Selection of isatuximab dosing regimen in pediatric patients with leukemia using population pharmacokinetics.

[PURPOSE] Isatuximab, an immunoglobulin G monoclonal antibody that targets a specific CD38 epitope, is approved in combination with dexamethasone plus either pomalidomide or carfilzomib for treatment of adults with relapsed or refractory (R/R) multiple myeloma. Isatuximab demonstrated significant anti-leukemic activity in preclinical models. In the phase 2 ISAKIDS study (NCT03860844), isatuximab was tested as combination therapy for pediatric patients with R/R acute lymphoblastic leukemia and acute myeloid leukemia. Here, we use population pharmacokinetics (PopPK) to select the appropriate isatuximab dose for infants aged 1-24 months in ISAKIDS.

[METHODS] An initial PK modeling and simulation strategy was applied to the first 18 tested patients to confirm the isatuximab 20-mg/kg dose administered to patients aged 24 months or older and to explore the dose needed for the youngest patients. The PK of isatuximab in children was characterized by pooling data from ISAKIDS with adult data from the phase 2 ISLAY study (NCT02999633).

[RESULTS] The PopPK model predicted a slight drug underexposure (median decrease of about 30%) in pediatric patients aged 10-24 months (9-12 kg) compared with reference adults (51-100 kg), which did not require a dose adjustment, as no isatuximab exposure versus efficacy relationships were observed in these clinical settings.

[CONCLUSION] The modeling and simulation strategies in this study support the previous selection of a 20-mg/kg dose for all age groups and enabled both de-risking of dose selection and the ability to pursue additional pediatric investigation of isatuximab in the youngest age group of patients with acute leukemias.