Evaluation of Gemtuzumab Ozogamicin with Chemotherapy on Minimal Residual Disease in Adult Patients with Favorable-Intermediate-Risk Acute Myeloid Leukemia

The primary objective of this Phase III study is to evaluate the **activity** of gemtuzumab ozogamicin in combination with standard chemotherapy in achieving minimal residual disease (MRD) negativity in adult patients aged 18-60 years with previously untreated, de novo, favorable-intermediate-risk acute myeloid leukemia (AML). Achieving MRD negativity is clinically significant as it is associated with improved long-term outcomes and reduced relapse rates in AML patients.

Secondary objectives include assessing:

• **Overall Survival (OS)**
• **Event Free Survival (EFS)**
• **Cumulative incidence of relapse (CIR)**
• Response rate after induction therapy
• Safety, focusing on adverse events (AE) and serious adverse events (SAE)
• OS, EFS, Disease Free Survival (DFS), and CIR in different risk groups
• OS, EFS, DFS, and CIR according to the minimal residual disease (MRD) level at each evaluation step
• Response rate, OS, EFS, DFS, and CIR according to baseline characteristics
• Quality of Life (QoL) evaluation

The clinical trial involves participants diagnosed with **Favorable-intermediate-risk Acute Myeloid Leukemia**. The study population includes both male and female subjects aged between 18 and 60 years. Participants are required to have a WHO performance status of 0-3 and must not have been previously treated for their acute myeloid leukemia with chemotherapeutic agents, except for a limited use of hydroxyurea. The trial includes individuals with adequate renal and liver function, as well as a left ventricular ejection fraction of at least 50%. Participants must not have severe concomitant neurological or psychiatric diseases, congestive heart failure, or active uncontrolled infections. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific inclusion criteria, ensuring the absence of psychological, familial, sociological, and geographical conditions that could hinder compliance with the study protocol. Both genders are included, and women of childbearing potential must have a negative serum pregnancy test prior to chemotherapy administration. The study also considers lifestyle factors, requiring participants to agree to employ effective birth control methods throughout the study and for a specified period after discontinuation of the study drug.

The clinical trial is designed to evaluate the efficacy of **gemtuzumab ozogamicin** in combination with standard chemotherapy in adult patients aged 18-60 years with previously untreated, de novo, favorable-intermediate-risk **acute myeloid leukemia** (AML). This is a Phase III, randomized, double-blind, controlled study. The trial aims to assess the achievement of minimal residual disease (MRD) negativity as the primary endpoint, with secondary endpoints including overall survival, event-free survival, and the incidence of relapse over a 24-month period. The study is expected to conclude by March 2027, with recruitment having commenced in September 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and organ function. Following the screening, participants will be randomized to receive either the investigational treatment or a control. The treatment phase will involve multiple cycles of chemotherapy, with each cycle followed by a follow-up visit to monitor response and adverse events. The end-of-study visit will occur after the final treatment cycle, where comprehensive assessments will be conducted to evaluate the primary and secondary endpoints.

The expected duration of participant involvement is approximately 24 months, encompassing the treatment and follow-up periods. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or non-compliance with the study protocol. Participants will be monitored closely throughout the trial to ensure safety and adherence to the protocol.

The clinical trial involves the administration of **gemtuzumab ozogamicin**, marketed as MYLOTARG, which is provided as a 5 mg powder for concentrate for solution for infusion. This experimental medication is administered intravenously. The dosing regimen includes a maximum daily dose of 3 mg/m² and a total maximum dose of 12 mg/m² over a treatment period of up to 4 weeks. The active substance, gemtuzumab ozogamicin, is a protein-based compound, and its administration is monitored to ensure compliance with the dosing schedule.

**Daunorubicin hydrochloride** is used as an auxiliary treatment in the study. It is available as a powder and solvent for solution for injection, administered intravenously. The maximum daily dose is 60 mg/m², with a total maximum dose of 660 mg/m² over a 12-week treatment period. This chemical-based medication is part of the standard chemotherapy regimen.

**Fludarabine** is another auxiliary treatment, provided as a concentrate for solution for infusion. It is administered intravenously, with a maximum daily dose of 40 mg/m² and a total maximum dose of 160 mg/m² over a 4-week period. Fludarabine is a chemical compound used in combination with other treatments in the study.

**Busulfan** is administered as a concentrate for solution for injection, given intravenously. The dosing schedule includes a maximum daily dose of 3.2 mg/kg and a total maximum dose of 12.8 mg/kg over a 4-week period. This chemical-based medication is part of the auxiliary treatments in the trial.

**Cytarabine** is provided as a solution for injection, administered intravenously. The maximum daily dose is 1000 mg/m², with a total maximum dose of 14800 mg/m² over a 38-week treatment period. Cytarabine is a chemical compound used as part of the standard chemotherapy regimen in the study.

**Treosulfan** is administered as a solution for infusion, given intravenously. The dosing regimen includes a maximum daily dose of 3.2 mg/kg and a total maximum dose of 12.8 mg/kg over a 4-week period. Treosulfan is a chemical-based auxiliary treatment in the trial.

**Cyclophosphamide** is provided as a powder for solution for injection or infusion, administered intravenously. The maximum daily dose is 60 mg/kg, with a total maximum dose of 120 mg/kg over a 2-week treatment period. Cyclophosphamide is a chemical compound used in combination with other treatments in the study.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **minimal residual disease (MRD)** negativity. The primary endpoint is the percentage of MRD negativity after consolidation in patients treated with gemtuzumab ozogamicin in combination with standard chemotherapy. Secondary endpoints include overall survival (OS) at 24 months, event-free survival (EFS) at 24 months, cumulative incidence of relapse (CIR) at 24 months, and response rate in terms of patients achieving complete remission (CR) after induction therapy. Additionally, safety will be evaluated by the number and type of adverse events (AE) and serious adverse events (SAE). The study will also analyze OS, EFS, disease-free survival (DFS), and CIR in favorable and intermediate-risk groups, as well as according to MRD levels after induction and consolidation. Response rate, OS, EFS, DFS, and CIR will be further assessed based on morphology, cytogenetic, and molecular baseline characteristics.