title: Phase I and pharmacokinetic study of Yondelis (Ecteinascidin-743; ET-743) administered as an infusion over 1 h or 3 h every 21 days in patients with solid tumours.
abstract: Yondelis (ET-743) is a novel anticancer agent isolated from the marine ascidian Ecteinascidia turbinata. ET-743 possesses potent antitumour activity and a novel mechanism of action at the level of gene transcription. We conducted two sequential phase I dose escalation and pharmacokinetic studies of ET-743 given as a 1- or a 3-h intravenous (i.v.) infusion. Seventy-two adults with metastatic or advanced solid tumours received ET-743 in escalating doses between 50 and 1100 microg/m(2), initially as a 1-h infusion, and later at doses between 1000 and 1800 microg/m(2) as a 3-h infusion every 3 weeks. The maximum tolerated dose (MTD) of ET-743 was 1100 microg/m(2) for the 1-h infusion schedule and 1800 microg/m(2) when given as a 3-h infusion. Dose-limiting toxicities (DLTs) were fatigue, neutropenia and thrombocytopenia. Transient non-cumulatives grade 3-4 increase in transaminases (not considered DLT) and grades 3-4 nausea and vomiting were frequently observed. Other toxicities (maximum grade 3) included anaemia, increased lactate dehydrogenase (LDH), bilirubin and alkaline phosphatase serum levels, and phlebitis; there were no toxic deaths. One pCR (melanoma), CR (uterine leiomyosarcoma), one PR (colon stromal sarcoma) and a MR (37% tumour shrinkage, gastric stromal sarcoma) were observed. A further 9 patients with colorectal, mesothelioma, bile duct carcinoma and bladder cancer had SD which lasted for six or more treatment cycles. ET-743 pharmacokinetics were linear with the 3-h infusion schedule. The haematological and hepatic toxicities of ET-743 were dose-dependent and not cumulative. Based on the current trial, the recommended dose of ET-743 for phase II studies is 1650 microg/m(2) given as a 3-h infusion.
authors.affiliation: Cancer Research UK, University of Glasgow, G61 1BD Glasgow, UK. c.twelves@bradford.ac.uk
authors.forename: C
authors.initials: C
authors.lastname: Twelves
authors.forename: K
authors.initials: K
authors.lastname: Hoekman
authors.forename: A
authors.initials: A
authors.lastname: Bowman
authors.forename: J B
authors.initials: JB
authors.lastname: Vermorken
authors.forename: A
authors.initials: A
authors.lastname: Anthoney
authors.forename: J
authors.initials: J
authors.lastname: Smyth
authors.forename: C
authors.initials: C
authors.lastname: van Kesteren
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: J
authors.initials: J
authors.lastname: Uiters
authors.forename: J
authors.initials: J
authors.lastname: Wanders
authors.forename: J
authors.initials: J
authors.lastname: Gomez
authors.forename: C
authors.initials: C
authors.lastname: Guzmán
authors.forename: J
authors.initials: J
authors.lastname: Jimeno
authors.forename: A
authors.initials: A
authors.lastname: Hanauske
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D015331:Cohort Studies; D004149:Dioxoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin