title: A phase I study of oral LY293111 given daily in combination with irinotecan in patients with solid tumours.
abstract: BACKGROUND
  LY293111 is an oral agent known to be a leukotriene B4 (LTB4) receptor antagonist and a 5-lipoxygenase inhibitor resulting in selective inhibition of the lipoxygenase pathway. Lipoxygenases metabolize arachidonic acid and have been involved in cancer cell proliferation and survival. In addition, LY293111 has been found to be a peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonist. Antineoplastic activity of LY293111 has been identified in preclinical models both alone and in combination with chemotherapy agents including irinotecan. The NCIC Clinical Trials Group studied LY293111 in combination with irinotecan to determine the recommended dose of the combination and to describe its tolerability and pharmacokinetic interaction. In addition the anti-tumour activity of LY293111 in combination with irinotecan was documented.
  
  
  METHODS
  Twenty-eight patients with advanced solid tumours were treated on seven dose levels with the combination of irinotecan and LY293111. Irinotecan was administered intravenously every 21-days as a single dose. LY293111 was administered twice daily continuously by mouth.
  
  
  RESULTS
  Dose limiting toxicity (DLT) of grade 3 diarrhea was seen in two patients with doses of irinotecan 300 mg/m(2) IV every 21-days in combination with LY293111 300 mg BID. Subsequently the dose of irinotecan was decreased to 250 mg/m(2) IV every 21-days with escalating doses of LY293111. A DLT of grade 3 abdominal pain was seen at dose 600 mg BID of LY293111 with irinotecan 250 mg/m(2). The pharmacokinetics (PK) indicated that the administration of LY293111 did not have an effect on the PK of irinotecan or its metabolite SN-38. No responses were seen; seven patients had stable disease of a median duration of 4.4 months (range 2.8-13 months).
  
  
  CONCLUSIONS
  The recommended phase II dose of LY293111 is 600 mg orally BID in combination with irinotecan 250 mg/m(2) IV every 21-days. Gastrointestinal adverse effects were common but could be well managed.
authors.affiliation: Cancer Centre of Southeastern Ontario, 25 King St West, Kingston, ON, K7L 5P9, Canada. tara.baetz@krcc.on.ca
authors.forename: Tara
authors.initials: T
authors.lastname: Baetz
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Eisenhauer
authors.forename: Lillian
authors.initials: L
authors.lastname: Siu
authors.forename: Martha
authors.initials: M
authors.lastname: MacLean
authors.forename: Karen
authors.initials: K
authors.lastname: Doppler
authors.forename: Wendy
authors.initials: W
authors.lastname: Walsh
authors.forename: Bryn
authors.initials: B
authors.lastname: Fisher
authors.forename: Azhar Z
authors.initials: AZ
authors.lastname: Khan
authors.forename: Dinesh P
authors.initials: DP
authors.lastname: de Alwis
authors.forename: A
authors.initials: A
authors.lastname: Weitzman
authors.forename: Leslie H
authors.initials: LH
authors.lastname: Brail
authors.forename: Malcolm
authors.initials: M
authors.lastname: Moore
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001565:Benzoates / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009864:Ontario; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D001565:Benzoates; C094099:LY 293111; D000077146:Irinotecan; D002166:Camptothecin