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

Stichting Hemato-Oncologie voor Volwassenen Nederland

Status and phase: Not yet enrolling; Phase 3

Conditions: Acute Myeloid Leukemia

Treatments: Drug: Bleximenib; Drug: Placebo; Drug: Cytarabine; Drug: Daunorubicin or Idarubicin

Study type: Interventional

Funder types: Other

Identifiers

NCT07223814

HOVON 181 AML

2025-522767-15-00 (EU Trial (CTIS) Number)

Details and patient eligibility

About

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.

Enrollment: 875 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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875 participants in 3 patient groups, including a placebo group

Arm 1: Standard of care treatment plus bleximenib and also maintenance treatment with bleximenib

Experimental group

Description:

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)

Treatment:

Drug: Daunorubicin or Idarubicin

Drug: Cytarabine

Drug: Bleximenib

Arm 2: Standard of care treatment plus bleximenib and maintenance treatment with a placebo.

Experimental group

Description:

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)

Treatment:

Drug: Daunorubicin or Idarubicin

Drug: Cytarabine

Drug: Placebo

Drug: Bleximenib

Arm 3: Standard of care treatment plus a placebo and maintenance treatment with a placebo.

Placebo Comparator group

Description:

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)

Treatment:

Drug: Daunorubicin or Idarubicin

Drug: Cytarabine

Drug: Placebo