Initial evidence of clinical benefit with ecteinascidin-743 (ET-743) in patients with sarcoma was provided during a Phase I pharmacokinetic study in which 52 patients received ET-743 at doses of 50-1800 micrograms/m2 as a 24 h continuous infusion every 3 weeks. Neutropenia and thrombocytopenia were the dose-limiting toxicities; liver toxicity (a severe but transient and reversible increase in transaminase concentrations) was not treatment limiting. In conjunction with results obtained with ET-743 in a compassionate-use program, these indications of activity in heavily pretreated patients with sarcoma prompted initiation of a French multicenter Phase II study of ET-743 in this population. From February 1999 to January 2001, 54 patients with advanced anthracycline-pretreated soft-tissue sarcoma (STS) received ET-743 at a dose of 1500 micrograms/m2 every 3 weeks by continuous 24 h infusion. The main histological subtype was leiomyosarcoma (37%); the majority of primary tumors were visceral (24%) or uterine (19%) sarcomas. In this Phase II population (> or = 25% negative prognostic or predictive factors of response to chemotherapy; > or = 50% anthracycline- and ifosfamide-resistant), safety data were comparable to those obtained in the Phase I and compassionate-use studies. Asymptomatic and reversible neutropenia and transaminitis (grade 3/4) were the most frequent toxicities (approximately 60% of patients); febrile neutropenia was infrequent (< 10%). No mucositis, alopecia, cardiac or neurotoxicity was observed. Two severe cases of rhabdomyolysis occurred. Side effects were non-cumulative, reversible and manageable. Of 52 evaluable patients, three (6%) achieved a long-lasting (8-13 months) partial response, four (8%) achieved a minor response (25-50% tumor reduction) and 22 (42%) achieved disease stabilization. With a 13-month median follow-up, median survival was almost 11 months. Progression-free survival at 6 months was 26.5% and the overall survival rate at 12 months was almost 50%. The response rate was uninfluenced by tumor metastatic site, size or anthracycline sensitivity status. These results, combined with the lack of cumulative toxicity, confirm the role of ET-743 in the treatment of advanced STS.