International multicenter, open-label clinical trial for the treatment of acute myeloid leukemia in children and adolescents

The primary objective of this international multicenter, open-label clinical trial is to evaluate the efficacy of various treatment regimens in children and adolescents with **Acute Myeloid Leukemia** (AML). Specifically, the study aims to determine if the event-free survival (EFS) of patients with de-novo AML, excluding acute promyelocytic leukemia (APL), can be improved with the use of CPX-351. Additionally, the trial seeks to assess the initial efficacy of Gemtuzumab Ozogamicin when added to standard chemotherapy in children with relapsed or refractory AML. For patients undergoing hematopoietic stem cell transplantation, the study compares the composite endpoint of Graft-versus-Host Disease Relapse-Free Survival (GVRDS) between those treated with a Treosulfan-based conditioning regimen and those treated with BuCyMel. This composite endpoint includes acute and chronic GvHD, veno-occlusive disease (VOD), clinical or molecular relapse, death from any cause, and the diagnosis of a second malignant neoplasm. The clinical relevance of these objectives lies in optimizing treatment strategies to improve survival outcomes and reduce treatment-related complications in pediatric AML patients.

Secondary objectives include: - Establishing a diagnostic and logistic network for individualized characterization of AML to facilitate targeted therapy. - Improving EFS through risk classification based on cytogenetic, molecular genetic, and minimal residual disease (MRD) parameters. - Validating risk stratification algorithms and comparing overall survival (OS) and EFS probabilities between different treatment arms. - Identifying molecular relapse through MRD monitoring and evaluating treatment-related mortality and toxicity. - Determining clinical outcomes in comparison to historical controls and identifying additional prognostic factors in pediatric relapsed AML. - Evaluating treatment-related toxicities, engraftment, donor chimerism, and GvHD outcomes over specified timeframes.

The clinical trial focuses on **Acute Myeloid Leukemia** (AML) and involves a study population comprising both male and female participants. The trial includes children and adolescents, with an age range from 1 month (28 days) to less than 18 years at diagnosis, and up to 21 years at the time of hematopoietic stem cell transplantation (HSCT) for Group C. Participants are selected based on specific criteria, including a diagnosis of de-novo AML, relapsed or refractory AML, and an indication for first allogenic HSCT with an HLA identical donor. The trial population is characterized by their ability to adhere to the study visit schedule and other protocol requirements. Lifestyle considerations such as the acceptance that vaccination with live vaccines is not possible during the trial are noted. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, emphasizing the need for written permission from parental or legal representatives before any study-related assessments or procedures. Participants must have a negative serum pregnancy test if they are females of child-bearing potential within 10 days prior to treatment.

The clinical trial is designed as an international multicenter, open-label study aimed at evaluating the treatment of **acute myeloid leukemia** (AML) in children and adolescents. The trial is structured into three groups, each with specific objectives and endpoints. Group A focuses on improving event-free survival in patients with de-novo AML using CPX-351. Group B assesses the initial efficacy of **gemtuzumab ozogamicin** when added to standard chemotherapy in relapsed or refractory AML. Group C compares the outcomes of patients treated with a **treosulfan**-based conditioning regimen versus those treated with BuCyMel, with a composite endpoint of graft-versus-host disease, VOD, relapse-free survival, and other events.

The trial employs a randomized, controlled design with an estimated duration extending until December 31, 2029. 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 ability to adhere to the study protocol. Follow-up visits will be scheduled to monitor treatment response, adverse events, and overall survival. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and collecting data for analysis.

Participant involvement is expected to last throughout the treatment period, with specific durations varying by group and treatment regimen. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or adverse events that necessitate discontinuation of treatment. The trial's primary endpoints include event-free survival for Group A, overall survival for Group B, and a composite endpoint for Group C. Secondary endpoints encompass overall survival, event-free survival, cumulative incidence of relapse, and non-relapse mortality across all groups.

The clinical trial involves the administration of several experimental and non-experimental medications for the treatment of **acute myeloid leukemia** in children and adolescents. The experimental medication **Fludarabine** is administered intravenously in a pharmaceutical form identified as PHF675. The dosage is calculated based on body surface area, with a maximum daily dose of 30 mg/m² and a total maximum dose of 150 mg/m² over a treatment period of up to 5 days. Fludarabine is classified as a neoplastic drug.

