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Originally published as JCO Early Release 10.1200/JCO.2005.02.766 on June 6 2005 © 2005 American Society of Clinical Oncology. Phase I and Pharmacokinetic Study of LY293111, an Orally Bioavailable LTB4 Receptor Antagonist, in Patients With Advanced Solid Tumors
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 (Cmax,ss) and area under the steady-state plasma concentration time curve 0 to 12 hours (AUC 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.
Emerging evidence now implicates both the intermediate hydroxyeicosatetraenoic acid (HETE) metabolites as well as leukotrienes in the process of carcinogenesis.1-3 The leukotrienes constitute a family of highly potent inflammatory mediators that are derived from the 5-lipoxygenase pathway of arachidonic acid metabolism (Fig 1).3,4 Leukotriene B4 (LTB4) is known to promote the directional movement of neutrophils and eosinophils, increase oxidant production, increase secretion of hydrolytic enzymes and stimulate secretion of specific cytokines. It has been detected in head and neck cancer and has also been shown to increase the proliferation of colon cancer cell lines.5,6 These proliferative effects can be reversed by a competitive antagonist of LTB4.5 In addition, inhibitors of the 5'- form have been demonstrated to cause apoptosis in prostate cancer cells, prevent lung tumorigenesis in carcinogen-treated mice and block proliferation of pancreatic cancer cells.7-9 Other lipoxygenases have also been shown to be essential regulators of cell survival and apoptosis.3 In addition, 5-HETE, a 5-lipoxygenase product and a precursor of the leukotrienes, has been implicated in tumor cell invasion of basement membranes, the principal barrier for the dissemination of malignant cells to distant sites.10 Thus, a molecule aimed at inhibiting the lipoxygenase pathway either directly through 5'-lipoxygenase or via antagonism of LTB4 may offer a potentially useful method of anticancer therapy, either alone or in combination with standard therapy.
LY293111 is a novel diaryl ether carboxylic acid derivative, characterized as a potent and selective LTB4 receptor antagonist in vitro (Fig 2, structure). The effects of LY293111 on human neutrophils include inhibition of LTB4-induced chemotaxis, aggregation, calcium mobilization, superoxide production, and upregulation of the CD11b/CD18 adhesion receptor.11 At micromolar concentrations, LY293111 inhibited production of LTB4 and thromboxane B2 by plasma-depleted human blood stimulated with N-formyl-L-methionyl-L-leucyl-L-phenylalanine and thrombin. In addition, at these concentrations, formation of LTB4 by A23187-activated whole blood and conversion of arachidonic acid to LTB4 by a human neutrophil cytosolic fraction were inhibited.12-14 These tests indicate that LY293111 is a potent and specific antagonist of the pro-inflammatory actions of LTB4.
LY293111 has been shown in vitro to inhibit proliferation and induce apoptosis in pancreatic cancer cell lines.15 In experiments with AsPC-1 and human pancreatic cancer (HPAC) xenografts, LY293111 at an oral dose of 250 mg/kg/day markedly inhibited tumor growth without significant toxicity.15 It also suppresses growth in a dose-dependent fashion of the BxPC3 pancreatic cancer xenograft (Eli Lilly, unpublished data). The highest oral dose tested in this model was 100 mg/kg/day, which achieved a steady-state maximum plasma concentration (Cmax,ss) of 1.8 µM. There is also recent data that LY293111 is a peroxisome proliferator activated receptor-gamma (PPAR ) agonist, as demonstrated by activity in both the rat ZDF diabetes model, and the induction of adipocyte differentiation.16 The pharmacokinetics of LY293111, at a dose of 200 mg, was evaluated previously in healthy volunteers following single- and multiple- dose administration. The drug was determined to be orally bioavailable with steady-state concentration (Css) of 0.9 µmol/L (Eli Lilly, unpublished data). These data, combined with the potential for continuous dosing with low toxicity, make LY293111 an attractive candidate for future clinical study in oncology. While the dose of 200 mg twice daily (BID) had been tested extensively in volunteers and subjects with inflammatory diseases for up to 8 weeks, the large variability in pharmacokinetic (PK) parameters seen in these trials to date and the absence of significant toxicity at 200 mg BID suggested that further dose escalation was feasible in cancer subjects. In addition, the preclinical studies against tumor cell lines and xenografts indicated a dose dependent effect. Thus, this study aims to investigate the potential for additional dose escalation beyond the levels previously described, to define a phase II dose, and to further characterize the PK profile of LY293111.
