New pediatric formulation of asciminib in children with chronic myeloid leukemia in chronic phase: Second interim analysis of pharmacokinetics and safety from the ASC4Kids study.

Abstract

10027 Background: More treatment (tx) options to improve efficacy and long-term safety to minimize adverse effects on growth are needed for pediatric patients (pts) with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP). Asciminib (ASC) is the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), approved for adults with newly diagnosed or previously treated CML-CP. The phase Ib/II, multi-center, open-label ASC4Kids study (NCT04925479) aims to identify the pediatric formulation (PF) dose (with food) leading to ASC exposure comparable to the adult formulation (AF) dose (fasted) of 40 mg twice daily (BID) and assess its safety. Methods: Pts aged 1– < 18 years (yrs) with CML-CP, without the T315I mutation, treated with ≥1 prior tyrosine kinase inhibitors are included. The primary objective is to characterize the pharmacokinetic (PK) profile of ASC in pediatric pts. Secondary endpoints include safety and molecular responses. In an exploratory AF group, pts 14‒ < 18 yrs were treated with the AF. In Part 1 (dose determination), the PF dose of 1.3 mg/kg BID was confirmed based on exposure in adult studies (40 mg BID) and no observed dose-limiting toxicities (DLTs) over the first 28 days. In Part 2 (dose expansion), additional pts are treated with the confirmed PF dose for further evaluation of exposure and DLTs (across Parts 1+2; 10 pts per group: 1‒ < 12 yrs and 12‒ < 18 yrs). In Part 3, 10 more pts will be enrolled to receive PF 2.6 mg/kg once daily (QD). This interim analysis was conducted after 10 pts in the PF 12‒ < 18 yrs group had completed 28 days of tx in Parts 1+2. Results: 19 pts were enrolled in the PF group (7 in 1‒ < 12 yrs and 12 in 12‒ < 18 yrs groups, respectively). At data cutoff (19-Aug-2024), all pts continued to receive tx. For the PF group (12‒ < 18 yrs), 10 pts were evaluable for PK. Averaged ASC exposure with PF 1.3 mg/kg BID was comparable to that observed in adult studies (median last measured concentration [AUClast]: 7091 vs 5130 hr*ng/mL; median maximum plasma concentration [Cmax]: 1031 vs 939 ng/mL, respectively). For all pts in the PF group, no DLTs were observed. With a median duration of exposure of 36.7 weeks, 18 pts experienced adverse events (AEs; any grade); 2 had Grade ≥3 AEs. From baseline (BL) to data cutoff for height percentile shift in the PF group; 9 pts stayed in the same percentile, 4 dropped and 6 increased. Four of 19 pts had notably low bone age at BL; 3 of these also at Week 52. At BL,16/18 pts in the PF group had BCR::ABL1 IS ≤10% and 6 were in major molecular response (MMR). Of 11 and 9 pts evaluable for efficacy at Weeks 28 and 40, 10 and 9 had BCR::ABL1 IS ≤1%, and 7 and 6 were in MMR, respectively. Conclusions: The confirmed PF ASC dose of 1.3 mg/kg BID was well tolerated in pediatric pts, with evidence of efficacy and no new safety signals. In Part 3, a 2.6 mg/kg dose QD will be evaluated. Clinical trial information: NCT04925479 .