Bleximenib in Combination With Standard Induction and Consolidation Therapy Followed by Maintenance for Treatment of Patients With Acute Myeloid Leukemia (AML)

Bleximenib or Placebo in Combination With Standard Induction and Consolidation Therapy Followed by Maintenance for the Treatment of Patients With Newly Diagnosed KMT2A-rearranged or NPM1-mutant Acute Myeloid Leukemia Eligible for Intensive Chemotherapy: a Double-blind Phase 3 Study

The current standard of care treatment for adult patients with acute myeloid leukemia (AML) consists of chemotherapy and, if indicated, donor stem cell transplantation.

Bleximenib blocks the interaction between a protein called menin and another protein called KMT2A in the leukemia cells. When this interaction is disrupted in AML with mutations in the NPM1 or KMT2A gene, bleximenib can cause leukemia cells to die.

The main objective is to assess if treatment with bleximenib, when added to chemotherapy treatment will improve treatment outcome in adult participants with newly diagnosed AML who present with mutations in the NPM1 or KMT2A genes.

This is a randomized, double-blind, placebo-controlled, phase 3 clinical trial. All of the participants will receive standard chemotherapy treatment, combined with either bleximenib or a placebo. A placebo is a substance that looks like the study medicine but has no active ingredients (e.g., a sugar pill). In a double blind trial neither the participant nor the doctor know if placebo or active study drug is given.

After the end of the protocol treatment there will be an observational follow-up of 4 years from the time of inclusion of the last patient. The results of the different treatment groups will be compared.

875 previously untreated patients with AML with a specific change in the DNA of the leukemia cells (a KMT2A rearrangement or a NPM1 mutation) will be included. Participants must be 18 years or older and considered eligible for intensive chemotherapy.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Bleximenib; Drug: Cytarabine; Drug: Daunorubicin or Idarubicin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 875
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: M.H.G.P. Raaijmakers; Phone Number: 010 7033740; Email: m.h.g.raaijmakers@erasmusmc.nl

Study Locations

• Germany
  • Ulm, Germany
    • Recruiting
    • DE-Ulm-UNIKLINKULM
    • Contact: H. Döhner
• Netherlands
  • Breda, Netherlands
    • Recruiting
    • NL-Breda-AMPHIA
    • Contact: R. Fiets
  • Eindhoven, Netherlands
    • Recruiting
    • NL-Eindhoven-MAXIMAMC
    • Contact: L. Tick
  • Leeuwarden, Netherlands
    • Recruiting
    • NL-Leeuwarden-FRISIUSMC
    • Contact: B. Franken
  • Nieuwegein, Netherlands
    • Recruiting
    • NL-Nieuwegein-ANTONIUS
    • Contact: M. Söhne
  • Rotterdam, Netherlands
    • Recruiting
    • NL-Rotterdam-ERASMUCMC
    • Contact: M.H.G. Raaijmakers
  • The Hague, Netherlands
    • Recruiting
    • NL-Den Haag-HAGA
    • Contact: D. Lammeren, van-Venema
• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Recruiting
      • US-Cincinnati OH-CINCY
      • Contact: E. Curran

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. ≥18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever is greater) at the time of informed consent.
2. New diagnosis of AML (≥10% blasts in BM or peripheral blood) with mutated NPM1 or with recurring rearrangements involving KMT2A according to ICC 2022 criteria.
3. Considered eligible for intensive chemotherapy.
4. WHO/ECOG performance status ≤2.
5. Adequate renal and hepatic functions prior to randomization.

Exclusion Criteria:

1. Prior (chemo-)therapy for AML, including prior treatment with hypomethylating agents
2. Known active leukemic involvement of the central nervous system (CNS).
3. Recipient of solid organ transplant.

