Phase I clinical and pharmacological trial of trabectedin (T) in 3 hour infusion every 3 weeks (3h/q3w) in patients with advanced cancer and hepatic function disorder

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2080 Background: Trabectedin (ET-743) is a marine-derived DNA and transcription interacting agent with activity in pretreated soft tissue sarcoma, breast, prostate and ovarian cancer. T is associated with 2 types of liver function alterations: a frequent acute and reversible elevation of ALT and AST and a less frequent cholestasis, usually reflected by low grade increases in alkaline phosphatase (AP) and bilirubin (B). The main predictors of dose limiting toxicity (DLT) or T-related serious adverse events appear to include elevated baseline or intercycle peaks of AP, B and ALT > 5 × ULN (Gomez J, ASCO 2000). The objectives of this trial are to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of T 3h/q3w in patients (pts) with advanced cancer and baseline liver dysfunction. Methods: All pts are stratified according to basal liver function as follows: STRATUM (S) I: ULN < AP ≤ 1.5 × ULN S II: 1.5 × ULN < AP ≤ 2.5 × ULN S III: AP > 2.5 × ULN All pts had to have AST and ALT ≤ 2.5 × ULN, albumin > 2.5 g/dl and B < 2.5 mg/dl. T concentrations in plasma are determined using a validated LC-MS/MS method. PK parameters were calculated by non-compartmental methods. Results: 32 pts were recruited.Median age: 54 years (26–76); PS≤1:28 pts; prior chemotherapy (CT): 31 pts (97%); median number of prior CT: 2 (1–6); B > ULN: 0 pts. In S I, T was administered at 1.1 mg/m2 (3 pts) and 1.3 mg/m2 (13 pts). Two DLTs were reported at 1.3 mg/m2: neutropenia G4 > 5 days with febrile neutropenia and G3 ALT not recovered by day +28. In S II no DLT occurred in 4 pts at T 0.9 mg/m2 nor 3 pts at T 1.1 mg/m2, 1 out of 4 pts at 1.3 mg/m2 suffered DLT: G3 AST not recovered by day +24. In S III one out of 2 pts at 0.9 mg/m2 had DLT: AP increase. Initial PK evaluation from S I and II (8 from each) showed a long half life (geometric mean (GM) S I: 124.6 h, S II: 118.8 h) and wide distribution (GM Vss S I: 2366 l/m2, S II: 3830 l/m2). GM clearance: 18.3 l/(hr*m2) in S I; 26.3 l/(hr*m2) in S II. Clearance is somewhat lower than in normal liver function population (GM under equal dexamethasone treatment 33.8 l/hr*m2) in study ET-B-010. Conclusions: The recommended dose (RD) of T for pts with mild AP elevations (< 1.5 ULN) and B levels < ULN is 1.3 mg/m2 3h/q3w. The study is ongoing to define the RD for S II and III [Table: see text]