Phase I clinical and pharmacokinetic investigation of didemnin B, a cyclic depsipeptide

Didemnin B (NSC-325319), a cyclic depsipeptide isolated from a marine tunicate, has been evaluated in a Phase I trial. The drug was administered in a single intravenous infusion in 150 cm3 of normal saline every 30 min given every 28 days. Forty-three patients received 80 courses of the drug at doses ranging from 0.14 to 4.51 mg/m2. The dose-limiting toxicity was nausea and vomiting which began during or shortly after the infusion and was of variable duration. This toxicity was somewhat ameliorated by pretreatment with an aggressive antiemetic regimen. Mild hepatic toxicity also occurred with mild elevations of transaminases and bilirubin. One patient experienced an allergic reaction during his second infusion, characterized by chills, diaphoresis, flushing and hypotension. No objective anti-tumor response was seen during this trial. The recommended dose for Phase II studies on a single-dose schedule is 2.67 mg/m2 without prophylactic antiemetics and 3.47 mg/m2 if an antiemetic regimen is used. Preliminary pharmacokinetics suggest that didemnin B is sequestered or rapidly converted to a metabolite not identified by the antibody used in the radioimmunoassay. Further evaluation will be performed during Phase II studies.