title: A phase I dose-escalating study of ES-285, a marine sphingolipid-derived compound, with repeat dose administration in patients with advanced solid tumors.
abstract: BACKGROUND
  ES-285 (Spisulosine) is a novel marine compound with antitumor activity in preclinical studies. A phase I study was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), establish a safety profile, and to evaluate pharmacokinetics and efficacy of the drug.
  
  
  METHODS
  Thirty patients from two centers were treated with a three-hour ES-285 intravenous infusion for five consecutive days, every 3 weeks. Eleven dose levels were explored.
  
  
  RESULTS
  No dose-limiting toxicity (DLT) occurred from 2 to 81 mg/m²/day. Three patients had DLT, one each at dose levels 160, 120 and 100 mg/m²/day; all had grade 4 transaminase increases, one of whom (160 mg/m²/day) had concomitant grade 4 hepatitis and grade 3 bilirubin elevation. The MTD of this regimen was not reached due to early termination of the ES-285 phase I program, but was considered to be 80 to 100 mg/m²/day. Other toxicities included mild to moderate asthenia, nausea, vomiting, anemia, lymphopenia, and injection site reaction. Pharmacokinetic analyses showed dose proportionality on Days 1 and 5, a wide distribution and a long half-life. Seven patients (five with colorectal cancer) had stable disease (1.2-4.1 months), lasting for more than 3 months in three patients.
  
  
  CONCLUSIONS
  Liver enzyme elevations were dose limiting for ES-285 in this administration schedule. Low antitumor activity was observed.
authors.affiliation: Department of Medical Oncology, Vall d'Hebron University Hospital, Ps. Vall d'Hebron, 119-129, 08035 Barcelona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Vilar
authors.forename: Viktor
authors.initials: V
authors.lastname: Grünwald
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Harald
authors.initials: H
authors.lastname: Singer
authors.forename: Ramon
authors.initials: R
authors.lastname: Salazar
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Iglesias
authors.forename: Esther
authors.initials: E
authors.lastname: Casado
authors.forename: Martin
authors.initials: M
authors.lastname: Cullell-Young
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
mesh_terms: D000328:Adult; D000368:Aged; D000473:Alkanes / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D005858:Germany; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008055:Lipids / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013030:Spain; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000473:Alkanes; D000970:Antineoplastic Agents; D008055:Lipids; C408363:spisulosine
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