Invest New Drugs. 2013 Mar 7.
Sessa C, Del Conte G, Christinat A, Cresta S, Perotti A, Gallerani E, Lardelli P, Kahatt C, Alfaro V, Iglesias JL, Fernández-Teruel C, Gianni L.
Source : Istituto Oncologico della Svizzera (IOSI), Ospedale San Giovanni, 6500, Bellinzona, Switzerland .
The aim of this phase I study was to identify a feasible dose and schedule for the combination of cisplatin and trabectedin. The regimen evaluated consisted of cisplatin at a fixed dose of 75Â mg/m2 1-hour intravenous (i.v.) infusion followed by escalating doses of trabectedin 3-hour i.v. infusion, both administered on day 1 every 3Â weeks (q3wks). Two dose-limiting toxicities (DLTs), grade 4 neutropenia longer than 7Â days duration and grade 3 vomiting despite standard antiemetic therapy, occurred at the starting dose of trabectedin (0.75Â mg/m2). The immediately lower dose (trabectedin 0.60Â mg/m2) was evaluated in a total of 8 patients; no DLTs occurred and this was declared the recommended dose (RD). The safety profile of the combination at this dose and schedule was consistent with the known side effects of each agent alone: nausea, fatigue, transient transaminase elevations and neutropenia. No new or unexpected adverse reactions were observed. Two partial responses were reported at the RD in patients with pretreated ovarian cancer. Comparison with population pharmacokinetic data suggests a PK interaction between trabectedin and cisplatin leading to increased plasma exposure of trabectedin in the first 48Â h, lower platinum clearance and longer half-life. 
In conclusion, although the trabectedin dose achieved with this combination was low (50Â % of single-agent when given q3wks), this day 1 q3wks trabectedin plus cisplatin combination showed a feasible administration, a tolerable safety profile and some antitumor activity.