Erschienen in:
27.11.2017 | PHASE III STUDIES
Hepatic safety analysis of trabectedin: results of a pharmacokinetic study with trabectedin in patients with hepatic impairment and experience from a phase 3 clinical trial
verfasst von:
Emiliano Calvo, Analia Azaro, Jordi Rodon, Luc Dirix, Manon Huizing, Francis Mark Senecal, Patricia LoRusso, Lorrin Yee, Italo Poggesi, Jan de Jong, Spyros Triantos, Youn C. Park, Roland E. Knoblauch, Trilok V. Parekh, George D. Demetri, Margaret von Mehren
Erschienen in:
Investigational New Drugs
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Ausgabe 3/2018
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Summary
Purpose Trabectedin is metabolized by the liver and has been associated with transient, noncumulative transaminase elevation. Two recent studies further characterize hepatic tolerability with trabectedin therapy: a phase 1 pharmacokinetic study (Study #1004; NCT01273493) in patients with advanced malignancies and hepatic impairment (HI), and a phase 3 study (Study #3007; NCT01343277) of trabectedin vs. dacarbazine in patients with advanced sarcomas and normal hepatic function. Methods In Study #1004, patients received a single 3-h intravenous (IV) infusion of trabectedin: control group, trabectedin 1.3 mg/m2; HI group (baseline total bilirubin >1.5 and ≤3× upper limit of normal [ULN]; AST and ALT ≤2.5× ULN), trabectedin 0.58 or 0.9 mg/m2. In Study #3007, the trabectedin group received 1.5 mg/m2 by 24-h IV infusion every 3 weeks until disease progression or unacceptable toxicity. Results In Study #1004, dose-normalized trabectedin exposure was higher in HI patients (n = 6) versus controls (n = 9) (geometric mean ratios [90% CI] AUClast: 1.97 [1.20; 3.22]). In Study #3007, following trabectedin administration, 90% of patients had elevated ALT (32% grade 3–4) and 84% had elevated AST (17% grade 3–4). Transaminase elevations were transient and noncumulative. Progression-free survival was similar in patients with grade 3–4 hepatotoxicity (n = 109) versus grade 0–2 hepatotoxicity (n = 231) (median [95% CI]: 4.63 [4.01, 5.85] months versus 3.55 [2.73, 4.63] months; P = 0.545, HR = 0.91 [0.68–1.23]). Conclusion Trabectedin treatment of patients with HI results in higher plasma exposures. Hepatotoxicity in patients with normal liver function can be effectively addressed through dose reductions and delays.