title: A Phase I clinical study of cisplatin-incorporated polymeric micelles (NC-6004) in patients with solid tumours.
abstract: BACKGROUND
  On the basis of preclinical studies of NC-6004, a cisplatin-incorporated micellar formulation, we hypothesised that NC-6004 could show lower toxicity than cisplatin and show greater anti-tumour activity in phase I study.
  
  
  METHODS
  A total of 17 patients were recruited in a range of advanced solid tumour types. NC-6004 was administered intravenously (i.v.) every 3 weeks. The dose escalation started at 10 mg m(-2) and was increased up to 120 mg m(-2) according to the accelerated titration method and modified Fibonacci method.
  
  
  RESULTS
  One dose-limiting toxicity (DLT) occurred in a patient who was given 90 mg m(-2) of NC-6004, otherwise any significant cisplatin-related toxicity was not observed or generally mild toxicity was observed. Despite the implementation of post-hydration and pre-medication regimen, renal impairment and hypersensitivity reactions still developed at 120 mg m(-2), which led to the conclusion that the maximum tolerated dose was 120 mg m(-2), and the recommended dose was 90 mg m(-2), although DLT was not defined as per protocol. Stable disease was observed in seven patients. The maximum concentration and area under the concentration-time curve of ultrafilterable platinum at 120 mg m(-2) NC-6004 were 34-fold smaller and 8.5-fold larger, respectively, than those for cisplatin.
  
  
  CONCLUSIONS
  The delayed and sustained release of cisplatin after i.v. administration contributes to the low toxicity of NC-6004.
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne NE2 4AD, UK.
authors.forename: R
authors.initials: R
authors.lastname: Plummer
authors.forename: R H
authors.initials: RH
authors.lastname: Wilson
authors.forename: H
authors.initials: H
authors.lastname: Calvert
authors.forename: A V
authors.initials: AV
authors.lastname: Boddy
authors.forename: M
authors.initials: M
authors.lastname: Griffin
authors.forename: J
authors.initials: J
authors.lastname: Sludden
authors.forename: M J
authors.initials: MJ
authors.lastname: Tilby
authors.forename: M
authors.initials: M
authors.lastname: Eatock
authors.forename: D G
authors.initials: DG
authors.lastname: Pearson
authors.forename: C J
authors.initials: CJ
authors.lastname: Ottley
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumura
authors.forename: K
authors.initials: K
authors.lastname: Kataoka
authors.forename: T
authors.initials: T
authors.lastname: Nishiya
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008823:Micelles; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011108:Polymers / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D009944:Organoplatinum Compounds; D011108:Polymers; D011099:Polyglutamic Acid; C557897:demplatin pegraglumer; D002945:Cisplatin