4. Cardiac disease:

   1. Any of the following within 6 months of randomization: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (NYHA Class III or IV), uncontrolled or symptomatic arrhythmias, stroke, or transient ischemic attack.
   2. QTc interval using Fridericia's formula (QTcF) ≥470 ms. Prolonged QTc interval associated with bundle branch block or pacemaking is permitted.
   3. Left ventricular ejection fraction (LVEF) <40% by ECHO or MUGA scan obtained within 28 days prior to the start of study treatment.
   4. Previously received cumulative dose of any combination of anthracyclines or anthracenediones of ≥500 mg/m2.
5. Chronic respiratory disease requiring supplemental oxygen.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Standard of care treatment plus bleximenib and also maintenance treatment with bleximenib; Bleximenib in combination with remission induction and consolidation therapy, followed by bleximenib maintenance therapy. Treatment will continue until PD, unacceptable toxicity or other protocol defined criteria for discontinuation (whichever comes first)	Drug: Bleximenib; Participants will receive bleximenib; Drug: Cytarabine; Participants will receive Cytarabine; Drug: Daunorubicin or Idarubicin; Participants will receive Daunorubicin or Idarubicin
Experimental: Arm 2: Standard of care treatment plus bleximenib and maintenance treatment with a placebo.; Bleximenib in combination with remission induction and consolidation therapy, followed by placebo maintenance therapy. Treatment will continue until PD, unacceptable toxicity or other protocol defined criteria for discontinuation (whichever comes first)	Drug: Bleximenib; Participants will receive bleximenib; Drug: Cytarabine; Participants will receive Cytarabine; Drug: Daunorubicin or Idarubicin; Participants will receive Daunorubicin or Idarubicin; Drug: Placebo; Participants will receive Placebo
Placebo Comparator: Arm 3: Standard of care treatment plus a placebo and maintenance treatment with a placebo.; Placebo comparator in combination with remission induction and consolidation therapy, followed by placebo maintenance therapy . Treatment will continue until PD, unacceptable toxicity or other protocol defined criteria for discontinuation (whichever comes first)	Drug: Cytarabine; Participants will receive Cytarabine; Drug: Daunorubicin or Idarubicin; Participants will receive Daunorubicin or Idarubicin; Drug: Placebo; Participants will receive Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free Survival (EFS) in adult patients with newly diagnosed NPM1m or KMT2Ar AML eligible for intensive chemotherapy	To assess if treatment with bleximenib, as compared with placebo, in combination with remission induction chemotherapy, prolongs event-free survival (EFS) measured from the time from randomization to failure to achieve CR after remission induction, hematologic relapse after achieving CR, or death, whichever occurs first.	Up to 4 years and 5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) in adult patients with newly diagnosed NPM1m or KMT2Ar AML eligible for intensive chemotherapy	To assess if treatment with bleximenib, as compared with placebo, in combination with remission induction and consolidation chemotherapy, followed by maintenance therapy, prolongs overall survival (OS) measured from randomization to death due to any cause.	Up to 7 years and 10 months
Rates of CR, CRh, CRi in adult patients with newly diagnosed NPM1m or KMT2Ar AML eligible for intensive chemotherapy	Defined as the proportion of participants achieving a given response after induction cycle 1 and after induction cycle 2.	Up to 7 years and 10 months
Prolongation of CR (DoCR) in adult patients with newly diagnosed NPM1m or KMT2Ar AML eligible for intensive chemotherapy	Defined as the time from achieving first response of CR to hematologic relapse or death from any cause, whichever occurs first.	Up to 4 years and 5 months
Percentage of participants undergoing an allo-SCT in adult patients with newly diagnosed NPM1m or KMT2Ar AML eligible for intensive chemotherapy	To assess the percentage of participants undergoing an allo-SCT as part of protocol treatment	Up to 7 years and 10 months

Collaborators and Investigators

• Sponsor: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Collaborators: German-Austrian Acute Myeloid Leukemia Study Group
• Investigators: Principal Investigator: M.H.G.P. Raaijmakers, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2026
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): December 1, 2033

Study Registration Dates

• First Submitted: October 30, 2025
• First Submitted That Met QC Criteria: October 30, 2025
• First Posted (Actual): November 3, 2025

Study Record Updates

• Last Update Posted (Actual): April 6, 2026
• Last Update Submitted That Met QC Criteria: March 31, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: adult; AML; KMT2A; NPM1; newly diagnosed AML
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Arabinonucleosides; Anthracyclines; Naphthacenes; Aminoglycosides; Cytarabine; Daunorubicin; Idarubicin
• Other Study ID Numbers: HOVON 181 AML; 2025-522767-15-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: According to the current publication policy the protocol and Statistica! Analysis Plan ( SAP) will be shared. The principal lnvestigators can be contacted for IPD sharing after the publication of the study results. According to 'HOVON sample and/or Data request Form' theHOVON director; chair of theHOVON Acute Myeloid Leukemie working group, the study PI and Coordinating lnvestigator should approve data/sample sharing.
• IPD Sharing Time Frame: After the publication of primary endpoint analysis
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No