Efficacy of Venetoclax and Azacitidine Versus Standard Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia with NPM1 Mutations

The primary objective of this study is to compare the **efficacy** of azacitidine plus venetoclax with standard intensive chemotherapy in patients with newly diagnosed acute myeloid leukemia (AML) and NPM1 mutations who are eligible for intensive treatment. This comparison is clinically relevant as it may offer insights into more effective treatment regimens for this specific patient population, potentially improving outcomes and survival rates.

Secondary objectives include evaluating the following:

• Tolerability of the treatment regimen.
• Rate of morphologic and molecular complete remission.
• Assessment of minimal residual disease (MRD).
• Molecular response and molecular persistence.
• Relapse-free survival, overall survival, and early mortality rates.
• Health-care resource use and health-related quality of life.

The clinical trial focuses on participants diagnosed with **acute myeloid leukemia** (AML), specifically those with newly diagnosed CD33-positive AML with an NPM1 mutation, as per WHO criteria. The study population includes both male and female subjects, aged between 18 and 70 years, who are fit for intensive chemotherapy. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate hepatic and renal function, and a white blood cell count of less than 25 x 10^9/L. The trial population was selected based on these criteria, ensuring that individuals are capable of understanding and willing to sign informed consent. Lifestyle considerations include the requirement for male subjects to refrain from unprotected sex and sperm donation during the study and for seven months after the last dose of the study drug. Women of childbearing potential must have a negative serum pregnancy test within 72 hours before the first dose. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of **azacitidine** plus **venetoclax** compared to standard intensive chemotherapy in patients with newly diagnosed acute myeloid leukemia (AML) with NPM1 mutations. This is a randomized, controlled, double-blind, phase 2 trial. The trial is expected to commence recruitment on October 17, 2024, and conclude by June 30, 2028. Participants will be randomly assigned to receive either the investigational treatment or the standard of care. The investigational arm will involve the administration of azacitidine and venetoclax, while the control arm will receive standard intensive chemotherapy, which may include agents such as **mitoxantrone**, **gemtuzumab ozogamicin**, **cytarabine**, and **daunorubicin hydrochloride**.

The trial will include several study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, diagnosis, and overall health status. Participants will be required to sign an informed consent form. The treatment phase will involve multiple cycles, with the investigational arm receiving up to three induction cycles and the control arm receiving up to two. Follow-up visits will be scheduled to monitor the participants' response to treatment, assess any adverse events, and evaluate primary and secondary endpoints, including modified event-free survival and overall survival. The end-of-study visit will occur after the completion of the treatment cycles and follow-up period, where final assessments will be conducted.

Participant involvement is expected to last up to 336 days, depending on the treatment arm and response to therapy. Conditions that may lead to early termination from the study include failure to achieve a complete response after the maximum number of induction cycles, hematologic relapse, molecular failure, or death. The trial will adhere to rigorous ethical standards, ensuring participant safety and data integrity throughout the study duration.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Mitoxantrone** is utilized in the trial as a **solution for infusion**. It is administered **intravenously** with a maximum daily dose of **10 mg/m²** and a total dose not exceeding **30 mg/m²** over a treatment period of up to **3 days**. This medication is classified under antineoplastic agents, specifically anthracyclines and related substances.

**Gemtuzumab ozogamicin** is another experimental medication used in the trial. It is provided as an **injection** and administered **intravenously**. The maximum daily dose is **3 mg/m²**, with a total dose limit of **9 mg/m²** over a **3-day** treatment period. This drug is categorized as an antineoplastic agent, specifically a monoclonal antibody.

**Cytarabine** is administered as a **solution for infusion** via the **intravenous route**. The maximum daily dose is **3000 mg/m²**, with a cumulative dose of **57000 mg/m²** over a treatment period of up to **19 days**. It is classified under cytostatics.

**Venetoclax** is provided in the form of **film-coated tablets** for **oral use**. The maximum daily dose is **400 mg**, with a total dose not exceeding **134400 mg** over a treatment period of up to **336 days**. Venetoclax is categorized as an antineoplastic agent, specifically a Bcl-2 inhibitor.

**Azacitidine** is administered as a **powder for suspension for injection** via the **subcutaneous route**. The maximum daily dose is **75 mg/m²**, with a total dose limit of **6300 mg/m²** over a treatment period of up to **84 days**. It is classified as an antineoplastic agent.

**Daunorubicin hydrochloride** is used in the trial as a **powder for solution for injection or infusion**. It is administered **intravenously** with a maximum daily dose of **60 mg/m²** and a total dose not exceeding **180 mg/m²** over a treatment period of up to **3 days**. This medication is classified under antineoplastic agents, specifically anthracyclines and related substances.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. Different manufacturers may be used during the trial for the production of these medications. The trial aims to compare the efficacy of azacitidine plus venetoclax with standard intensive therapy in patients with newly diagnosed acute myeloid leukemia (AML) and NPM1 mutations eligible for intensive treatment.

The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is **Modified Event-free Survival (mEFS)**, which includes events such as failure to achieve complete remission (CR), complete remission with incomplete hematologic recovery (CRi), or complete remission with partial hematologic recovery (CRh) after a specified number of induction cycles, hematologic relapse, molecular failure, and death. These events are defined in detail to ensure precise measurement and analysis.

Secondary endpoints include the cumulative occurrence of grade 3 and 4 adverse events, the rate of morphologic CR and CR/CRi/CRh with minimal residual disease (MRD) negativity, MRD detection by multiparameter flow cytometry (MFC) and MRD kinetics in NPM1 real-time PCR, rate of molecular response and persistence, relapse-free survival, overall survival, early mortality at specified time points, changes in health-related quality of life, and cumulative healthcare resource use at 12 and 24 months. These endpoints will be measured and analyzed using validated methods and tools to ensure the reliability and validity of the results.