Phase i clinical and pharmacokinetic study of trabectedin and cisplatin given every three weeks in patients with advanced solid tumors

Cristiana Sessa, Gianluca Del Conte, Alexandre Christinat, Sara Cresta, Antonella Perotti, Elisa Gallerani, Pilar Lardelli, Carmen Kahatt, Vicente Alfaro, Jorge L. Iglesias, Carlos Fernández-Teruel, Luca Gianni

Research output: Contribution to journalArticle

Abstract

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 75 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 3 weeks (q3wks). Two dose-limiting toxicities (DLTs), grade 4 neutropenia longer than 7 days duration and grade 3 vomiting despite standard antiemetic therapy, occurred at the starting dose of trabectedin (0.75 mg/m2). The immediately lower dose (trabectedin 0.60 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 48 h, lower platinum clearance and longer half-life. In conclusion, although the trabectedin dose achieved with this combination was low (50 % 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.

Original languageEnglish
Pages (from-to)1236-1243
Number of pages8
JournalInvestigational New Drugs
Volume31
Issue number5
DOIs
Publication statusPublished - Oct 2013

Keywords

  • Antitumor
  • Cisplatin
  • Cytotoxic
  • Dose-limiting toxicities
  • Phase I
  • Trabectedin

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

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    Sessa, C., Del Conte, G., Christinat, A., Cresta, S., Perotti, A., Gallerani, E., Lardelli, P., Kahatt, C., Alfaro, V., Iglesias, J. L., Fernández-Teruel, C., & Gianni, L. (2013). Phase i clinical and pharmacokinetic study of trabectedin and cisplatin given every three weeks in patients with advanced solid tumors. Investigational New Drugs, 31(5), 1236-1243. https://doi.org/10.1007/s10637-013-9942-y