Abstract 4062: A computational driven protocol of metronomic oral vinorelbine in metastatic non small cell lung cancer
2017
Over the last decade, metronomic chemotherapy (MC) has emerged as an alternative way to administrate chemotherapy. MC can be defined as regular administration of low/less-toxic doses without extended drug-free breaks. Because countless schedules are possible, testing them empirically looks like an unachievable goal. Therefore, mathematical modeling can be an effective tool to determine appropriate metronomic strategies. A phase Ia/Ib study based on a mathematical model of oral vinorelbine in metastatic NSCLC and malignant pleural mesothelioma was designed to confirm safety and evaluate efficacy of a new metronomic regimen (Elharrar et al. 2016). The optimized schedule providing weekly Day1 (D1), D2 and D4 with respective doses of 60, 30 and 60 mg was suggested by in silico simulations using a Pharmacokinetic-Pharmacodynamic (PKPD) model taking into account vinorelbine PK, PD toxicities and PD efficacy (Faivre et al. 2013). Trial recruitment will be two-staged, as 12 patients have been enrolled to confirm safety and consolidate the calibration of model parameters. An extension phase on 20-extra patients will be conducted to evaluate the efficacy of the optimized protocol. Monolix 4.3.3 was used for population PKPD analysis. A three-compartment model best described oral vinorelbine PK data. PK analysis revealed a high inter-individual variability on drug exposure (CV=73%). PD toxicity (neutropenia) was adequately described by a modified Friberg model (Friberg et al. 2002), considering continuous administrations of metronomic dosing regimen. On the 12 recruited patients, 3 (25%) presented either a stable disease (SD) or a partial response (PR). No direct link has been established between toxicity (grade 4 neutropenia) and drug exposure. However, responders to treatment were those presenting a higher vinorelbine area under the curve (p=0.02). Tumor assessments were used to adjust efficacy parameters. The model was used to simulate alternative metronomic scenarios targeting higher efficacy with similar toxicity. Simulations showed that the initial proposed schedule was the most appropriate in terms of efficacy/toxicity balance. Its efficacy will be evaluated in the second part of the study. This trial can be considered as a proof-of-concept study demonstrating the feasibility to run a computational-driven protocol to ensure an optimal efficacy/toxicity balance in cancer patients. Citation Format: Diane-Charlotte Imbs, Raouf El Cheikh, Joseph Ciccolini, Raphael Serre, Fabrice Barlesi, Dominique Barbolosi. A computational driven protocol of metronomic oral vinorelbine in metastatic non small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4062. doi:10.1158/1538-7445.AM2017-4062
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
0
References
0
Citations
NaN
KQI