Randomized Controlled Trial of Cladribine-Based Induction Regimens in Acute Myeloid Leukemia: Evaluating Efficacy in CBF-AML and FLT3-Mutated Subtypes

The primary objective of the study is to evaluate the **efficacy** of induction treatment in patients with **Acute Myeloid Leukemia** (AML) by measuring event-free survival (EFS). This is assessed through three specific treatment protocols: (i) the DAC+GO protocol, which includes cladribine, daunorubicin, cytosine arabinoside, and gemtuzumab ozogamicin, compared to the DAC protocol in CBF-AML patients; (ii) the DAC+M protocol, which includes cladribine, daunorubicin, cytosine arabinoside, and midostaurin, compared to the DA+M protocol in AML patients with FLT3 gene mutations; and (iii) the DAC+Ven protocol, which includes venetoclax, cladribine, daunorubicin, and cytosine arabinoside, compared to the DAC protocol plus placebo in other AML patients. This objective is clinically relevant as it aims to determine the most effective personalized treatment strategy for improving survival outcomes in AML patients.

The secondary objectives include:

• Comparison of patients achieving composite complete remission with no measurable residual disease (CR+CRh MRD-) between treatment and control groups for each arm.
• Comparison of overall survival (OS) between study and control groups for each arm.
• Comparison of relapse-free survival (RFS) between study and control groups for each arm.
• Comparison of cumulative incidence of relapse (CIR) between treatment and control groups for each arm.
• Comparison of the percentage of patients experiencing complete remission (CR) between the study and control groups for each arm.
• Comparison of the percentage of patients experiencing complete remission with hematologic recovery (CRh) between the study and control groups for each arm.
• Comparison of the percentage of patients experiencing composite complete remission (cCR) between the study and control groups for each arm.
• Comparison of the percentage of patients who did not achieve a response between the study and control groups for each arm.
• Comparison of the percentage of patients experiencing early death (ED) between the study and control groups for each arm.
• Comparison of the percentage of patients undergoing allogeneic transplantation between the study and control groups for each arm.
• Assessment of quality of life as measured by the EORTC QLQ-C30 questionnaire at baseline and after the first induction.

The clinical trial involves participants diagnosed with **Acute Myeloid Leukemia** according to the WHO 2016 criteria. The study population includes both male and female subjects, aged between 18 and 65 years, with a general health status of ECOG scale ≤ 2 and an HCT-CI comorbidity index score ≤ 3. The trial population was selected based on these criteria, and participants are required to provide informed, written consent to participate. Additionally, both male and female participants must agree to use effective contraception during the study. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include a negative serum or urine pregnancy test for women of childbearing age. The trial aims to compare the efficacy of various induction treatments in different subgroups of AML patients.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of various induction treatments for **Acute Myeloid Leukemia** (AML). The trial will compare the event-free survival (EFS) of patients receiving different combinations of **cladribine**, **daunorubicin**, **cytarabine**, and other agents, such as **gemtuzumab ozogamicin**, **midostaurin**, and **venetoclax**, against standard protocols. The study is set to commence recruitment on March 1, 2024, and is expected to conclude by November 30, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, general health status, and specific diagnostic criteria for AML. Following successful screening, participants will be randomized into treatment arms. The trial includes multiple follow-up visits to monitor treatment response, adverse events, and overall health status. The end-of-study visit will assess the final outcomes, including primary and secondary endpoints such as overall survival and remission rates.

The expected duration of participant involvement varies depending on the treatment arm, with the maximum treatment period being 19 weeks. Participants may be withdrawn from the study early due to reasons such as adverse reactions, withdrawal of consent, or failure to adhere to study protocols. The trial aims to provide comprehensive data on the efficacy and safety of personalized treatment strategies for AML, contributing to the optimization of therapeutic approaches for this condition.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. **Cytarabine**, also known as Ara-C or Cytosine Arabinoside, is administered intravenously. It is an antineoplastic agent with a maximum daily dose of 4000 mg/m² and a total maximum dose of 43400 mg/m² over a treatment period of 19 days. The pharmaceutical form is coded as PHF00230MIG.

**Venetoclax**, marketed as Venclyxto, is provided in the form of 100 mg film-coated tablets. It is administered orally with a maximum daily dose of 400 mg and a total maximum dose of 9800 mg over a 5-day treatment period. The product is modified from its original packaging to ensure blinding in the study.

**Midostaurin** is administered orally in the form of soft capsules. The maximum daily dose is 100 mg, with a total maximum dose of 7000 mg over a 10-day treatment period. It is classified as an antineoplastic agent.

**Cladribine** is used in two formulations: as a solution for infusion and as BIODRIBIN, a 1 mg/ml solution for infusion. Both are administered intravenously. The maximum daily dose for Cladribine is 5 mg/m², with a total maximum dose of 50 mg/m² over a 10-day period, while BIODRIBIN has a total maximum dose of 25 mg/m² over a 5-day period. Both are antineoplastic agents.

**Daunorubicin Hydrochloride** is administered intravenously with a maximum daily dose of 60 mg/m² and a total maximum dose of 360 mg/m² over a 6-day treatment period. It is also classified as an antineoplastic agent.

**Gemtuzumab Ozogamicin**, marketed as MYLOTARG, is provided as a powder for concentrate for solution for infusion. It is administered intravenously with a maximum daily and total dose of 5 mg over a single day. It is an antibody-drug conjugate.

The study also includes a **placebo** in the form of 0 mg film-coated tablets, which serves as a comparator treatment. The placebo is used to maintain blinding and ensure the integrity of the study results.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Event-Free Survival (EFS)**. This endpoint will evaluate the time from randomization to the occurrence of any of the following events: failure to achieve complete remission, relapse, or death from any cause. Secondary efficacy endpoints include complex complete remission with no measurable residual disease (CR+CRh+CRi MRD-), overall survival (OS), relapse-free survival (RFS), cumulative relapse rate (CIR), and the proportion of patients experiencing complete remission (CR). Additional secondary endpoints involve the proportion of remission with partial hematological recovery (CRh) or remission with incomplete hematopoietic regeneration (CRi), the proportion of patients who did not achieve a response (NR), the percentage of patients experiencing early death (ED), the percentage of patients undergoing allogeneic transplantation, the EORTC QLQ-C30 score, and the proportion of patients experiencing a composite complete remission (cCR).

The trial will compare the efficacy of different induction treatment protocols in patients with **Acute Myeloid Leukemia (AML)**. These include the DAC+GO protocol for CBF-AML patients, the DAC+M protocol for AML patients with FLT3 gene mutations, and the DAC+Ven protocol for other AML patients. The efficacy parameters will be collected and analyzed at various timepoints throughout the trial, with the primary endpoint being assessed at the end of the treatment period. The trial is designed to provide a comprehensive evaluation of the treatment strategies, with the aim of improving patient outcomes in AML.