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Phase II and Pharmacokinetic Study of Ecteinascidin 743 in Patients With Progressive Sarcomas of Soft Tissues Refractory to Chemotherapy

From the Dana-Farber Cancer Institute and Massachusetts General Hospital, Harvard Medical School, Boston, MA; Memorial Sloan-Kettering Cancer Center, New York, NY; and Clinical Research and Development, PharmaMar, Madrid, Spain.

Address reprint requests to George D. Demetri, MD, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Shields Warren Bldg, Room G530, 44 Binney St, Boston, MA 02115; e-mail: gdemetri{at}partners.org

PURPOSE: To assess the efficacy of the marine-derived alkaloid ecteinascidin 743 (ET-743) in patients with soft tissue sarcomas that progressed despite prior conventional chemotherapy and to characterize the pharmacokinetic profiles of ET-743 in this patient population.

PATIENTS AND METHODS: Thirty-six previously treated soft tissue sarcoma patients from three institutions received ET-743 as a 24-hour continuous intravenous (IV) infusion at a dose of 1,500 µg/m² every 3 weeks. Pharmacokinetic studies were also performed. Patients were restaged every two cycles for response by objective criteria.

RESULTS: Objective responses were observed in three patients, with one complete response and two partial responses, for an overall response rate of 8% (95% CI, 2% to 23%). Responses were durable for up to 20 months. Two minor responses (43% and 47% tumor reduction) were observed, for an overall clinical benefit rate of 14%. The predominant toxicities were neutropenia and self-limited transaminitis of grade 3 to 4 severity in 34% and 26% of patients, respectively. The estimated 1-year time to progression and overall survival rates were 9% (95% CI, 3% to 27%) and 53% (95% CI, 39% to 73%), respectively. The maximum observed plasma concentration and total plasma clearance of ET-743 (mean ± standard deviation), 1.04 ± 0.48 ng/mL and 35.6 ± 16.2 L/h/m², respectively, were consistent with previously reported values from phase I studies of the drug given as a 24-hour IV infusion.

CONCLUSION: ET-743 is a promising new option for the management of several histologic subtypes of sarcoma. Durable objective responses were obtained in a subset of sarcoma patients with disease progression despite prior chemotherapy. Additionally, the relatively high survival rate noted in this series of previously treated patients further justifies development of this agent.

Supported in part by a grant of the Ministerio de Educacion y Cultura, Spain (R.G.-C.), and by research support from PharmaMar, Madrid, Spain.

Preliminary results of the study were presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001.

Both R.G.-C. and J.G.S. contributed equally to this work.

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

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