Patient Selection Adult patients (  18 years old) with histologically confirmed solid tumors refractory to standard therapy (or for which there was no standard therapy) were eligible for the study. The presence of measurable or assessable disease was required. The patient had to have discontinued all previous chemotherapy, immunotherapy, or radiotherapy at least 4 weeks before study entry (6 weeks for nitrosoureas and for mitomycin) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 was required. Required laboratory tests included adequate hematopoietic function, defined as having a total WBC count 3,500/mm3, a total absolute neutrophil count (ANC) > 1,500/mm3, and a platelet count 100,000/mm3. The patient was required to have adequate renal function, defined as having a serum creatinine less than 1.5 mg/dL; adequate hepatic function, defined as having a total serum bilirubin less 1.5 mg/dL; and serum AST and ALT levels less than 2.5x the institutional upper limit of normal. Patients were excluded from participation in the study for any of the following reasons: presence of any serious or uncontrolled infection, symptomatic CNS metastases, pregnancy, or breast feeding. The protocol was reviewed and approved by the participating sites' institutional review boards. Written, informed consent was obtained from each patient.
Treatment Plan The National Cancer Institute Common Toxicity Criteria (CTC, version 2.0) was used to evaluate toxicity and adverse events. DLT was defined as toxicity CTC grade 3 or higher (excluding anemia, electrolyte changes, alopecia, or nausea and vomiting that was not controlled with maximum medical support); CTC grade 2 toxicity that persisted for longer than 7 days, despite optimal symptomatic treatment (ie, nausea and vomiting); or CTC grade 2 hyperbilirubinemia that persisted for longer than 7 days. Provided that no more than one of six patients had reported unacceptable drug-related toxicity and all patients had competed at least 21 days of treatment, accrual to the next dose level could proceed. Patients who completed 21 days of therapy but were not assessable for PK analysis were replaced to ensure adequate PK information (unless accrual to that cohort was stopped because of DLTs). On the basis of capsule size, seven dose levels were planned with BID dosing: 200 mg (Cohort 1), 300 mg (Cohort 2), 400 mg (Cohort 3), 600 mg (Cohort 4), 800 mg (Cohort 5), 1,000 mg (Cohort 6), and 1,200 mg (Cohort 7). If at any time two or more patients at a given dose level reported unacceptable drug-related toxicity (CTC grade 3 toxicity or higher; CTC grade 2 toxicity that persisted for longer than 7 days, despite optimal symptomatic treatment; or CTC grade 2 hyperbilirubinemia that persisted for longer than 7 days) within the first 21 days of treatment, accrual to that cohort ceased and that dose was considered above the maximum-tolerated dose (MTD). In such an event, either the previous dose level would be declared the MTD or additional subjects were to be treated at intermediate doses between the previous dose level and the level above the MTD. In case of any unacceptable drug-related toxicity, dosing could be omitted for a maximum of two weeks. Upon resolution of toxicity, treatment was to be reinitiated and maintained with the next lowest dose level. If this occurred in Cohort 1, treatment was to continue at 100 mg BID. The dose recommended for phase II studies was defined as either the MTD in which fewer than two of six patients experienced unacceptable toxicity (CTC grade 3 or higher, CTC grade 2 toxicity which occurs despite optimal symptomatic treatment, or any grade 2 biochemical toxicity that persists for longer than 7 days) or the dose at which saturable absorptive kinetics becomes apparent, whereby higher doses fail to produce increases in area under the plasma concentration time curve (AUC) or Css or the observation of non-linearity in PK parameters. At this dose level, a total of 11 patients were to be enrolled to better define toxicity and also to obtain additional information regarding PK. Measurable lesions were evaluated by computed tomography (CT) scan or magnetic resonance imaging (MRI) after two cycles (6 weeks) of therapy. A response to therapy was defined according to standard WHO criteria. Patients were continued on therapy unless one of the following criteria was met: (1) objective disease progression; (2) unacceptable toxicity not responsive to dose attenuation; (3) investigator considered it unsafe to continue treatment; (4) the patient was unwilling or unable to continue (dropped out); (5) the patient died; or (6) the patient was lost to follow-up.
Drug Supply
Pharmacokinetics Pharmacokinetics sampling Patients received a single dose of LY293111 on day 1 followed by 72 hours of blood sampling (predose, 0.5, 1, 2, 3, 4, 6, 10, 24, 48 and 72 hours post dose for 200- and 600-mg dose groups only) for assessment of single-dose pharmacokinetics. During this period (after dosing to day 3) no further doses of study medication were administered. For the assessment of multiple dose pharmacokinetics, LY293111 was administered twice daily (BID, q 12 hrs) starting on day 4. Blood samples were collected on day 8 (steady-state) for assessment of steady-state pharmacokinetics from all patients (predose, 0.5, 1, 2, 3, 4, 6, and 10 hours postdose for all dose groups).
