title: Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Shields Warren Bldg, Room G530, 44 Binney St, Boston, MA 02115, USA. gdemetri@partners.org
authors.forename: R
authors.initials: R
authors.lastname: Garcia-Carbonero
authors.forename: J G
authors.initials: JG
authors.lastname: Supko
authors.forename: J
authors.initials: J
authors.lastname: Manola
authors.forename: M V
authors.initials: MV
authors.lastname: Seiden
authors.forename: D
authors.initials: D
authors.lastname: Harmon
authors.forename: D P
authors.initials: DP
authors.lastname: Ryan
authors.forename: M T
authors.initials: MT
authors.lastname: Quigley
authors.forename: P
authors.initials: P
authors.lastname: Merriam
authors.forename: J
authors.initials: J
authors.lastname: Canniff
authors.forename: G
authors.initials: G
authors.lastname: Goss
authors.forename: U
authors.initials: U
authors.lastname: Matulonis
authors.forename: R G
authors.initials: RG
authors.lastname: Maki
authors.forename: T
authors.initials: T
authors.lastname: Lopez
authors.forename: T A
authors.initials: TA
authors.lastname: Puchalski
authors.forename: M A
authors.initials: MA
authors.lastname: Sancho
authors.forename: J
authors.initials: J
authors.lastname: Gomez
authors.forename: C
authors.initials: C
authors.lastname: Guzman
authors.forename: J
authors.initials: J
authors.lastname: Jimeno
authors.forename: G D
authors.initials: GD
authors.lastname: Demetri
mesh_terms: D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004149:Dioxoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012509:Sarcoma / Q000188:drug therapy*; D012983:Soft Tissue Neoplasms / Q000188:drug therapy*; D015996:Survival Rate; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin