Evaluation of Pegaspargase Efficacy and Tolerance in Pediatric Acute Lymphoblastic Leukemia Stratified by Risk and Immunophenotype

The primary objectives of the study are to evaluate the pharmacokinetics (**PK**) and tolerance of different pegaspargase administration schedules in children and adolescents with acute lymphoblastic leukemia (**ALL**). For patients with standard or medium risk ALL, the study aims to: 1) assess the superiority of a fractionated dosing scheme in terms of PK at day 33, and 2) determine the equivalence in tolerance between two dosing schemes from day 12 of induction to day 49. In the high/very high-risk group, the objectives are: 1) to evaluate PK at day 33, and 2) to assess the toxicity of an intensified dosing scheme from day 12 of induction to day 49. These objectives are clinically relevant as they aim to optimize treatment efficacy and minimize adverse effects in pediatric ALL patients.

The secondary objectives include evaluating the incidence and prognostic value of rare ALL subgroups, such as the "B-other" subgroup, and assessing the 5-year event-free survival (**EFS**), disease-free survival (**DFS**), and overall survival (**OS**) in patients with suboptimal response to therapy or ABL-class fusions treated with imatinib. Additionally, the study aims to monitor imatinib-related adverse events in these patients, both immediate and long-term.

The clinical trial involves a study population of children and adolescents aged **12 months to less than 18 years** who have been newly diagnosed with standard or medium-risk **acute lymphoblastic leukemia (ALL)**. The trial includes both male and female participants, and the population is stratified based on immunophenotypic characterization, specifically B-lineage or T-lineage ALL. The sponsor has not provided the total number of participants involved in the study. Participants were selected based on specific inclusion criteria, including the requirement for written informed consent obtained before day 8 of treatment. The trial population is considered vulnerable due to the age group and health condition. No specific lifestyle considerations such as diet or physical activity are mentioned in the available data.

The clinical trial is a **prospective**, French, multicenter, open-label study designed to evaluate the efficacy and tolerance of different schedules of **pegaspargase** in patients aged 12 months to less than 18 years who are newly diagnosed with standard or medium-risk acute lymphoblastic leukemia (ALL). The trial is stratified based on the immunophenotypic characterization (B- or T-lineage) and the patient risk group. The primary objectives for children and adolescents with standard or medium risk ALL are to assess the superiority in terms of pharmacokinetics (PK) at Day 33 of the fractionated scheme and to evaluate the equivalence in tolerance of the two schemes from Day 12 of induction to Day 49. For the high/very high-risk group, the primary objectives include assessing the PK at Day 33 and evaluating the toxicity of the intensified scheme from Day 12 of induction to Day 49.

The trial is expected to run from September 19, 2016, to July 1, 2025. Participants will be involved in the study for the duration of their treatment, which includes an initial screening visit to confirm eligibility based on criteria such as age and diagnosis of B-lineage or T-lineage ALL. Written informed consent must be obtained before Day 8 of treatment. The study includes multiple visits, with key assessments occurring at Day 33 and between Day 12 and Day 49 of treatment. The primary endpoints include adequate asparaginase activity (>100 IU/L) at Day 33 of induction and the incidence of severe toxicities (Grade ≥ 3) directly related to asparaginase, such as CNS thrombosis, pancreatitis, anaphylaxis, and hyperbilirubinemia, between Day 12 and Day 49 of treatment. Secondary endpoints focus on evaluating the incidence of rare subgroups of ALL and their prognostic value, as well as the 5-year event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) of patients with suboptimal response to therapy.

Participants may be terminated early from the study if they experience severe adverse events or if they do not adhere to the study protocol. The trial does not include a pediatric formulation of the drug, and the administration route is by injection. The study aims to provide valuable insights into the treatment of ALL in children and adolescents, contributing to the optimization of therapeutic strategies for this patient population.

The clinical trial involves the administration of **PEGASPARGASE**, a chemotherapeutic agent, as the experimental medication. **PEGASPARGASE** is a protein-based substance, specifically classified under the ATC code L01XX24. It is administered in the form of an injection, with the pharmaceutical form designated as PHF00231MIG. The dosing schedule for **PEGASPARGASE** is structured to assess pharmacokinetics (PK) and tolerance in children and adolescents diagnosed with acute lymphoblastic leukemia (ALL). The trial aims to evaluate the superiority of a fractionated dosing scheme in terms of PK at Day 33 and to assess the equivalence in tolerance between two dosing schemes from Day 12 of induction to Day 49. The administration frequency and specific dosage amounts are not detailed in the provided data.

In addition to the experimental treatment, the study may involve the use of standard-of-care therapies as non-experimental treatments, although specific details regarding these therapies are not provided. The trial does not include a placebo or comparator treatment as part of the study design. Participant compliance with the dosing schedule will be monitored throughout the trial period to ensure adherence to the treatment protocol. The trial is focused on evaluating the treatment's effects in both standard/medium risk and high/very high-risk groups of ALL patients, with specific objectives related to PK and toxicity assessments.

The clinical trial aims to evaluate the efficacy of **PEGASPARGASE** in the treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. Efficacy will be assessed through primary endpoints, which include measuring adequate asparaginase activity, defined as greater than 100 IU/L, at Day 33 of induction. Additionally, the incidence of severe toxicities, such as central nervous system thrombosis, pancreatitis, anaphylaxis, and hyperbilirubinemia, will be monitored between Day 12 and Day 49 of treatment, and before Day 8 of consolidation.

Secondary endpoints will focus on evaluating the incidence and prognostic value of rare subgroups of ALL, such as the "B-other" subgroup, and assessing the 5-year event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) of patients with suboptimal response to therapy. The trial will also monitor imatinib-related adverse events in patients with suboptimal response to therapy. The study is designed as a prospective, multicenter, open-label trial, stratified by immunophenotypic characterization and patient risk group, to evaluate the efficacy and tolerance of different schedules of **PEGASPARGASE** in newly diagnosed patients aged 12 months to less than 18 years with standard or medium-risk ALL.