Alectinib in pediatric patients with solid or CNS tumors harboring ALK-fusions: Emerging pharmacokinetic data from the iMATRIX alectinib phase I/II open-label, multi-center study.

3098 Background: Alectinib (a small orally administered CNS-penetrant molecule, inhibiting ALK-fusion proteins) is being evaluated within the iMATRIX Alectinib study (NCT04774718). The study consists of three parts (i.e., dose confirmation, initial expansion gated on response rate and additional expansion). Here we present the most recent pharmacokinetic (PK) results from all enrolled subjects within the ongoing study. Methods: Patients with ALK fusion-positive solid or CNS tumors for whom prior treatment has proven to be ineffective or for whom there is no satisfactory treatment available, less than 18 years of age, were enrolled in this study. Patients were recruited in Part 1, to confirm the Recommended Phase 2 Dose and to identify pediatric PK. PK sample analysis was expedited to provide an individualized dosing recommendation for each patient, and where necessary a dose adjustment. The pediatric starting doses within the dose confirmation phase are determined using population pharmacokinetic (popPK) analysis and simulations to match the exposures of 600 mg BID dose of alectinib in adults. Since body weight (BW) is a significant covariate influencing alectinib PK, the popPK model that accounts for BW was used as a strategy to match the PK exposures between the adult and pediatric populations. PK exposures after starting dose administration were evaluated during the first 28-day treatment cycle and doses were adjusted as needed for subsequent cycles. Results: A total of 16 patients were enrolled in the study (cut-off Jan 4th, 2024), of which 15 patients were considered PK-evaluable as they received at least one dose of alectinib and had at least one post-dose PK sample collected. Patients ranged from infants (lowest age enrolled 6 months / lowest BW 7 kg) to adolescents (highest age enrolled 17 years / highest BW 91 kg). None of the 11 pediatric subjects who were >2 years old at enrolment required any dose adjustment to match the Alectinib and its active metabolite, M4, target exposure ranges observed in adult patients. Doses for 3 out of 4 pediatric subjects < 2 years old at enrolment were below the target exposure ranges. Consequently, the administered doses were increased stepwise to bring these pediatric subjects’ exposure within the target ranges. Conclusions: The BW based popPK model successfully predicted the starting doses of all 11 treated subjects > 2 years old, leading to target exposures within range. Since 3 out of 4 subjects < 2 years old had exposure below target, the starting dose for subjects <2 years needs to be increased while ensuring that the optimal benefit/risk ratio is maintained. Clinical trial information: NCT04774718 .