals/cardiovascular-diseases/calculators/corrected-qt-interval-qtc-calculator/itt-20487211]), or calculated using the Boghossian simplified formula (QTc=QT-0.5*QRS).
- Diagnosis of an uncontrolled infection. Note: Patients with an active infection may be eligible provided that the infection is controlled by appropriate antimicrobial therapy in the opinion of the Investigator.
- Known severe hypersensitivity to the product or similar chemical structure and class to the study drugs evaluated in this study or 1 of the active or inactive excipients.
- Women who are pregnant or breastfeeding.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 02 Mar 2026 | 49 |
 Czechia | Recruiting | 02 Mar 2026 | 40 |
 France | Recruiting | 02 Mar 2026 | 136 |
 Germany | Recruiting | 02 Mar 2026 | 84 |
 Greece | Recruiting | 02 Mar 2026 | 42 |
 Hungary | Recruiting | 02 Mar 2026 | 40 |
 Italy | Recruiting | 02 Mar 2026 | 144 |
 Poland | Recruiting | 02 Mar 2026 | 40 |
 Portugal | Recruiting | 02 Mar 2026 | 32 |
 Spain | Recruiting | 02 Mar 2026 | 112 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Ziftomenib Placebo | Placebo | N/A | — | — | — | N/A |
CYTARABINE | Test | — | INTRAVENOUS USE | 6000 | 4 | SUB06880MIG |
VENETOCLAX | Test | — | ORAL USE | 400 | 24 | SUB176260 |
AZACITIDINE | Test | — | INTRAVENOUS USE | 75 | 24 | SUB05624MIG |
VENETOCLAX | Test | — | ORAL USE | 400 | 24 | SUB176260 |
Daunoblastin® 20 mg Pulver zur Herstellung einer Infusions- oder Injektionslösung | Test | PULVER ZUR HERSTELLUNG EINER INFUSIONS- ODER INJEKTIONSLÖSUNG | INTRAVENOUS USE | 60 | 2 | PRD11829093 |
Ziftomenib | Test | CAPSULE, HARD | ORAL | 0 | 24 | PRD8079333 |
VENETOCLAX | Test | — | ORAL USE | 400 | 24 | SUB176260 |
CYTARABINE | Test | — | INTRAVENOUS USE | 200 | 2 | SUB06880MIG |