Dose and Safety Evaluation of Asciminib in Pediatric Patients with Philadelphia Chromosome Positive Chronic Myeloid Leukemia in Chronic Phase

The primary objective of this study is to characterize the **pharmacokinetic** profile of asciminib in pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP), who have been previously treated with one or more tyrosine kinase inhibitors. The goal is to identify the pediatric formulation dose (fed) that results in asciminib exposure comparable to 40 mg BID in adult patients (fasted). This is clinically relevant as it aims to optimize dosing for pediatric patients, ensuring effective and safe treatment outcomes.

Secondary objectives include:

• To assess the safety and tolerability of asciminib.
• To assess pharmacodynamic markers of asciminib's anti-leukemic activity.
• To assess acceptability and palatability of the pediatric formulation.
• To assess long-term safety of asciminib.

The clinical trial involves a total of **23 participants** diagnosed with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (**Ph+ CML-CP**), who have previously been treated with one or more tyrosine kinase inhibitors. The study population includes both male and female pediatric patients, with an age range of 1 to less than 18 years. Participants are required to have a body weight of at least 40 kg if they are in the adult formulation group. The trial population was selected based on specific laboratory values and prior treatment history, ensuring that participants have failed or shown intolerance to their most recent tyrosine kinase inhibitor therapy. The study also requires evidence of the typical BCR-ABL fusion gene transcript, which is amenable to standardized real-time quantitative polymerase chain reaction quantification. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the general health status or lifestyle habits of the participants.

The clinical trial is designed as a **multi-center, open-label study** to evaluate the dose and safety of oral **asciminib** in pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP), who have been previously treated with one or more tyrosine kinase inhibitors. The primary objective is to characterize the pharmacokinetic profile of asciminib in this population, aiming to identify a pediatric formulation dose that achieves exposure comparable to 40 mg BID in adult patients. The trial is categorized as an integrated phase 1-2 study, with an estimated recruitment start date of September 28, 2022, and an estimated end date of September 30, 2031.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific laboratory values and prior treatment history. The inclusion criteria require participants to be between 1 and less than 18 years of age, with specific hematologic parameters and evidence of the BCR-ABL fusion gene. Follow-up visits will be scheduled to monitor pharmacokinetic parameters, safety, and efficacy, including hematologic and molecular responses. The end-of-study visit will conclude the participant's involvement, which is expected to last until the study's completion unless early termination is warranted.

Early termination from the study may occur if participants experience significant adverse events, fail to comply with study procedures, or withdraw consent. The primary endpoints include the assessment of primary pharmacokinetic parameters such as AUClast and AUCtau, while secondary endpoints focus on safety data, treatment-emergent adverse events, and assessments of growth and sexual maturation. The study will also evaluate the acceptability and palatability of the formulation through questionnaires administered after the first dose and at 4 and 52 weeks. The trial's design ensures a comprehensive evaluation of asciminib's safety and efficacy in the target pediatric population.

The clinical trial involves the administration of **Asciminib**, a film-coated tablet, as the experimental medication. Asciminib is chemically derived and is provided in a pediatric formulation. The active substance in the tablet is **asciminib hydrochloride**. The medication is administered orally, with the dosage and frequency tailored to achieve exposure levels comparable to 40 mg taken twice daily (BID) in adult patients, although specific dosing details for pediatric patients are not provided. The tablets are packaged in bottles specifically for clinical trials, differing from the commercial blister pack presentation. The shelf life for the clinical packaging is 48 months, compared to 36 months for the commercial packaging.

In this study, there are no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments mentioned. The focus is solely on the administration of Asciminib to evaluate its pharmacokinetic profile in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (Ph+ CML-CP), who have been previously treated with one or more tyrosine kinase inhibitors. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure accurate assessment of the medication's safety and efficacy.

The efficacy of the clinical trial involving **asciminib** in pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on the pharmacokinetic (PK) parameters of **asciminib**, specifically AUClast and AUCtau. Secondary PK parameters include Cmax, Tmax, and Ctrough. These parameters will be measured to determine the drug's exposure and absorption characteristics in the pediatric population.

Secondary endpoints will evaluate the safety and activity of the treatment. This includes the number, seriousness, severity, and causality assessments of treatment-emergent adverse events. Additionally, hematologic and molecular responses will be monitored to assess the therapeutic activity of **asciminib**. Patient-reported outcomes will be collected through a questionnaire on the acceptability and palatability of the treatment after the first dose, and at weeks 4 and 52. Safety data will also encompass growth and sexual maturation assessments.