Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy

Garcia-Carbonero, R., Supko, J. G., Manola, J., Seiden, M. V., Harmon, D., Ryan, D. P., Quigley, M. T., Merriam, P., Canniff, J., Goss, G., Matulonis, U., Maki, R. G., Lopez, T., Puchalski, T. A., Sancho, M. A., Gomez, J., Guzman, C., Jimeno, J., Demetri, G. D. (April 2004) Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol, 22 (8). pp. 1480-90. ISSN 0732-183X (Print)0732-183X (Linking)

DOI: 10.1200/JCO.2004.02.098


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 microg/m(2) 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/m(2), 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.

Item Type: Paper
Uncontrolled Keywords: Adult Antineoplastic Agents, Alkylating/pharmacokinetics/*therapeutic use Dioxoles/adverse effects/pharmacokinetics/*therapeutic use Disease Progression Disease-Free Survival Drug Administration Schedule Drug Resistance, Neoplasm Female Humans Isoquinolines/adverse effects/pharmacokinetics/*therapeutic use Male Middle Aged Neoplasm Metastasis Sarcoma/*drug therapy Soft Tissue Neoplasms/*drug therapy Survival Rate Tetrahydroisoquinolines
Subjects: diseases & disorders > cancer > drugs and therapies > chemotherapy
diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > sarcoma
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: 15 April 2004
Date Deposited: 26 Oct 2016 20:52
Last Modified: 26 Oct 2016 20:52
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