title: A multicentre phase I and pharmacokinetic study of BN80915 (diflomotecan) administered daily as a 20-min intravenous infusion for 5 days every 3 weeks to patients with advanced solid tumours.
abstract: BACKGROUND
  BN80915 (diflomotecan) is an E-ring modified camptothecin analogue, which possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors. This phase I study was carried out using a daily times five administration schedule (dx5) repeated three weekly. The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for phase II studies. Secondary objectives were to determine the safety and pharmacokinetic (PK) profile, and to make a preliminary assessment of antitumour activity.
  
  
  METHODS
  Diflomotecan was administered intravenously on days 1-5 every 3 weeks. Patients were treated in cohorts of three to six per dose level and the dose of diflomotecan was escalated according to modified Fibonacci schedule. Plasma concentrations of diflomotecan and its metabolite BN80942 were quantified.
  
  
  RESULTS
  Thirty patients were assessable for toxicity. Dose levels explored were 0.05, 0.1, 0.125 and 0.15 mg/m(2)/day. The 0.15-mg/m(2) dose level was determined to be the MTD. Toxicity was acceptable at the 0.125-mg/m(2)/day dose level. PK analysis showed the principal parameters were neither time nor dose dependent. There was a wide interpatient variability in PK at all dose levels. One patient with colorectal cancer, previously treated with irinotecan, had a partial response. A further eight patients had disease stabilisation.
  
  
  CONCLUSIONS
  The MTD and RD of diflomotecan administered according to a dx5 repeated three weekly are 0.15 and 0.125 mg/m(2)/day, respectively. In general, treatment was well tolerated; the principal toxicity was reversible myelosuppression. An objective response was seen in a patient previously treated with irinotecan.
authors.affiliation: Cancer Research UK, Centre for Oncology and Applied Pharmacology, University of Glasgow, Glasgow G61 1BD, UK.
authors.forename: L
authors.initials: L
authors.lastname: Scott
authors.forename: O
authors.initials: O
authors.lastname: Soepenberg
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: M J A
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: A S
authors.initials: AS
authors.lastname: Th Planting
authors.forename: D
authors.initials: D
authors.lastname: McGovern
authors.forename: P
authors.initials: P
authors.lastname: Principe
authors.forename: R
authors.initials: R
authors.lastname: Obach
authors.forename: C
authors.initials: C
authors.lastname: Twelves
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D005060:Europe; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D059004:Topoisomerase I Inhibitors; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; C424962:diflomotecan; D002166:Camptothecin