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Ecteinascidin-743 (ET-743) for Chemotherapy-Naive Patients With Advanced Soft Tissue Sarcomas: Multicenter Phase II and Pharmacokinetic Study

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

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

PURPOSE: To evaluate the response rate, toxicity profile, and pharmacokinetics of ecteinascidin-743 (ET-743) as first-line therapy in patients with unresectable advanced soft tissue sarcoma (STS).

PATIENTS AND METHODS: Thirty-six patients with STS were enrolled onto the study between September 1999 and August 2000. Patients were treated with 1.5 mg/m² of ET-743 given as a 24-hour continuous intravenous (IV) infusion every 21 days. Pharmacokinetic sampling was performed in 23 patients.

RESULTS: One complete and five partial responses were achieved in 35 assessable patients for an overall response rate of 17.1% (95% CI, 6.6% to 33.6%). In addition, one patient had a minor response, leading to an overall clinical benefit of 20%. Neutropenia and transaminitis were the main grade 3 to 4 toxicities, which occurred in 33% and 36% of the patients. The estimated 1-year progression-free and overall survival rates were 21% (95% CI, 11% to 41%) and 72% (95% CI, 59% to 88%), respectively. Total body clearance (L/h) was not significantly correlated with body-surface area (r = –0.28; P = .21). Mild hepatic impairment or the extent of prior cytotoxic therapy does not seem to contribute significantly to the high interpatient variability (49%) in the clearance of this drug. Severity of treatment-related toxicity was not correlated with pharmacokinetic variables.

CONCLUSION: ET-743 demonstrates clinical activity as first-line therapy against STS with acceptable toxicity. Additional studies to establish empirical dosing guidelines may be necessary to improve the safety of the drug in patients with varying degrees of hepatic dysfunction and definitively establish the role of ET-743 for patients with these malignancies.

Supported in part by research support from PharmaMar, S.A. (Madrid, Spain) and from grants from the Leslie's Links Foundation and the Quick Family Sarcoma Research Fund. R.G.-C. was supported in part by a grant from the Ministerio de Educacion y Cultura (Spain).

Presented most recently at the 37th Annual Meeting of the American Society of Clinical Oncology, May 12-15, 2001, San Francisco, CA (preliminary results).

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

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Related Editorial

• Ecteinascidin-743 (ET-743): Early Test or Effective Treatment in Soft Tissue Sarcomas?
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  JCO 2005 23: 5420-5423 [Full Text]

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