RecruitingAcute Myeloid Leukemia, Adult

Revumenib in Combination With Azacitidine + Venetoclax in Patients NPM1-mutated or KMT2A-rearranged AML

Eligible age

18+ yrs

Accepts

All genders

Locations

14 states

Healthy volunteers

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About this study

Treatment of patients with newly diagnosed AML who are not eligible for intensive chemotherapy has remained an area of high unmet medical need. The combination therapy with two medicines, azacitidine and venetoclax, is the usual plan of action. This has brought significant progress in the treatment, but it nevertheless is not curative and the disease does relapse over time. Revumenib blocks a specific molecule called menin in the cell nucleus. Some types of AML are reliant on menin working properly. These are leukemia cells with a change in the DNA, i.e. a mutation in the NPM1 or KMT2A gene. Revumenib can prevent the production of these types of leukemia cells by disrupting the production of this menin. The current study investigates whether adding revumenib to the combination therapy improves the prognosis for AML patients with a mutation in the NPM1 or KMT2A gene. This is a randomized, double-blind, placebo-controlled clinical study where subjects will be treated until disease progression, or development of side effects or death. From the moment of inclusion of the last patient, there will be a 4-year observational follow-up study in order to register survival duration and follow-up visits. Approximately 448 previously untreated patients with a mutation in the NPM1 or KMT2A gene and with newly diagnosed AML, who are not eligible for intensive chemotherapy. Patients must be ≥18 years of age.

Sponsor: Stichting Hemato-Oncologie voor Volwassenen Nederland

You may qualify if…

✓ In order to be eligible to participate in this study, a patient must meet all of the following criteria:
✓ 1. Patient with newly diagnosed NPM1-mutated AML, consistent with NPM1c, according to the 2022 International Consensus Classification (i.e. ≥ 10% blasts).
✓ OR Patient with newly diagnosed KMT2A-rearranged AML according to the 2022 International Consensus Classification (i.e. ≥ 10% blasts). KMT2A partial tandem duplications or deletions are NOT eligible.
✓ Of note: in case both NPM1 and IDH1 are mutated and both EVOLVE-1 (HO173) and EVOLVE-2 (HO177) are open for inclusion at your site, then patients can only be included in the EVOLVE-1 trial (HO173)
✓ 2. Central confirmation of NPM1 mutation or KMT2A rearrangement in one of the dedicated central genetic laboratories.
✓ 3. Age ≥ 18 years, no upper age limit.
✓ 4. Patient is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:
✓ ≥ 75 years of age: ineligible for intensive chemotherapy per physician's discretion (with an ECOG performance status 0-2) .

You may not qualify if…

✕ Subject has previously been treated for AML; a treatment period with hydroxyurea to control WBC counts is allowed; prior treatment with a hypomethylating agent for MDS-EB is not allowed; prior treatment with erythropoiesis-stimulating agents or luspatercept for MDS is allowed.
✕ 2\. Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes. 3. AML with BCR-ABL1; or myeloid blast crisis of CML. 4. Significant active cardiac disease within 3 months prior to the start of study treatment, including:
✕ New York Heart Association (NYHA) class III or IV congestive heart failure
✕ Myocardial infarction
✕ Unstable angina
✕ Severe cardiac arrhythmias
✕ Congenital long QT syndrome of family member with this condition QTcF \>450 msec on screening electrogram for males and \>470msec on screening electrogram for females (mean of triplicate recordings; calculated using Fridericia's correction). 5. Severe obstructive or restrictive ventilation disorder. 6. History of stroke or intracranial hemorrhage within 6 months prior to randomization.
✕ 7\. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening. 8. Active infection, including hepatitis B or hepatitis C or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or which could expose the patient to undue risk through the participation in the clinical trial; an infection controlled with an approved antibiotic/ antiviral/ antifungal treatment that is not a strong or moderate CYP3A inducer is allowed. Patients with COVID-19 infection can be enrolled, if the patient has no symptoms and was tested negative twice by PCR test prior to inclusion in the trial. 9. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation. 10. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.