Translational model-based approach to assist the dose-range selection of an antibody-drug conjugate entering Phase I
P. Mazzei (1), G. Smania (1), C. Piana (1), P. Magni (2), M. Binaschi (1), M. Bigioni (1), G. Merlino (1), R. Bugianesi (1), V. Chirulli (1), C. Simonelli (1), A. Capriati (1), A. Pellacani (1)
(1) Menarini Ricerche S.p.A., Florence and Pomezia (Italy). (2) Department of Electrical, Computer and Biomedical Engineering, University of Pavia (Italy)
Objectives: MEN1309 is an antibody-drug conjugate (ADC) specifically targeting cells expressing CD205/Ly75 antigen, inducing potent cytotoxic and antitumoral effect in preclinical models. This analysis aimed to propose a model-based strategy to support the design of the dosing regimen for the first-in-human (FIH) study, leveraging available data from toxicokinetic studies in monkey and in-vivo tumor growth experiments in mouse xenograft.
Methods: First, allometric approaches were applied to monkey PK data to predict the human PK profile. Second, a population PK/PD model was developed to scale the time-course of MEN1309-induced neutropenia from monkey to patients. Third, tumor growth inhibition data in mice were modelled to define the target exposure in human. Finally, the risk-benefit profile of the proposed dosing schedule was evaluated based on predicted neutropenia and expected antitumor activity in patients. Clinical trial simulations (CTS) were also performed to explore plausible scenarios for the FIH study (e.g., sample size and dose limiting toxicity occurrences). Data analysis was performed in NONMEM, Matlab and R software.
Results: MEN1309 monkey PK were described by a 2-compartment model with linear and non-linear elimination from the central compartment; both linear and non-linear clearance were scaled based on body weight using an allometric exponent of 1 [1]. Myelosuppression in monkey was modelled by the Friberg model [2] that adequately described the observed neutropenia after single and repeat dose; time-courses of neutropenia in patients were then predicted based on expected PK in human, typical human system-related parameters reported in the literature and drug-effect parameters estimated in monkey [3]. Tumor growth dynamics in mice was described by the Simeoni TGI model [4], from which the concentration threshold and target exposure in human were computed. Finally, CTS enabled the computation of several quantities of interest that supported the feasibility of the proposed accelerated titration design with 100% dose escalations that reverts to a more conservative design with smaller dose escalations once Grade ≥ 2 toxicity is observed.
Conclusions: By effectively allowing a model-based “humanization” of preclinical efficacy and toxicity data that otherwise are difficult to interpret from a clinical point of view, the proposed translational strategy supports the regimen design for the FIH study.
References:
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