Pharmacokinetics and statistical methods
PK analyses consisted of a noncompartmental assessment of LY293111 plasma-concentration data using WinNonlin Professional Version 3.1 (Pharsight, Mountain View, CA). The PK parameters determined following a single oral dose of LY293111 were AUC, Cmax (maximum observed plasma concentration), tmax (time at Cmax), t1/2 (elimination half-life) and
AUC (0-tn), where tn is the last quantifiable time point above the lower limit of quantification, and AUC°
 z was estimated from a linear regression of concentration [ln(c)] versus time over the terminal log-linear drug disposition portion of the concentration-time profiles. The start of the terminal phase for each subject was defined by visual inspection of the semi-logarithmic plasma concentration versus time profiles. The terminal half-life was calculated according to the following equation:
 ,ss (AUC over the dosing interval at day 8). To determine AUC,ss, an extrapolation from the 10-hour time point through 12 hours was necessary using the half-life equation defined above.
Dose proportionality was examined using the power model for AUC
,ss, after multiple doses (day 8) using Cohort 1 and Cohort 4.
Patient Characteristics Table 1 lists the patient characteristics. Thirty-eight patients were registered to the study and 37 were assessable for toxicity. This included six patients at each of the five tested dose levels, three patients added to replace those who did not compete their PK studies, and five patients added at the recommended phase II dosing level. One patient in Cohort 5 (800 mg BID) received only one dose of drug and was considered unassessable for toxicity. The most common primary cancer diagnoses were as follows: colorectal carcinoma (eight), pancreas adenocarcinoma (seven), sarcoma (six), melanoma (three), hepatoma (three), esophagus adenocarcinoma (two), and adenocarcinoma of unknown primary (two). Other tumors included adrenal cortical carcinoma, cholangiocarcinoma, renal cell cancer, small-cell lung cancer, thyroid cancer, and prostate cancer. There were 24 males and 14 females with a median age of 64.5 years (range, 33 years to 82 years). The median ECOG performance status was 1 (range, 0 to 2). Twenty-nine patients had prior chemotherapy, 25 patients had prior surgery, 16 patients had prior radiotherapy, two patients had prior radiotherapy, and one patient had prior hormonal therapy. The median number of prior regimens was two (range, 0 to 5).
A total of 101 cycles of LY293111 was administered. The mean number of cycles completed was 2.7. Three patients completed one cycle, 27 patients completed two cycles, three patients completed three cycles, three patients completed four cycles, one patient completed eight cycles, and one patient completed 16 cycles of therapy. Of the 38 patients enrolled on the study, 36 discontinued treatment for progression of disease. Two additional patients were discontinued from therapy before restaging CT scans, one for decreasing performance status in Cohort 4 (600 mg BID) in cycle two, and the other in Cohort 5 (800 mg BID) for the development of grade 2 insomnia during cycle one after only one dose of therapy.
Toxicity
In Cohort 5 (800 mg BID), two of the first six assessable patients experienced grade 3 diarrhea that did not respond to anti-diarrheal therapy and were adjudicated to be DLTs. The second patient with this DLT in Cohort 5 developed diarrhea the third week of cycle 1, but this did not become dose-limiting until day 24 (the start of cycle 2). In view of the chronicity of these symptoms relative to the daily dosing of the drug, as well as the overall increase in grade 1 to 2 diarrhea, nausea, abdominal pain and flatulence noted at this dose level, dose escalation was stopped and dose level 4 (600 mg BID) was considered the MTD. By the time this decision was made, three additional patients had already been added to Cohort 5 because PK samples were not assessable on three patients already treated at this level. One of the additional patients received only 1 dose of therapy and was considered unassessable for toxicity and the other two both completed cycle 1 without DLT. Dose level 4 (600 mg BID) was next expanded to include an additional five patients. At this expanded dose level no additional patients developed dose-limiting diarrhea. Overall, 73% of patients developed some degree of diarrhea on this clinical trial, though this did not become dose-limiting until Cohort 5. Nausea was observed in 22% of patients but was not dose-limiting in any of these patients. Other gastrointestinal toxicities that occurred in > 5% of patients included abdominal pain (11%), flatulence (8%), and vomiting (8%). There were no dose-limiting hematologic toxicities in cycle 1. These are summarized by dose level with the other laboratory abnormalities in Table 3. Grade 3 lymphopenia was observed in two patients on cycles 1 and 2, grade 3 thrombocytopenia was observed in one patient on cycle 2, and grade 3 anemia was observed in one patient on cycles 1 and 2. There was no dose-dependent decrease in ANC. Only one patient experienced a grade 4 laboratory abnormality on cycle 1. At 600 mg BID, after 3 days of therapy, one patient with a history of gouty arthritis developed an acute attack of gout with grade 4 hyperuricemia. Though this was believed unrelated to LY293111, therapy was held starting on day 4. He resumed full dose therapy by day 10, but was then discontinued from the study before starting cycle 2. One patient in cohort 6 (800 mg BID) took only one dose of drug on day 1 of cycle 1 and developed grade 2 insomnia. Therapy was held for 15 days and the symptoms persisted. Because this toxicity was observed in no other patients and occurred after only one dose of drug, it was considered unrelated to therapy. Other nonhematologic grade 3 laboratory abnormalities include AST (two patients), alkaline phosphatase (two patients) and ALT (one patient), all of which were attributable to disease progression. There were no treatment related deaths on the study.
