title: ET-743: the US experience in sarcomas of soft tissues.
abstract: Ecteinascidin-743 (ET-743) has shown promise as a new and effective treatment for soft-tissue sarcomas. Two independent, multicenter, Phase II studies have been performed in the USA for patients with unresectable soft-tissue sarcomas (either chemotherapy-naïve or pretreated patients). The patients received ET-743 at a dose of 1500 micrograms/m2 as a 24 h continuous intravenous infusion every 3 weeks on an outpatient basis. Assessments were conducted every 6 weeks until documented progressive disease, unacceptable toxicity, or withdrawal. Responses were assessed in accordance with conventional oncological criteria and toxicities were graded using the National Cancer Institute common toxicity criteria. A total of 72 patients were enrolled: 36 patients to each study. Confirmed objective response rates were 14% (95% confidence interval (CI) 5 to 30%) and 8% (95% CI 2 to 23%) in chemotherapy-naïve and pretreated patients, respectively. In chemotherapy-naïve patients, 12-month progression-free and overall survival rates were 18% (95% CI 4 to 32%) and 49% (95% CI 20 to 78%), respectively. For patients with progressive disease despite prior conventional chemotherapy, 12-month progression-free and overall survival rates were 11% (95% CI 2 to 24%) and 55% (95% CI 35 to 75%), respectively. The median duration of response was 11 months. The durability of major responses in a subset of patients was impressive, as was the number of patients who achieved disease stabilization without showing objective response. Overall, ET-743 had a favorable safety profile. The most common grade 3-4 toxicities included neutropenia and transiently increased transaminase concentrations. ET-743 did not cause alopecia, mucositis, cardiotoxicity or neurotoxicity. The side effects were reversible, non-cumulative and manageable. There were no treatment-associated deaths. In conclusion, ET-743 is an active chemotherapeutic agent that can induce objective responses and clinical benefit in a subset of patients with metastatic or advanced soft-tissue sarcoma.
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. gdemetri@partners.org
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D004149:Dioxoles / Q000008:administration & dosage / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D006801:Humans; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D015337:Multicenter Studies as Topic; D012509:Sarcoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D016896:Treatment Outcome; D014481:United States
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin