title: Phase I and pharmacokinetic study of LY293111, an orally bioavailable LTB4 receptor antagonist, in patients with advanced solid tumors.
abstract: OBJECTIVE
  LY293111, a novel diaryl ether carboxylic acid derivative, is a potent and selective inhibitor of the lipoxygenase pathway either directly through 5'-lipoxygenase or via antagonism of the leukotriene B4 (LTB4) receptor. More recently it has been determined to have peroxisome proliferator activated receptor-gamma agonist (PPARgamma) activity. LY293111 has antineoplastic activity in a variety of preclinical models. The tolerability and pharmacokinetics of LY293111 administered continuously, by mouth, BID for repeat cycles of 21 days was evaluated.
  
  
  METHODS
  Thirty-eight patients with advanced solid tumors were treated at five dose levels (200 to 800 mg BID) for a total of 102 cycles.
  
  
  RESULTS
  The most common toxicity was diarrhea (76%). One patient at 600 mg BID (n = 11) and two at 800 mg BID (n = 8), experienced dose-limiting grade 3 diarrhea. Dose reductions and/or delays were infrequent. Increases in steady-state maximum plasma concentration (Cmax,ss) and area under the steady-state plasma concentration time curve 0 to 12 hours (AUCtau,ss) on day 8 could be considered to be dose-proportional over the four-fold-dose range. Interpatient variability in Cmax,ss and AUCtau,ss was estimated to be 65% and 71% respectively. There was a small increase in AUC (1.37; 90% CI, 0.85 to 2.21) between single and multiple doses. Two patients with progressive chondrosarcoma and melanoma had stable disease lasting approximately 336 and 168 days, respectively.
  
  
  CONCLUSIONS
  LY293111 can be administered safely by continuous oral therapy with mild toxicities. Diarrhea is dose-limiting. The recommended phase II dose will be 600 mg BID. The steady-state concentrations in humans exceed relevant levels observed in preclinical models.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY, USA. Schwartg@mskcc.org
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
authors.forename: Aaron
authors.initials: A
authors.lastname: Weitzman
authors.forename: Eileen
authors.initials: E
authors.lastname: O'Reilly
authors.forename: Les
authors.initials: L
authors.lastname: Brail
authors.forename: Dinesh P
authors.initials: DP
authors.lastname: de Alwis
authors.forename: Ann
authors.initials: A
authors.lastname: Cleverly
authors.forename: Barbara
authors.initials: B
authors.lastname: Barile-Thiem
authors.forename: Vincent
authors.initials: V
authors.lastname: Vinciguerra
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Budman
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001565:Benzoates / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D012449:Safety
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; C094099:LY 293111; D018102:Receptors, Leukotriene B4