title: A phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer.
abstract: OBJECTIVE
  OSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK) of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma.
  
  
  METHODS
  A 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of efficacy and toxicity.
  
  
  RESULTS
  Fourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m(2), oxaliplatin 130 mg/m(2)) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients.
  
  
  CONCLUSIONS
  The recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2).
authors.affiliation: Cancer Research UK and University of Manchester Department of Medical Oncology, Christie Hospital, Wilmslow Road, Manchester, M20 4BX, UK. Andrew.Clamp@christie.nhs.uk
authors.forename: A R
authors.initials: AR
authors.lastname: Clamp
authors.forename: P
authors.initials: P
authors.lastname: Schöffski
authors.forename: J W
authors.initials: JW
authors.lastname: Valle
authors.forename: R H
authors.initials: RH
authors.lastname: Wilson
authors.forename: S
authors.initials: S
authors.lastname: Marreaud
authors.forename: A-S
authors.initials: AS
authors.lastname: Govaerts
authors.forename: M
authors.initials: M
authors.lastname: Debois
authors.forename: D
authors.initials: D
authors.lastname: Lacombe
authors.forename: C
authors.initials: C
authors.lastname: Twelves
authors.forename: J
authors.initials: J
authors.lastname: Chick
authors.forename: G C
authors.initials: GC
authors.lastname: Jayson
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005977:Glutarates / Q000008:administration & dosage; D006801:Humans; D054833:Isoindoles / Q000008:administration & dosage; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011799:Quinazolines / Q000008:administration & dosage; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C506644:((S)-2-(5-(1,2-dihydro-3-methyl-1-oxobenzo(f)-quinazoline-9-yl)methyl)amino-1-oxo-2-isoindolynyl)-glutaric acid; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005977:Glutarates; D054833:Isoindoles; D008081:Liposomes; D009944:Organoplatinum Compounds; D011799:Quinazolines; D000077150:Oxaliplatin; D013940:Thymidylate Synthase