title: A multi-centre dose-escalation and pharmacokinetic study of diflomotecan in patients with advanced malignancy.
abstract: OBJECTIVE
  Diflomotecan, a homocamptothecin, targets DNA topoisomerase I. Previous clinical trials have demonstrated a variable degree of dose limiting toxicity. The purpose of this study was to further evaluate the safety and pharmacokinetic profile of a range of diflomotecan doses administered intravenously.
  
  
  METHODS
  Patients with advanced solid malignant tumours, refractory to standard therapies, with adequate haematologic, renal and hepatic function, received diflomotecan administered as a 20 min intravenous infusion every 21 days. Cohorts of six patients were recruited sequentially to one of three fixed starting dose groups-2, 4, or 7 mg, with drug administered by fixed-dose rather than dosing by body surface area. Pharmacokinetic analyses were performed on serial blood samples taken over the first 24 h after diflomotecan administration (cycles 1 and 2). Cytochrome P450 3A4 (CYP3A4) activity was determined by an erythromycin breath test (EBT) prior to diflomotecan administration in cycles 1 and 2.
  
  
  RESULTS
  Thirteen patients, were treated with a starting dose of either 2 mg (n = 8) or 4 mg (n = 5) of diflomotecan. Dose limiting toxicities (DLTs) were observed in 1 patient in the 2 mg starting dose level (grade 4 neutropenia which lasted for 8 days), and in 2 of 5 patients enrolled at the 4 mg starting dose level (grade 4 neutropenia for 11 days; grade 4 neutropenia leading to withdrawal from the study), and no further dose escalation was performed. Pharmacokinetic analyses revealed a less than dose-proportional increase in diflomotecan and for the two metabolites BN80942 and P-20, with a magnitude of P-20 exposure similar to the parent drug. There was a high inter-patient variability in diflomotecan exposure similar to that observed with other camptothecin derivatives. One minor response was observed in a patient with oesophageal cancer.
  
  
  CONCLUSIONS
  Diflomotecan administered as a 20-min intravenous infusion 3-weekly is characterised by a variable pharmacokinetic profile. Alternative oral dosing schedules of diflomotecan have been shown to display a more predictable PK/PD and safety profile and should be selected for further evaluation in Phase II clinical trials.
authors.affiliation: The Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, G12 OYN, UK. j.graham@imperial.ac.uk
authors.forename: Janet S
authors.initials: JS
authors.lastname: Graham
authors.forename: Stephen
authors.initials: S
authors.lastname: Falk
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Samuel
authors.forename: Josep M
authors.initials: JM
authors.lastname: Cendros
authors.forename: T R Jeffry
authors.initials: TR
authors.lastname: Evans
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D001944:Breath Tests; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004917:Erythromycin; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011379:Prognosis; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004917:Erythromycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C424962:diflomotecan; D002166:Camptothecin