Phase 2 Multicentric Study of Venetoclax and Azacitidine in Adult NPM1-Mutated Acute Myeloid Leukemia with Molecular Relapse/Progression

The primary objective of this study is to determine the efficacy of **venetoclax** and **azacitidine** in preventing morphological relapse in adult patients with Acute Myeloid Leukemia (AML) characterized by an NPM1 mutation. This is particularly relevant for patients who experience molecular relapse or progression during chemotherapy treatment or subsequent follow-up monitoring. The clinical significance of this objective lies in its potential to improve patient outcomes by preventing disease progression and maintaining remission.

Secondary objectives include:

• Evaluating the rate of MRD-negativity achieved with venetoclax-azacitidine.
• Assessing the number of patients who proceed to allogeneic stem cell transplant (alloSCT).
• Determining the number of patients who proceed to alloSCT in MRD-negativity.
• Evaluating Overall Survival (OS).
• Assessing Progression-Free Survival (PFS).
• Evaluating Molecular Disease-Free Survival (MDFS).
• Assessing Molecular progression-free survival (MPFS).
• Evaluating the safety and toxicity of venetoclax-azacitidine in the experimental setting.

The clinical trial involves participants diagnosed with **Acute Myeloid Leukemia** with an NPM1 mutation. The study population includes both male and female subjects, aged 18 years and older, who have previously been diagnosed with NPM1mut AML, with or without concomitant FLT3-TKD or FLT3-ITD mutations. Participants must have undergone at least two cycles of conventional anthracycline- and cytarabine-based chemotherapy, achieving first complete remission (CR1), and must be in morphological CR1 with bone marrow detectable minimal residual disease (MRD) positivity. The trial includes individuals with a projected life expectancy of at least 12 weeks and an Eastern Cooperative Oncology Group (ECOG) Performance status of less than 2. Participants are required to have adequate renal and hepatic function, as defined by specific laboratory criteria. The trial population was selected based on these criteria, and both genders are included. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of a combination therapy involving **venetoclax** and **azacitidine** in managing molecular relapse or progression in adult patients with Acute Myeloid Leukemia (AML) characterized by an NPM1 mutation. This is a multicentric, Phase II study employing a randomized, double-blind, controlled trial design. The trial is expected to span from March 2022 to December 2028, with participant involvement lasting up to 168 days, depending on individual response and treatment adherence.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, previous diagnosis, and health status. The screening will include assessments like pregnancy tests for females of childbearing potential and confirmation of NPM1 mutant transcripts. Following successful screening, participants will be randomized to receive either the investigational treatment or a control, with dosing regimens tailored to the specific drugs: **venetoclax** administered orally and **azacitidine** subcutaneously.

Subsequent follow-up visits will occur at regular intervals to monitor the primary endpoint, which is the percentage of patients who do not experience overt relapse at six months or within stem cell transplant. Secondary endpoints include MRD negativity rates, disease progression rates, and overall survival metrics. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and any adverse effects experienced during the trial.

Participants may be withdrawn from the study prematurely if they experience significant adverse effects, fail to adhere to the treatment protocol, or if the investigator deems it in the participant's best interest. The trial's rigorous design ensures that data collected will contribute valuable insights into the treatment of AML with NPM1 mutation, potentially informing future therapeutic strategies.

The clinical trial involves the administration of **VENETOCLAX**, a chemical active substance, in the form of a film-coated tablet. The maximum daily dose of venetoclax is 400 mg, with a total maximum dose of 66.7 g over the treatment period. The medication is administered orally, and the maximum treatment period is 168 days. The product is not a paediatric formulation and is used as an investigational medicinal product (IMP) in the trial. The administration of venetoclax is monitored to ensure participant compliance with the dosing schedule.

**AZACITIDINE** is also utilized in this clinical trial. It is provided as a powder and solution for suspension for injection. The maximum daily dose is 75 mg/m², with a total maximum dose of 3150 mg/m² over the treatment period. Azacitidine is administered subcutaneously, and the maximum treatment period is 42 days. Similar to venetoclax, azacitidine is not a paediatric formulation and is used as an IMP in the study. Participant compliance with the dosing schedule is monitored throughout the trial.

Both venetoclax and azacitidine are used in combination to assess their efficacy in preventing morphological relapse in adult patients with NPM1-mutated acute myeloid leukemia (AML) who experience molecular relapse or progression during chemotherapy treatment or subsequent follow-up monitoring. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The administration of these medications is carefully monitored to ensure adherence to the prescribed dosing schedules and to evaluate the therapeutic outcomes in the study population.

The efficacy of the combination of **venetoclax** and **azacitidine** in the management of molecular relapse or progression in adult patients with NPM1-mutated acute myeloid leukemia (AML) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percentage of patients who do not experience overt relapse at 6 months or within the period of stem cell transplant. Secondary endpoints include the minimal residual disease (MRD) negativity rate at 3 and 6 months and at transplant, the percentage of patients undergoing allogeneic stem cell transplantation (alloSCT) in complete remission (CR) and MRD negativity, disease progression rate at 3, 6, and 12 months and at transplant, and molecular disease progression at the same intervals.

Additional secondary endpoints encompass overall survival (OS), progression-free survival (PFS), molecular disease-free survival (MDFS), and molecular progression-free survival (MPFS). These will be defined by the number of days from the first administration of the study drug to various events such as death, disease progression, or molecular disease progression. Safety and toxicity of the venetoclax-azacitidine regimen will also be evaluated. The efficacy parameters will be measured and collected at specified timepoints, including 3, 6, and 12 months, as well as at the time of transplant, using appropriate clinical and laboratory assessments.