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Phase II Study of Ecteinascidin-743 in Advanced Pretreated Soft Tissue Sarcoma Patients

From the Hôpital Paul Brousse; Institut Gustave Roussy, Villejuif; Cvitkovic et Associés Consultants, Kremlin Bicêtre; Centre René Huguenin, Saint Cloud; Centre Léon Bérard, Lyon, France; and PharmaMar SA Clinical Research and Development, Madrid, Spain.

Address reprint requests to J.L. Misset, MD, Hôpital St Louis, Unité d'Oncologie Médicale, 1 av. Claude Vellefaux, 75010 Paris, France; e-mail: jean-louis.misset{at}sls.ap-hop-paris.fr

PURPOSE: A multicenter phase II study evaluating efficacy, safety, and pharmacokinetics of ecteinascidin-743 (ET-743) in pretreated advanced soft tissue sarcoma patients.

PATIENTS AND METHODS: Patients received ET-743 1,500 µg/m² (24-hour intravenous infusion) every 3 weeks (group 1, 26 patients with one to two prior single agents or one previous combination chemotherapy; group 2, 28 patients with three or more prior single agents or two or more previous combination chemotherapies).

RESULTS: Patients (30 women, 24 men) had a median age of 48 years (range, 22 to 71 years); 41% had leiomyosarcoma (eight of 22 of uterine origin), a median of two involved organs (range, one to four), and 93% had documented progressive disease at study entry. Patients received a median of three cycles (range, one to 20); 28% received six or more cycles. Fifty-two patients were assessable for response (WHO criteria): two partial responses, four minor responses, and nine with stable disease ( 6 months). Three patients were rendered tumor free after surgery. Median progression-free survival was 1.9 months (range, 0.69 to 17.90 months); 24% of patients were progression free at 6 months. Median survival was 12.8 months, with 30% of patients alive at 2 years. Four patients withdrew because of treatment-related toxicity. Two treatment-related deaths occurred (renal failure and febrile neutropenia, and rhabdomyolysis and decompensated cirrhosis, respectively) that were probably related to protocol eligibility violations. Reversible grade 3 to 4 AST or ALT occurred in 50% of patients and grade 3 to 4 neutropenia occurred in 61% of patients, with six episodes of febrile neutropenia. Nausea, vomiting, and asthenia were prevalent but mild and manageable.

CONCLUSION: With a 4% overall response rate (95% CI, 0.5 to 12.8) and an 11% rate of third-party-verified tumor regression (overall response rate + minor response), ET-743 has a 24% 6-month disease progression control rate, confirming evidence of antitumoral activity and a manageable safety profile in patients experiencing disease progression with pretreated soft tissue sarcoma.

Supported by PharmaMar SA and part of the 5th EU Framework Anticancer Program in the framework of the European Union BIOMED II Lifesciences Demonstration Project BMH4-CT98-3614.

Presented in part at the 36th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.

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

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