title: Phase I clinical and pharmacokinetic study of trabectedin and cisplatin given every three weeks in patients with advanced solid tumors.
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/m(2) 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/m(2)). The immediately lower dose (trabectedin 0.60 mg/m(2)) 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.
authors: Istituto Oncologico della Svizzera (IOSI), Ospedale San Giovanni, 6500, Bellinzona, Switzerland, Cristiana.Sessa@eoc.ch.
authors: Cristiana
authors: C
authors: Sessa
authors: Gianluca
authors: G
authors: Del Conte
authors: Alexandre
authors: A
authors: Christinat
authors: Sara
authors: S
authors: Cresta
authors: Antonella
authors: A
authors: Perotti
authors: Elisa
authors: E
authors: Gallerani
authors: Pilar
authors: P
authors: Lardelli
authors: Carmen
authors: C
authors: Kahatt
authors: Vicente
authors: V
authors: Alfaro
authors: Jorge L
authors: JL
authors: Iglesias
authors: Carlos
authors: C
authors: Fernández-Teruel
authors: Luca
authors: L
authors: Gianni
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004149:Dioxoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077606:Trabectedin; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D002945:Cisplatin