Originally published as JCO Early Release 10.1200/JCO.2005.02.766 on June 6 2005

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Phase I and Pharmacokinetic Study of LY293111, an Orally Bioavailable LTB₄ Receptor Antagonist, in Patients With Advanced Solid Tumors

Gary K. Schwartz, Aaron Weitzman, Eileen O'Reilly, Les Brail, Dinesh P. de Alwis, Ann Cleverly, Barbara Barile-Thiem, Vincent Vinciguerra, Daniel R. Budman

From the Memorial Sloan-Kettering Cancer Center, New York; North Shore University Hospital–New York University, Manhasset, NY; and Lilly Research Laboratories, Indianapolis, IN

Address reprint requests to Gary K. Schwartz, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY; e-mail: Schwartg{at}mskcc.org.

PURPOSE: 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 (PPAR) 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.

PATIENTS AND 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 (C_max,ss) and area under the steady-state plasma concentration time curve 0 to 12 hours (AUC_,ss) on day 8 could be considered to be dose-proportional over the four-fold-dose range. Interpatient variability in C_max,ss and AUC_,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.

CONCLUSION: 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.

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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