Phase I and pharmacokinetic study of LY293111, an orally bioavailable LTB4 receptor antagonist, in patients with advanced solid tumors Journal Article
| Authors: | Schwartz, G. K.; Weitzman, A.; O'reilly, E.; Brail, L.; De Alwis, D. P.; Cleverly, A.; Barile-Thiem, B.; Vinciguerra, V.; Budman, D. R. |
| Article Title: | Phase I and pharmacokinetic study of LY293111, an orally bioavailable LTB4 receptor antagonist, in patients with advanced solid tumors |
| Abstract: | 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 (PPARγ) 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 (Cmax,ss) and area under the steady-state plasma concentration time curve 0 to 12 hours (AUCτ,SS) on day 8 could be considered to be dose-proportional over the four-fold-dose range. Interpatient variability in Cmax,SS and AUCτ,ss was estimated to be 65% and 71% respectively. There was a small increase in AUC (1.37; 90% Cl, 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. © 2005 by American Society of Clinical Oncology. |
| Keywords: | adult; clinical article; aged; aged, 80 and over; middle aged; clinical trial; drug tolerability; area under the curve; cancer growth; diarrhea; drug dose reduction; liver cell carcinoma; side effect; solid tumor; antineoplastic agents; antineoplastic agent; neoplasm; neoplasms; metabolism; melanoma; multiple cycle treatment; thrombocyte; steady state; nausea; vomiting; hypercalcemia; drug structure; kidney carcinoma; abdominal pain; adrenal cortex carcinoma; colorectal carcinoma; drug dose escalation; hyperuricemia; lymphocytopenia; prostate cancer; sarcoma; hyperkalemia; hypoalbuminemia; hypokalemia; hyponatremia; insomnia; lung small cell cancer; drug antagonism; neutrophil; drug response; area under curve; bile duct carcinoma; safety; thyroid cancer; antiemetic agent; hyperbilirubinemia; drug blood level; maximum tolerated dose; phase 1 clinical trial; flatulence; administration, oral; esophageal adenocarcinoma; chondrosarcoma; benzoic acid derivative; hypernatremia; hypocalcemia; oral drug administration; benzoic acids; 2 [2 propyl 3 [3 [2 ethyl 4 (4 fluorophenyl) 5 hydroxyphenoxy]propoxy]phenoxy]benzoic acid; leukotriene b4 receptor; receptors, leukotriene b4 |
| Journal Title: | Journal of Clinical Oncology |
| Volume: | 23 |
| Issue: | 23 |
| ISSN: | 0732-183X |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2005-08-10 |
| Start Page: | 5365 |
| End Page: | 5373 |
| Language: | English |
| DOI: | 10.1200/jco.2005.02.766 |
| PUBMED: | 15939925 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 14" - "Export Date: 24 October 2012" - "CODEN: JCOND" - "Source: Scopus" |
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