Model-based drug development to support isatuximab dosing regimen selection in Phase II multiple myeloma patients
Hoai-Thu Thai (1), Li Liu (2), Dorothée Semiond (1), Claire Brillac (1), Eric Charpentier (2), Laurent Nguyen (1), Christine Veyrat-Follet (1)
(1) Drug Disposition, Sanofi, Paris, France (2) Biostatistics and Programming, Sanofi, US
Objectives: Isatuximab (ISA) is a humanized anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement [1]. The objective of this work was to optimize the phase II dosing-regimen of ISA in multiple myeloma (MM) patients using modeling and simulation.
Methods: The proposed framework associated exposure-response analysis with disease modeling of tumor burden. The preliminary data from a phase I/II monotherapy trial [2] included: PK, serum M-protein and best overall response (BOR) in 170 patients receiving ISA from 1 to 20 mg/kg every 2 weeks or weekly. First, we developed a population PK model for ISA then the relationship between various PK parameters and BOR was investigated in an exploratory exposure-response analysis. Baseline covariates were also considered in the model to reduce their potential confounding effects. Disease progression was captured in a subset of 122 evaluable patients with the dynamics of the serum M-protein and accounted for dropout using a joint model. Simulations were then performed to evaluate different dosing regimens of interest in terms of efficacy.
Results: ISA PK was best described by a two-compartment model with parallel linear and nonlinear elimination and time-dependence on clearance while serum M-protein kinetics was adequately described by an exposure-driven tumor growth inhibition model [3]. The exposure-response relationships (logit Emax model) suggested that high Ctrough at 4 weeks lead to better efficacy. Interestingly, patients with lower linear clearance were more likely to respond. Longitudinal modeling of M-protein provided more insights in the response of patients over time. Therefore, a high loading dose of 20 mg/kg weekly over 4 weeks was chosen for maximizing the tumor response and a maintenance dose of 20 mg/kg every 2 weeks appeared sufficient to sustain efficacy. This dosing regimen presented a probability of success of 85% to reach 30% overall response rate with 100 patients and would allow 53% reduction of serum M-protein from baseline at 2 months of treatment. In addition, ISA appeared to be well tolerated at this dose level.
Conclusions: Model-based drug development has been successfully applied to support phase II ISA dosing regimen selection in MM patients. This approach increases both the robustness of decision making and the chances of success of the future Phase III program.
References:
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