title: A phase I and pharmacokinetic study of ecteinascidin-743 on a daily x 5 schedule in patients with solid malignancies.
abstract: OBJECTIVE
  The purpose of this study was to (a) assess the feasibility of administering ecteinascidin-743 (ET-743), a novel DNA minor-groove disrupting agent of marine origin, administered as a daily i.v. infusion for 5 days every 3 weeks; (b) recommend a dose for Phase II studies; (c) characterize its pharmacokinetic behavior; and (d) seek preliminary evidence of anticancer activity.
  
  
  METHODS
  Patients with advanced solid malignancies were treated with escalating doses of ET-743 as a daily 1-h i.v. infusion for 5 days every 3 weeks. Plasma and urine were sampled on both days 1 and 5 of the first course. Pharmacokinetic parameters were related to the principal toxicities.
  
  
  RESULTS
  Forty-two patients were treated with 118 courses of ET-743 at doses ranging from 6 to 380 microg/m(2)/day. Elevations in hepatic transaminases were common at ET-743 dose levels > or =216 microg/m(2)/day, resolved rapidly, and were never dose limiting nor cumulative. Instead, hematological toxicity was the principal toxicity that precluded dose escalation. The maximum tolerated dose of ET-743 that could be administered repetitively was 325 microg/m(2)/day. Antitumor activity was noted in three patients with leiomyosarcoma and primary peritoneal and ovarian carcinomas. The pharmacokinetics of ET-743 were dose independent, and drug accumulation over the 5 days of treatment was modest, with the ratio of the area under the plasma-versus-time curve on day 5 to that on day 1 averaging 2.05. The volume of distribution at steady state was large (mean, 1037 liters/m(2)), and the mean terminal half life on day 5 was 26.81 h.
  
  
  CONCLUSIONS
  The maximum tolerated dose of ET-743 that can be administered repetitively is 325 microg/m(2)/day daily x 5 every 3 weeks, which is recommended for disease-directed clinical trials. The acceptable toxicity profile of ET-743 on the divided-dose schedule evaluated in this trial, as well as the generally superior antitumor activity associated with divided-dose schedules in preclinical studies, provides a rationale for further evaluation of ET-743 on this administration schedule.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, 78229, USA. villalona-1@medctr.osu.edu
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Weiss
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Charlotte
authors.initials: C
authors.lastname: van Kesteren
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Campbell
authors.forename: Maura
authors.initials: M
authors.lastname: Kraynak
authors.forename: Luis
authors.initials: L
authors.lastname: Lopez-Lazaro
authors.forename: Cecilia
authors.initials: C
authors.lastname: Guzman
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Jose
authors.initials: J
authors.lastname: Jimeno
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000378:metabolism; D004149:Dioxoles / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D044005:Tetrahydroisoquinolines; D013997:Time Factors; D014018:Tissue Distribution; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077606:Trabectedin