Evaluation of Revumenib Combined with Azacitidine and Venetoclax in Newly Diagnosed NPM1-Mutated or KMT2A-Rearranged AML Patients Ineligible for Intensive Chemotherapy

The primary objective of this study is to evaluate whether treatment with **revumenib**, in combination with azacitidine and venetoclax, prolongs overall survival (OS) in adult patients with newly diagnosed NPM1-mutated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. This is clinically relevant as improving OS is a critical endpoint in the management of AML, particularly for patients who cannot undergo intensive treatment regimens.

Secondary objectives include:

• Assessing if the treatment prolongs event-free survival (EFS).
• Evaluating the increase in the combined rate of complete remission (CR) and CR with partial hematologic recovery (CRh).
• Determining the increase in the rate of CR and CRh individually.
• Assessing the increase in the combined rate of CR and CR with incomplete hematologic recovery (CRi).
• Evaluating the increase in the rate of CR, CR/CRh, and CR/CRi without measurable residual disease (MRD) using quantitative PCR and multiparameter flow cytometry.
• Assessing the time to response and duration of response (DoR).
• Evaluating OS, EFS, DoR, and remission rates by prognostic variables, including clinical variables, European LeukemiaNet (ELN) risk groups, geographical region, and specific AML genotypes.
• Evaluating resistance mechanisms post-treatment.
• Assessing the impact on quality of life (QoL) using EORTC QLQ-C30 and EQ-5D-5.
• Characterizing the pharmacokinetics (PK) of revumenib and relevant metabolites.
• Evaluating the pharmacodynamic relationship with safety, efficacy, and biomarkers.
• Assessing the incidence and severity of adverse events (AEs) according to CTCAE v5.0.
• Evaluating time to hematopoietic recovery and the need for blood transfusions and hospital stay duration.

The clinical trial involves a total of **290 participants** diagnosed with **Acute Myeloid Leukemia (AML)**, specifically those with newly diagnosed NPM1-mutated AML or KMT2A-rearranged AML. The study population includes both male and female adults aged 18 years and older, with no upper age limit. Participants are selected based on their ineligibility for intensive chemotherapy, which may be due to age (≥75 years) or specific comorbidities such as cardiac history, reduced lung function, or moderate hepatic impairment. The trial population is characterized by a requirement for adequate renal and hepatic function, and a projected life expectancy of at least 12 weeks. Lifestyle considerations include the use of effective birth control methods for participants of childbearing potential and restrictions on sperm and ova donation during and after the study period. The trial includes a vulnerable population, ensuring ethical considerations are met. Participants must have a white cell blood count of less than 25 x 10^9/L, with hydroxyurea permitted to achieve this criterion prior to enrollment.

The clinical trial is designed to evaluate the efficacy of **revumenib** in combination with **azacitidine** and **venetoclax** in adult patients with newly diagnosed **Acute Myeloid Leukemia (AML)** who are ineligible for intensive chemotherapy. This is a randomized, double-blind, controlled trial, with a primary objective to assess whether the combination therapy prolongs overall survival (OS) in the specified patient population. The trial is expected to conclude by April 2031, with recruitment starting in December 2024. Participants will be involved in the study for a maximum treatment period of 76 weeks.

The trial includes several key study visits. The initial visit is the inclusion (screening) visit, where eligibility criteria are confirmed, including the presence of NPM1 mutation or KMT2A rearrangement, and informed consent is obtained. Following randomization, participants will undergo regular follow-up visits to monitor treatment response, adverse events, and overall health status. These visits will include assessments of hematologic parameters, liver and kidney function, and other relevant clinical evaluations. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, where final assessments will be conducted to evaluate the primary and secondary endpoints.

Participants are expected to adhere to the study protocol throughout the trial duration. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any medical condition that, in the opinion of the investigator, would compromise the participant's safety or the integrity of the study data. The trial will employ a placebo control for **revumenib** to ensure the validity of the results, with participants receiving either the active drug or placebo in a blinded manner. The study will also explore secondary endpoints such as event-free survival (EFS), complete remission rates, and quality of life assessments, providing a comprehensive evaluation of the treatment's impact on patients with AML.

The clinical trial involves the administration of **Revumenib**, an experimental medication, in the form of a **tablet**. Revumenib is chemically synthesized and is administered orally. The maximum daily dose is 160 mg, with a total maximum dose of 340,480 mg over a treatment period of 76 weeks. The medication is provided by HOVON and is identified by the sponsor product code SUB253376. Participant compliance with the dosing schedule is monitored throughout the trial.

**Venclyxto** is another medication used in the trial, available in two dosages: 50 mg and 10 mg film-coated tablets. The active substance in Venclyxto is **venetoclax**, a chemical compound. The medication is administered orally, with a maximum daily dose of 50 mg and a total maximum dose of 55,300 mg over the 76-week treatment period. Venclyxto is supplied by ABBVIE DEUTSCHLAND GMBH & CO. KG, and the outer carton is modified for clinical trial use.

**Azacitidine Seacross** is administered as a 25 mg/mL powder for suspension for injection. The active substance, **azacitidine**, is chemically derived and administered subcutaneously. The maximum daily dose is 75 mg/m², with a total maximum dose of 39,900 mg/m² over the treatment period. The product is provided by SEACROSS PHARMA (EUROPE) LTD and is over-labeled for clinical trial purposes.

Placebos are used in the trial to maintain blinding and assess the efficacy of Revumenib. These include placebos for Revumenib at dosages of 160 mg, 110 mg, and 25 mg. The placebos do not contain any active substances and are used to compare against the active treatment groups.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is overall survival (OS) in adult patients with newly diagnosed NPM1-mutated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. OS will be measured from the date of randomization to the date of death from any cause, with patients not known to have died at the last follow-up being censored on the date they were last known to be alive.

Secondary endpoints include event-free survival (EFS), which will be measured from the date of randomization to the date of treatment failure, hematologic relapse from complete remission (CR) or complete remission with partial hematologic recovery (CRh), or death from any cause, whichever occurs first. Additional secondary endpoints involve the rate of CR/CRh, defined as the proportion of patients achieving CR or CRh at any time-point during protocol therapy, and the rate of response (CRh and CR/CRi), defined as the proportion of patients with response at any time-point during protocol therapy.

Other secondary endpoints include the rates of CR, CR/CRh, and CR/CRi without measurable residual disease (MRD), assessed by quantitative PCR and multiparameter flow cytometry, and the time to achievement of response, defined as the time from the date of randomization to the first occurrence of the response. The duration of response (DoR) will also be measured from the date of achievement of response until the date of hematologic relapse or death from any cause, with patients without any of these events being censored on the date of the last clinical assessment.

Quality of life (QoL) will be assessed using the EORTC QLC-C30 and EQ-5D-5L questionnaires. Additionally, the study will evaluate resistance mechanisms after combined treatment with azacitidine, venetoclax, and **revumenib**, and provide a descriptive summary of plasma concentrations of **revumenib** and relevant metabolites. The pharmacodynamics of **revumenib** in relation to safety, efficacy, and correlative biomarkers will also be summarized, potentially including immunophenotyping of circulating peripheral blood mononuclear cells (PBMC) and/or bone marrow, gene expression, mutational analysis, and minimal residual disease (MRD).