Translational Modeling Predicts Efficacious Therapeutic Dosing Range of Teclistamab for Multiple Myeloma.

Autor: Girgis S; Janssen Research & Development, 920 Route 202, Raritan, NJ, 08869, USA. SGirgis@its.jnj.com., Lin SXW; Janssen Research & Development, Spring House, PA, USA., Pillarisetti K; Janssen Research & Development, Spring House, PA, USA., Banerjee A; Janssen Research & Development, Spring House, PA, USA., Stephenson T; Janssen Research & Development, Spring House, PA, USA., Ma X; Janssen Research & Development, Spring House, PA, USA., Shetty S; Janssen Research & Development, Spring House, PA, USA., Yang TY; Janssen Research & Development, Spring House, PA, USA., Hilder BW; Janssen Research & Development, Spring House, PA, USA., Jiao Q; Janssen Research & Development, Spring House, PA, USA., Hanna B; Janssen Research & Development, Spring House, PA, USA., Adams HC 3rd; Janssen Research & Development, Spring House, PA, USA., Sun YN; Janssen Research & Development, Spring House, PA, USA., Sharma A; Janssen Research & Development, Tokyo, Japan., Smit J; Janssen Research & Development, Spring House, PA, USA., Infante JR; Janssen Research & Development, 920 Route 202, Raritan, NJ, 08869, USA., Goldberg JD; Janssen Research & Development, 920 Route 202, Raritan, NJ, 08869, USA., Elsayed Y; Janssen Research & Development, Spring House, PA, USA.
Jazyk: angličtina
Zdroj: Targeted oncology [Target Oncol] 2022 Jul; Vol. 17 (4), pp. 433-439. Date of Electronic Publication: 2022 Jun 24.
DOI: 10.1007/s11523-022-00893-y
Abstrakt: Background: Teclistamab (JNJ-64007957), a B-cell maturation antigen × CD3 bispecific antibody, displayed potent T-cell-mediated cytotoxicity of multiple myeloma cells in preclinical studies.
Objective: A first-in-human, Phase I, dose escalation study (MajesTEC-1) is evaluating teclistamab in patients with relapsed/refractory multiple myeloma.
Patients and Methods: To estimate the efficacious therapeutic dosing range of teclistamab, pharmacokinetic (PK) data following the first cycle doses in the low-dose cohorts in the Phase I study were modeled using a 2-compartment model and simulated to predict the doses that would have average and trough serum teclistamab concentrations in the expected therapeutic range (between EC 50 and EC 90 values from an ex vivo cytotoxicity assay).
Results: The doses predicted to have average serum concentrations between the EC 50 and EC 90 range were validated. In addition, simulations showed that weekly intravenous and subcutaneous doses of 0.70 mg/kg and 0.72 mg/kg, respectively, resulted in mean trough levels comparable to the maximum EC 90 . The most active doses in the Phase I study were weekly intravenous doses of 0.27 and 0.72 mg/kg and weekly subcutaneous doses of 0.72 and 1.5 mg/kg, with the weekly 1.5 mg/kg subcutaneous doses selected as the recommended Phase II dose (RP2D). With active doses, exposure was maintained above the mean EC 90 . All patients who responded to the RP2D of teclistamab had exposure above the maximum EC 90 in both serum and bone marrow on cycle 3, Day 1 of treatment.
Conclusions: Our findings show that PK simulations of early clinical data together with ex vivo cytotoxicity estimates can inform the identification of a bispecific antibody's therapeutic range.
Clinical Trial Registration: NCT03145181, date of registration: May 9, 2017.
(© 2022. The Author(s).)
Databáze: MEDLINE
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