Phase I and pharmacokinetic study of trabectedin 3-hour infusion every three weeks in patients with advanced cancer and alteration of hepatic function

Maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics (PK) were evaluated for trabectedin 3-h every-3-weeks schedule in 33 cancer patients stratified according to liver dysfunction degree as per baseline alkaline phosphatase (AP). Stratification was as follows: stratum I [upper limit of normal (ULN) < AP <= 1.5 x ULN; n = 16], stratum II [1.5 x ULN < AP <= 2.5 x ULN; n = 12], and stratum III [AP >2.5 x ULN; n = 5] (bilirubin <2.5 x ULN for all 3 strata). In each stratum, patients were treated in sequential cohorts at escalating doses. Dose-limiting toxicities (DLTs) were grade 3 transaminase increases not recovering baseline values on day 21, febrile neutropenia/grade 4 neutropenia lasting >5 days and AP increase more than twice over baseline. The MTD and RD for stratum I (mild baseline AP) was 1.3 mg/m(2). Recruitment was stopped early in strata II/III (moderate/severe baseline AP) without reaching the MTD due to slow accrual and difficulty in finding patients. Biochemical parameters other than AP (bilirubin, AST or ALT) were similar between strata. No relevant PK differences were found between strata. In conclusion, the MTD and RD (1.3 mg/m(2)) were confirmed only for stratum I. Stratification criteria based on baseline AP apparently did not segregate the patients according to their liver dysfunction degree. Antitumor activity was found in patients with pretreated ovarian cancer.