Phase I and pharmacokinetic study of ecteinaseidin-743, a new marine compound, administered as a 24-hour continuous infusion in patients with solid tumors

Purpose: To define the maximum-tolerated dose (MTD) and the phase II recommended dose (RD) of ecteinascidin-743 (ET-743) given as a 24-hour continuous infusion every 3 weeks to patients with treatment-refractory solid tumors. Patients and Methods: Fifty-two patients received a total of 158 cycles of ET-743 at one of nine dose levels (DLs) ranging from 50 to 1,800 mug/m(2). Results: The MTD was defined as 1,800 mug/m(2) (DL 9), and the phase II RD was 1,500 mug/m(2) (DL 8) for moderately pretreated patients with performance status (PS) 0 to 1 and good hepatobiliary function. Neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs) and were severe at the MTD (1,800 mug/m(2)) in 94% and 25% of cycles, respectively. At the RD (1,500 mug/m(2)), neutropenia and thrombocytopenia were present in 33% and 10% of cycles, respectively. Transient acute elevated transaminase levels occurred in almost all cycles and was severe in 38% of cycles. Severe toxicities and DLTs were observed in patients with poor PS or abnormal liver function or who had received a large number of previous chemotherapy regimens. Antitumor activity wets observed at the three highest DLs, including three partial responses (breast cancer, osteosarcoma, and liposarcoma), and four patients (all with progressing soft tissue sarcomas) had stable disease lasting greater than or equal to 3 months. Pharmacokinetic studies were performed on all patients for at least the first cycle, giving a linear pharmacokinetic profile; this showed a relationship between area under the curve (AUC) and transaminitis grade and a clear correlation between AUC and severe hematologic toxicity likelihood. Conclusion: The RD for a 24-hour continuous intravenous infusion of ET-743 is 1,500 mug/m(2), with the most prevalent DLTs being hematologic. Patients with minor baseline hepatobiliary function abnormalities have a higher likelihood of severe hematologic toxicities and AUC-related DLTs, requiring dose adjustments or delays. J Clin Oncol 19:1256-1265. (C) 2001 by American Society of Clinical Oncology.