**Mylotarg**, containing the active substance **Gemtuzumab Ozogamicin**, is provided as a powder for concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 4.5 mg/m² and a total maximum dose of 9 mg/m² over a 2-day treatment period. This medication is also categorized as a neoplastic drug.

**Treosulfan** is administered intravenously in a pharmaceutical form denoted as PHF00230MIG. The dosing is based on body surface area, with a maximum daily dose of 14,000 mg/m² and a total maximum dose of 42,000 mg/m² over a 3-day treatment period. Treosulfan is classified as a neoplastic drug.

**Idarubicin Hydrochloride** is provided as a solution for injection, administered intravenously. The dosage is 12 mg/m² per day, with a total maximum dose of 36 mg/m² over a 3-day treatment period. It is classified as a cytostatic drug.

**Busulfan** is administered intravenously in a pharmaceutical form identified as PHF00230MIG. The dosage is based on body weight, with a maximum daily dose of 4.8 mg/kg and a total maximum dose of 19.2 mg/kg over a 4-day treatment period. Busulfan is categorized as a neoplastic drug.

**Melphalan** is provided as a powder and solvent for solution for injection/infusion, administered intravenously. The maximum daily and total dose is 140 mg/m², administered over a single day. It is classified as a cytostatic drug.

**Cytarabine** is administered intravenously as a solution for injection, with a maximum daily dose of 6,000 mg/m² and a total maximum dose of 18,000 mg/m² over a 3-day treatment period. It is classified as a cytostatic drug.

**Prednisolone** is administered intrathecally in a pharmaceutical form denoted as PHF00245MIG. The maximum daily dose is 10 mg, with a total maximum dose of 50 mg over a 5-day treatment period. Prednisolone is classified as a glucocorticoid.

**Anhydrous Cyclophosphamide** is administered intravenously in a pharmaceutical form identified as PHF00231MIG. The dosage is based on body weight, with a maximum daily dose of 60 mg/kg and a total maximum dose of 120 mg/kg over a 2-day treatment period. It is categorized as a neoplastic drug.

**Vyxeos Liposomal**, containing **Cytarabine** and **Daunorubicin**, is provided as a powder for concentrate for solution for infusion, administered intravenously. The maximum daily dose is 135 mg/m², with a total maximum dose of 405 mg/m² over a 3-day treatment period. It is classified as a cytostatic drug.

**Etoposide** is administered as a concentrate for solution for infusion, with a maximum daily dose of 125 mg/m² and a total maximum dose of 625 mg/m² over a 5-day treatment period. It is classified as a cytotoxic drug.

**Mitoxantrone Hydrochloride** is provided as a concentrate for solution for infusion, administered intravenously. The maximum daily dose is 10 mg/m², with a total maximum dose of 20 mg/m² over a 2-day treatment period. It is classified as a cytostatic drug.

**Methotrexate** is administered intrathecally in a pharmaceutical form denoted as PHF00231MIG. The maximum daily dose is 12 mg, with a total maximum dose of 60 mg over a 5-day treatment period. It is categorized as a neoplastic drug.

**Thiotepa** is provided as a solution for infusion, administered intravenously. The maximum daily and total dose is 10 mg/kg, administered over a single day. It is classified as a cytostatic drug.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial does not include any placebo or comparator treatments, as all participants receive active medications as part of the study design.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints tailored to the specific objectives of each group within the study. For Group A, the primary endpoint is **Event-Free Survival (EFS)**, which measures the time from the start of treatment to the occurrence of any event such as relapse or death. Group B will focus on **Overall Survival (OS)**, defined as the time from inclusion to death from any cause, with survivors censored at the last follow-up. Group C will utilize a composite endpoint known as **Graft-versus-host disease, VOD, Relapse-Free Survival (GVRDS)**, which includes events such as acute and chronic GvHD, VOD, relapse, death, and diagnosis of a second malignant neoplasm.

Secondary endpoints across the groups include **Overall Survival (OS)** for Groups A and C, **Event-Free Survival (EFS)** for Groups B and C, and **Cumulative Incidence of Relapse (CIR)** and **Non-relapse Mortality (NRM)** for all groups. Additional specific secondary endpoints for Group A include primary induction failures, risk-group after induction 2 disease-free survival (DFS), blast presence at Ind1, and MRD-levels at Ind1 and Ind2. For Groups A-C, adverse events, early death complete remission (CR), and CNS infestation (CICNS) will be monitored. Group C will also assess graft failure, engraftment, acute and chronic GvHD, and VOD Grade 3/4.