Pharmacokinetics and Pharmacodynamics effects of Everolimus and Sorafenib combination: Impact of doses and sequence of administration on the combination Thesis

Abstract

Rationale of EVESOR study • The development of everolimus and sorafenib combination was stopped by drug companies, due to the high toxicity index and the lack of a clear benefit/toxicity ratio to guide dose recommendations for a phase II trial. Daily monotherapy regimens of both drugs were used. However, sorafenib dosing schedule may impact on everolimus tumor delivery and thus on toxicity & efficacy. It should be possible to determine the optimized doses and dosing schedules of both drugs, which are able to maximize the benefit/toxicity ratio, using modeling and simulation studies. We designed the first multi-parameter phase I study (EVESOR), based on mathematical modeling of data provided from an adequately designed trial with this objective. Design of EVESOR trial • EVESOR trial was a four-arm, multiparameter Phase I trial of everolimus and sorafenib. This is an open-label, phase Ib trial where patients with metastatic or locally advanced cancers who are deemed eligible were treated with the combination of sorafenib an