Originally published as JCO Early Release 10.1200/JCO.2005.09.357 on September 19 2005

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Phase I and Pharmacokinetic Study of Aplidine, a New Marine Cyclodepsipeptide in Patients With Advanced Malignancies

From the Department of Medicine, Institute Gustave-Roussy, Villejuif, France; and PharmaMar R&D, Colmenar Viejo, Madrid, Spain

Address reprint requests to Eric Raymond, MD, PhD, Service Inter-Hospitalier de Cancérologie Bichat-Beaujon, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110 Clichy Cedex, France; e-mail: eric.raymond{at}bjn.ap-hop-paris.fr

PURPOSE: To establish the safety, pharmacokinetic parameters, maximum-tolerated dose, and recommended dose of aplidine, a novel marine cyclodepsipeptide, in patients with advanced cancer.

PATIENTS AND METHODS: Using a modified Fibonacci method, we performed a phase I and pharmacokinetic study of aplidine administered as a 24-hour intravenous infusion every 2 weeks.

RESULTS: Sixty-seven patients received aplidine at a dose ranging from 0.2 to 8 mg/m². Dose-limiting myotoxicity corresponding to grade 2 to 3 creatine phosphokinase elevation and grade 1 to 2 myalgia and muscle weakness occurred in two of six patients at 6 mg/m². No cardiac toxicity was observed. Electron microscopy analysis showed the disappearance of thick filaments of myosin. Grade 3 muscle toxicity occurred in three of 14 patients at the recommended dose of 5 mg/m² and seemed to be more readily reversible with oral carnitine (1 g/10 kg). Therefore, dose escalation was resumed using carnitine prophylactically, allowing an increase in the recommended dose to 7 mg/m². Other toxicities were nausea and vomiting, diarrhea, asthenia, and transaminase elevation with mild hematologic toxicity. Aplidine displayed a long half-life (21 to 44 hours), low clearance (45 to 49 L/h), and a high volume of distribution (1,036 to 1,124 L) with high interpatient variability in plasma, whereas in whole blood, clearance ranged from 3.0 to 6.2 L/h. Minor responses and prolonged tumor stabilizations were observed in patients with medullary thyroid carcinoma.

CONCLUSION: Muscle toxicity was dose limiting in this study. Recommended doses of aplidine were 5 and 7 mg/m² without and with carnitine, respectively. The role of carnitine will be further explored in phase II studies.

Supported in part by PharmaMar, Madrid, Spain.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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