Population-Pharmacokinetic and Covariate Analysis of Lurbinectedin (PM01183), a New RNA Polymerase II Inhibitor, in Pooled Phase I/II Trials in Patients with Cancer.

Background And Objectives: Lurbinectedin is an inhibitor of RNA polymerase II currently under clinical development for intravenous administration as a single agent and in combination with other anti-tumor agents for the treatment of several tumor types. The objective of this work was to develop a population-pharmacokinetic model in this patient setting and to elucidate the main predictors to guide the late stages of development.

Methods: Data from 443 patients with solid and hematologic malignancies treated in six phase I and three phase II trials with lurbinectedin as a single agent or combined with other agents were included in the analysis.

A phase I and pharmacokinetic study of plitidepsin in children with advanced solid tumours: an Innovative Therapies for Children with Cancer (ITCC) study.

Aims: To determine the maximum tolerated dose, the recommended dose (RD) for phase II studies, dose-limiting toxicities and pharmacokinetics (PK) for plitidepsin administered as a 3-h intravenous infusion every 2weeks (one cycle) to children with refractory or relapsed solid tumours.

Methods: Consecutive cohorts of patients were treated according to a standard '3+3' design with escalating doses of plitidepsin at 4, 5 and 6mg/m(2). Additional 15 patients were recruited at the RD to further evaluate safety and pharmacokinetic associations with respect to age, dose level and toxicity.