Asciminib pediatric formulation shows a tolerable safety profile in pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP): Second interim analysis from the ASC4KIDS study Free

Introduction: Standard of care tyrosine kinase inhibitors (TKIs) improve the outcomes for children with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP); however, their chronic use may lead to adverse events. Novel treatment options with substantially improved long-term safety and minimal effects on growth and quality of life are a high unmet need for these patients. Asciminib is the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP) and is approved for adults with newly diagnosed (agnostic, US) or pretreated Ph+ CML-CP (≥2 TKIs, worldwide). The phase 1b/2, multicenter, open-label ASC4KIDS study (NCT04925479) aims to assess the pharmacokinetic (PK), safety and efficacy profile of a pediatric formulation (PF) of asciminib in pediatric patients. Here, we present the second interim analysis results from this study.

Methods: The study included patients aged 1 to <18 years with Ph+ CML-CP, without the T315I mutation, treated with ≥1 prior TKIs. The primary endpoint of the study is tocharacterize the PK profile of asciminib in children and to identify a PF dose (with food) that results in exposure comparable to the adult formulation (AF) dose (fasted) of 40 mg twice daily (BID). Secondary endpoints comprise safety including growth trajectory on treatment and efficacy based on molecular responses.

In study part 1, the PF dose of 1.3 mg/kg BID was confirmed based on the comparable exposure observed in adult studies (40 mg BID) and absence of dose-limiting toxicities (DLTs) over the first 28 days. In study part 2, at least 20 patients were treated with the confirmed PF dose in 2 age groups (10 per group; 1 to <12 [younger] and 12 to <18 yrs [older]) for further evaluation of exposure, safety, and efficacy. In study part 3, 10 additional patients (5 per group) will be enrolled to receive PF at 2.6 mg/kg once daily (QD).

This interim analysis was conducted after 10 evaluable patients in the older PF group completed 28 days of treatment in parts 1+2. PK is reported for the older PF group, as well as safety, growth, and efficacy for the overall PF group. PK data for the younger PF group will be presented at the ASH 2025 meeting.

Results: In the overall PF group, 19 patients were enrolled (7 in the younger and 12 in the older PF groups, respectively). All were ongoing treatment at data cutoff (August 19, 2024). Median duration of exposure for all patients was 36.7 weeks (range: 3.7–102.6 weeks).

For the 10 patients evaluable for PK in the older PF group, average asciminib exposure (median [range]) with PF 1.3 mg/kg BID was comparable to that observed (10^th and 90^th percentiles of medians) in the phase 3 ASCEMBL trial with adult patients (median last measured concentration [AUC_last]: 7091 {2701.3–12518.3} vs 5130 {2683.7–8476.3} h*ng/mL; median maximum plasma concentration [C_max]: 1031 {343.0–2160.0} vs 939 {473.0–1547.0} ng/mL, respectively).

Any-grade adverse events (AEs) were experienced by nearly all patients (94.7%) in the overall PF group; 2 patients had grade ≥3 AEs. The most common AEs (≥3 patients) were vomiting (n=6, 31.6%) and upper respiratory tract infection (n=4, 21.1%). Grade 3 AEs were leukopenia and neutropenia, and abdominal pain (n=1 each). AEs leading to dose interruption occurred in 3 patients (worsening neutropenia [Grade 3], n=1; vomiting [Grade 1], n=1; and vomiting and abdominal pain [Grade 1], n=1). No grade 4 AEs, serious AEs, DLTs, or AEs leading to discontinuation were reported.

For height percentile shift from baseline to data cutoff in the overall PF group, 9 patients stayed in the same percentile, 6 increased, and 4 decreased their growth trajectory. Notably, low bone age at baseline was reported in 4/19 patients, which was also reported for 3 of these patients at week 52.

BCR::ABL1^IS levels remained stable in almost all patients through week 40. At baseline,16 of 19 patients in the overall PF group had BCR::ABL1^IS≤10%; 6 were in major molecular response (MMR, BCR::ABL1^IS≤0.1%). Of 11 and 9 patients evaluable at weeks 28 and 40, respectively, 10 and 9 patients had BCR::ABL1^IS≤1%, and 7 and 6 patients were in MMR, respectively.

Conclusions: The confirmed PF dose of 1.3 mg/kg BID was well tolerated and efficacious in patients aged 12 to <18 years. Preliminary data suggest that asciminib, unlike other TKIs, may not have a negative impact on growth in most patients. In study part 3, a 2.6 mg/kg QD dose will be assessed.