Optimization of trabectedin temporal protocol using mathematical PK/PD modeling.

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e23553 Background: Trabectedin (ET-743, Yondelis) is an antineoplastic agent indicated for the treatment of advanced soft tissue sarcomas (STS). Despite its efficacy, Trabectedin induces severe toxic side effects, especially neutropenia. In clinical settings, this leads to empirical dosing adjustments that disrupt the efficacy-toxicity balance. Developing a quantitative tool that allows for better dosing adjustments using patients-specific data would be of great utility. Methods: Retrospective hematologic, demographic and disease status data from 39 patients with metastatic STS were collected and analyzed. All patients received Trabectedin standard protocol (24-h infusion at the dose of 1.5 mg/m2 every 3 weeks). A mathematical PK/PD model describing the time course of neutrophils under Trabectedin treatment was developed. Model parameters were estimated using nonlinear mixed effects analysis under the software MONOLIX. Further statistical analyses to look for covariates impacting neutropenia incidence were performed. Results: Using the mathematical model and optimization techniques, we propose a new protocol that reduces neutropenia incidence. The optimized protocol consists of three Trabectedin injections: 0.65 mg/m2 D1, 0.3 mg/m2 D8 and 0.55 mg/m2 D15 within a cycle of 28 days. Statistical analysis showed significant correlation (Log-rank p = 0.015) between baseline absolute neutrophil count (ANC) and progression-free survival (PFS). Patients with baseline ANC < 7.5 G/L had a median PFS of 158.5 days, while patients with baseline ANC > 7.5G/L had a median PFS of 71 days. We did not observe significant correlation between demographic covariates, disease status and neutropenia incidence. Conclusions: Mathematical modeling offers a valuable tool to optimize the dosing regimen for Trabectedin treatment. Baseline value of absolute neutrophil count was shown to impact disease evolution; therefore, it should be considered when adjusting Trabectedin protocol to improve dosing personalization.

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