Abstract 5182: Population pharmacokinetic modeling of ciltacabtagene autoleucel in subjects with relapsed or refractory multiple myeloma
Authors: Wu Liviawati S. , Su Yaming , Li Claire , Zhou Wangda , Jackson Carolyn , Sun Yu-Nien , Zhou Honghui 
Published: June 2022

Abstract
Objectives: Ciltacabtagene autoleucel (cilta-cel, CARVYKTI, previously JNJ-68284528) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma. Due to the restricted expression of BCMA in normal tissue and expression primarily on late-stage B-cells, plasma cells and malignant B-lineage cells, BCMA is an attractive target for cell therapy for multiple myeloma. The chimeric antigen receptor (CAR) consists of two BCMA-targeting single domain antibodies designed to confer avidity, a CD3ζ signaling domain and a 4-1BB costimulatory domain. The aims of this work were to develop a population pharmacokinetic (PK) model for CAR transgene after single intravenous infusion administration of cilta-cel and to evaluate the effects of subjects’ demographic characteristics and other covariates on CAR transgene PK.
Methods: Subjects CAR transgene level in blood, as measured by quantitative polymerase chain reaction (qPCR) were available from 97 subjects in a Phase 1b/2 CARTITUDE-1 study (NCT03548207). A targeted cilta-cel dose of 0.75x106 (range 0.5-1.0x106) CAR-positive viable T-cells/kg body weight was given 5-7 days after lymphodepletion (300 mg/m2 cyclophosphamide, 30 mg/m2 fludarabine daily for 3 d). The data were analyzed by a non-linear mixed effects modeling approach implemented in NONMEM V7.4.3. The population PK model development was based on existing information on CAR T-cell (CAR-T) PK with some modifications. Model qualification was guided by the objective function value, diagnostic plots, standard error of parameters, evaluation of condition number, shrinkage, and visual predictive checks.
Results: The PK of cilta-cel following IV infusion was adequately described by a 2-compartment model (with a fast and a slow apparent decline rate from each compartment, respectively) and a chain of 4 transit compartments with a lag time empirically representing the process from infused CAR-T cell to measurable CAR transgene. The model diagram is shown in Figure 1, consisting of 5 parameters and their respective inter-individual variability (lognormal distribution). The dose was defined as the number of CAR-positive viable T cells infused, and the fitted CAR transgene level (units of copies/μg genomic DNA) observation was the sum of the 2 CAR-T cell compartments.
Conclusion: A population PK model has been developed to characterize CAR transgene level of cilta-cel in blood following IV infusion of 0.75x106 (range 0.5-1.0x106) CAR-positive viable T-cells/kg body weight. The developed model is robust and adequate for investigating the covariate effects on CAR transgene level of cilta-cel and enabling subsequent exposure-safety and exposure-efficacy analyses.
Citation Format: Liviawati S. Wu, Yaming Su, Claire Li, Wangda Zhou, Carolyn Jackson, Yu-Nien Sun, Honghui Zhou. Population pharmacokinetic modeling of ciltacabtagene autoleucel in subjects with relapsed or refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5182.