Bleximenib with standard induction/consolidation chemotherapy followed by maintenance for newly diagnosed AML with NPM1 or KMT2A changes

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

This trial will test whether adding bleximenib to standard chemotherapy and maintenance helps adults with newly diagnosed AML who have NPM1 mutations or KMT2A rearrangements.

Quick facts

• Phase: PHASE3
• Study type: Interventional
• Enrollment: 875 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Stichting Hemato-Oncologie voor Volwassenen Nederland (other)
• Drugs / interventions: chemotherapy
• Locations: 8 sites (Cincinnati, Ohio and 7 other locations)
• Trial ID: NCT07223814 on ClinicalTrials.gov

What this trial studies

This is a randomized, double-blind, placebo-controlled Phase 3 trial in adults with newly diagnosed AML harboring NPM1 mutations or KMT2A rearrangements. All participants receive standard intensive induction and consolidation chemotherapy (cytarabine plus daunorubicin or idarubicin) and are randomized to receive either bleximenib or matching placebo, followed by maintenance with the assigned drug. Bleximenib is a menin inhibitor designed to disrupt menin–KMT2A interactions that drive leukemia in these genetic subtypes. The trial is conducted at multiple centers in the US, Germany, and the Netherlands and enrolls patients eligible for intensive chemotherapy.

Who should consider this trial

Good fit: Adults (≥18) with newly diagnosed AML carrying NPM1 mutations or KMT2A rearrangements who are eligible for intensive chemotherapy, have ECOG ≤2, and adequate liver and kidney function are the intended participants.

Not a fit: Patients without the specified NPM1 or KMT2A genetic changes, those who have received prior AML therapy, have active CNS leukemic involvement, recent major cardiac events, or a history of solid organ transplant are unlikely to benefit or be eligible.

Why it matters

Potential benefit: If successful, adding bleximenib could increase remission rates and extend survival for adults with NPM1-mutant or KMT2A-rearranged AML.

How similar studies have performed: Early-phase studies of menin inhibitors, including bleximenib and related agents, have shown promising activity in NPM1-mutant and KMT2A-rearranged AML, but definitive phase 3 results are still needed.

Eligibility criteria

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.

Where this trial is running

Cincinnati, Ohio and 7 other locations

• US-Cincinnati OH-CINCY — Cincinnati, Ohio, United States (RECRUITING)
• DE-Ulm-UNIKLINKULM — Ulm, Germany (RECRUITING)
• NL-Breda-AMPHIA — Breda, Netherlands (RECRUITING)
• NL-Eindhoven-MAXIMAMC — Eindhoven, Netherlands (RECRUITING)
• NL-Leeuwarden-FRISIUSMC — Leeuwarden, Netherlands (RECRUITING)
• NL-Nieuwegein-ANTONIUS — Nieuwegein, Netherlands (RECRUITING)
• NL-Rotterdam-ERASMUCMC — Rotterdam, Netherlands (RECRUITING)
• NL-Den Haag-HAGA — The Hague, Netherlands (RECRUITING)

Study contacts

• Principal investigator: M.H.G.P. Raaijmakers — Erasmus Medical Center
• Study coordinator: M.H.G.P. Raaijmakers

Conditions: Acute Myeloid Leukemia, AML, adult, newly diagnosed AML, NPM1, KMT2A