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Pharmacokinetics and Pharmacodynamics of the Novel Marine-derived Anticancer Agent Ecteinascidin 743 in a Phase I Dose-finding Study 1

Ecteinascidin (ET) 743 is an anticancer agent derived from the Caribbean tunicate Ecteinascidia turbinata. Preclinical studies revealed activity of ET-743 against different tumor types. A Phase I clinical trial was designed with ET-743 to identify the maximum tolerated dose and doselimiting toxicities (DLTs). Furthermore, the pharmacokinetics of ET-743 and relationships with pharmacodynamics were evaluated. Adult patients with solid, resistant tumors received ET-743 as a 24-h i.v. infusion every 21 days. Blood samples were obtained during the first treatment course and in several consecutive courses. Noncompartmental pharmacokinetic analysis was performed. Relationships between pharmacokinetics and hepatic and hematological toxicities were explored. Fifty-two patients were treated at nine dose levels (50–1800mg/m). The DLTs, neutropenia and thrombocytopenia, were experienced at 1800 mg/m. Twenty-five patients were treated at the recommended Phase II dose of 1500 mg/m. At this dose, the mean value6 SD for total body clearance was 596 31 liters/h, and the mean t 1/2 was 896 41 h. Pharmacokinetics were linear over the dose range tested. Prior exposure to ET-743 did not alter the pharmacokinetics in subsequent courses. The percentage of decrease in WBC count and absolute neutrophil count was correlated to the area under the plasma concentrationversus time curve (AUC). Hepatic toxicity, defined as rise in alanine aminotransferase and aspartate aminotransferase, increased with dose and AUC but was reversible and not dose limiting. In conclusion, ET-743 administered as a 24-h i.v. infusion at a dose of 1500mg/m is clinically feasible; severe thrombocytopenia and neutropenia are the DLTs.