Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Bleximenib, Venetoclax, and Azacitidine in Acute Myeloid Leukemia with KMT2A Rearrangements or NPM1 Mutations

The primary objective of this Phase 3 randomized, double-blind, placebo-controlled study is to compare the **efficacy** of the combination of bleximenib, venetoclax, and azacitidine (VEN+AZA) versus VEN+AZA alone in participants with newly diagnosed **Acute Myeloid Leukemia** (AML) harboring KMT2A rearrangements or NPM1 mutations who are ineligible for intensive chemotherapy. This comparison is clinically relevant as it aims to determine whether the addition of bleximenib can enhance treatment outcomes in this specific patient population, potentially offering a more effective therapeutic option for those unable to undergo intensive chemotherapy.

The clinical trial involves a total of **338 participants** diagnosed with **Acute Myeloid Leukemia** (AML). The study population includes both male and female subjects, aged 18 years and older, who have not previously received treatment for KMT2Ar or NPM1m AML with at least 10% blasts as per the 2022 ICC criteria. Participants are selected based on their ineligibility for intensive chemotherapy, which is determined by age (≥75 years) or specific comorbidities for those aged 18 to <75 years, such as severe cardiac or pulmonary disorders, or renal impairment. The trial includes individuals with adequate renal and hepatic functions and a white blood cell count of less than 25 x 10^9/L. The population is considered vulnerable, and the selection process ensures that participants meet the necessary health criteria to partake in the study. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of **bleximenib**, **venetoclax**, and **azacitidine** in participants with newly diagnosed **acute myeloid leukemia** (AML) harboring KMT2A rearrangements or NPM1 mutations who are ineligible for intensive chemotherapy. The trial aims to compare the combination of bleximenib with venetoclax and azacitidine against venetoclax and azacitidine alone. The study is expected to run until August 27, 2029, with recruitment starting on May 2, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, untreated AML status, and ineligibility for intensive chemotherapy. The screening will include a bone marrow assessment and evaluation of renal and hepatic functions. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. The end-of-study visit will conclude the participant's involvement, assessing the primary endpoints of complete remission (CR) and overall survival (OS).

The expected length of participant involvement is determined by the treatment period, which can extend up to 999 days, depending on individual response and tolerance. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any medical condition that, in the investigator's opinion, makes continued participation unsafe. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements to ensure participant safety and data integrity.

The clinical trial involves the administration of several treatments, including the experimental medication **Bleximenib**. Bleximenib is provided in the form of a film-coated tablet, identified by the product code JNJ-75276617. It is administered orally. The specific dosage and frequency of administration are not detailed in the provided data, but the maximum treatment period is indicated as 999 days. Participant compliance with the medication regimen will be monitored throughout the trial.

In addition to Bleximenib, the trial includes the use of **Venetoclax**, marketed as Venclyxto, which is available in film-coated tablet form. Venetoclax is also administered orally. The trial utilizes two strengths of Venclyxto: 50 mg and 100 mg tablets. The maximum treatment period for Venetoclax is similarly set at 999 days. The medication is repackaged and relabeled for the trial, and participant adherence to the dosing schedule will be closely monitored.

Another treatment used in the trial is **Azacitidine**, provided as a powder for suspension for injection under the name Azacitidine betapharm 25 mg/mL. This medication is administered intravenously. The maximum treatment period for Azacitidine is also 999 days. The product is repackaged and relabeled for the purposes of the trial, and compliance with the administration schedule will be tracked.

The trial also includes the use of placebo treatments, which are designed to match the appearance of the active medications. These placebos are used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the specific treatment assignments. The placebo treatments are provided in forms that match the 50 mg, 30 mg, and 100 mg active treatments, although specific details about their administration are not provided in the data.

The efficacy of the clinical trial will be assessed using dual primary endpoints: complete remission (CR) and overall survival (OS). These endpoints are critical in evaluating the effectiveness of the treatment regimen involving **bleximenib**, venetoclax, and azacitidine in participants with newly diagnosed acute myeloid leukemia (AML) harboring KMT2A rearrangements or NPM1 mutations who are ineligible for intensive chemotherapy.

The measurement and analysis of these endpoints will be conducted at specified intervals throughout the trial duration. The trial is designed as a Phase 3 randomized, double-blind, placebo-controlled study, ensuring rigorous assessment of the treatment's efficacy. The endpoints will be collected and analyzed using standardized methods to ensure the reliability and validity of the results. The trial's estimated end date is August 27, 2029, with recruitment starting on May 2, 2025.