Novartis is advancing a comprehensive pediatric development program for asciminib, the first-in-class allosteric ABL kinase inhibitor, through the multicenter ASC4KIDS trial designed to establish optimal dosing strategies for children and adolescents with chronic myeloid leukemia in chronic phase (CML-CP).
The Phase 1b/2 study (NCT04925479) represents a critical step in expanding treatment options for pediatric CML patients, addressing an unmet medical need in a population where more effective and safer therapeutic alternatives are required beyond current tyrosine kinase inhibitor (TKI) standards of care.
Novel Mechanism Targets Unmet Pediatric Need
Asciminib distinguishes itself from conventional TKIs through its unique allosteric mechanism, specifically targeting the ABL myristoyl pocket (STAMP) without inhibiting other protein kinases. This selectivity profile contributed to its FDA approval for adult patients aged 18 years and older with Philadelphia chromosome-positive CML-CP who have received at least two prior TKIs.
The drug demonstrated superior efficacy in the pivotal ASCEMBL study, achieving major molecular response rates of 25.5% versus 13.2% at week 24 compared with bosutinib 500 mg once daily in adult patients, while maintaining a favorable safety profile.
Comprehensive Pediatric Dosing Strategy
The ASC4KIDS trial employs a sophisticated three-part design to characterize pharmacokinetics and establish appropriate dosing across pediatric age groups. The study targets patients aged 1 to less than 18 years with Philadelphia chromosome-positive CML-CP, excluding those with the T315I mutation, who have received at least one prior TKI.
Part 1 serves as the dose-determining cohort, enrolling 4-6 patients to receive asciminib pediatric formulation at 1.3 mg/kg twice daily with food. The primary objective focuses on achieving asciminib exposure comparable to the established adult dose of 40 mg twice daily under fasted conditions.
Following interim analysis and potential dose adjustments, Part 2 expands enrollment to 14-16 patients receiving the optimized dose from Part 1. Part 3 introduces a once-daily regimen evaluation with 10 patients (5 per age group) receiving the same total daily dose as a single administration.
Age-Stratified Enrollment Approach
The trial design ensures adequate representation across pediatric age ranges, requiring at least 15 participants in each of two key categories: 1 to less than 12 years and 12 to less than 18 years. This stratification addresses potential developmental differences in drug metabolism and response.
Due to pediatric formulation development timelines, the study initially recruited adolescent patients aged 14 to less than 18 years weighing at least 40 kg, who received the adult tablet formulation at 40 mg twice daily under fasted conditions.
Extended Treatment and Analysis Timeline
The comprehensive study design incorporates a 5-year treatment period (260 weeks), allowing patients who demonstrate clinical benefit to continue therapy throughout the entire duration. Primary analysis for the twice-daily regimen is planned after all participants in Parts 1 and 2 complete at least 52 weeks of treatment or discontinue earlier.
The combined regimen analysis will occur after all participants across all three parts complete 52 weeks of treatment, providing robust long-term safety and efficacy data to support regulatory submissions.
Global Recruitment Progress
As of February 2023, the international trial spanning 34 study sites across 14 countries had enrolled 10 patients, with 4 in the exploratory group and 6 in the pediatric formulation cohort. This global approach ensures diverse patient representation and accelerated enrollment.
Full Extrapolation Strategy
The development program leverages a full extrapolation approach based on established similarities between pediatric and adult CML pathogenesis, clinical characteristics, and disease progression patterns. This strategy aims to minimize pediatric patient exposure to investigational treatments while maintaining regulatory rigor.
The study's primary pharmacokinetic objective seeks to identify optimal pediatric dosing that achieves exposure levels comparable to the proven adult regimen, supporting potential label expansion to younger patient populations with this novel therapeutic mechanism.
