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

Abstract

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 × ULN; n = 16], stratum II [1.5 × ULN < AP ≤ 2.5 × ULN; n = 12], and stratum III [AP >2.5 × ULN; n = 5] (bilirubin <2.5 × 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.

Phase I and pharmacokinetic study of trabectedin, a DNA minor groove binder, administered as a 24-h continuous infusion in Japanese patients with soft tissue sarcoma

“…3d). Because the clearance of trabectedin correlated with clearance of midazolam, it is apparent that the clearance of trabectedin depends on the hepatic clearance by CYP3A4 which is a main metabolism enzyme for trabectedin [23]. It is reported that there is not ethnic difference over individual difference in pharmacokinetics of midazolam [24].…”

Clinical utility of trabectedin for the treatment of ovarian cancer: current evidence

“…Interestingly enough, there was no difference in serum level of markers of liver function (bilirubin, transaminases, etc) according to different serum AP levels;39 this finding has been confirmed in a pharmacokinetic analysis in which no relation was evident between AP or transaminase levels with trabectedin pharmacokinetics 31. In conclusion, as far as the available data are concerned, trabectedin (at the dose of 1.3 mg/m 2 ) can be utilized in patients with mild hepatic dysfunction, who nevertheless should be closely monitored 39…”

“…Moreover, the distribution volume at steady state was generally reported to be large (up to 4,000 L) in the weekly administration as well as in the 3-weekly schedules 32–39…”

“…Table 1 summarizes the studies investigating the safety and assessing the maximum tolerated dose (MTD) for trabectedin used as single agent;32–39 different dose escalation and schedules have been explored, including 3-weekly schedules (1 day, 1-hour to 72-hour infusion; 5 consecutive days, 1-hour infusion), or every 4 weeks schedule (1 day, 1-hour to 3-hour infusion) (Table 1). …”

Review Trabectedin as a single agent and in combination with pegylated liposomal doxorubicin – activity against ovarian cancer cells

“…The most common side effects are fatigue, nausea, anorexia, vomiting, constipation, atelectasis, dyspnoea, neutropenia, haemorrhoids, and intestinal obstruction. There were no indications of renal toxicity in rats (or mice and dogs) [ 7 , 14 , 17 , 18 ]. There is also no cardiac toxicity and no ECG changes (considered as prolongation of QT/QTc interval) after treatment with trabectedin [ 17 ].…”