Pharmacokinetics PK parameters were calculated for LY293111 for AUC ,ss and Cmax,ss on day 8 for the 200-mg, 300-mg, 400-mg, 600-mg, and 800-mg BID dose groups. The results from the power model are summarized in Figure 3 and Table 4. The fitted LS geometric means for AUC,ss and Cmax,ss at 600 mg BID (the MTD) were 14,090 µg · h/L and 2,402 µg/L, respectively. Across all dose levels, the dose proportionality ratios for AUC,ss and Cmax,ss were estimated to be 2.05 and 2.46, respectively. Interpatient variability pooled across all cohorts (200 to 800 mg BID; n = 31) for AUC,ss and Cmax,ss were high and estimated to be 71% and 65%, respectively. The slope estimate and its 90% CI for AUC,ss was 1.01 and 0.52 to 1.50, and for Cmax,ss was 1.02 and 0.63 to 1.40, respectively.
Single- versus multiple-dose PK comparison is listed in Table 5. Intra- and interpatient coefficients of variation were estimated to be 46% and 67% for AUC, pooled across the two cohorts (200 and 600 mg BID; n = 9), averaged across patients, and after adjusting for the effects of dose. Averaged across the two doses, there is a 1.37-fold increase (90% CI, 0.85 to 2.21) in AUC between single and multiple doses.
Response There were no major clinical responses observed in this study. The best response was stable disease observed in two patients on the study (chondrosarcoma, 11 months; melanoma, 5 months at the 200 mg BID dose [Cohort 1]). All other patients experienced disease progression.
LY293111 is a novel targeted therapy that inhibits LTB4 receptor and 5'-lipoxygenase.11-14 In pancreatic cancer cell lines that express the LTB4 receptor, LY293111 inhibits growth and induces apoptosis in nanomolar concentrations.15 Previously, LY293111 was developed as an orally bioavailable agent for the treatment of inflammatory diseases including asthma, inflammatory bowel disease and psoriasis. With doses up to 200 mg BID, there were no DLTs in these volunteer studies. In this phase I study, the DLT was diarrhea at a LY293111 dose of 800 mg BID and the recommended phase II dose will be 600 mg BID. As noted in Table 2, with increasing LY293111 doses there was a trend towards increasing gastrointestinal toxicity. Though Cmax and AUC did on average increase with increasing dose, there was no apparent correlation between unusual elevations in Cmax or AUC and the observed DLTs.
Steady-state pharmacokinetics of LY293111 were found to be highly variable across the dose range. (Interpatient AUC
For the 200 mg BID dose group, the geometric mean for AUC LY293111 PK comparison between single and multiple doses showed on average a 1.37-fold increase (90% CI, 0.85 to 2.21) in AUC. Since the 90% CIs contain 1, there is no evidence for time-dependent pharmacokinetics. However, intrapatient variability within the study was high (46%). Intrapatient variability can be considered as comprising two components—intrinsic compound variability and inter-occasion variability. Intrapatient variability from a single dose healthy volunteer study was estimated as 28%. Because conditions for each patient from occasion to occasion are far more controlled in healthy volunteer studies, this value could be a guide to the intrinsic compound component of the intrapatient variability. The inter-occasion variability in our patient population is not estimable and is probably caused by the inability to control for all external factors that affect a cancer patient's pharmacokinetics from visit to visit, especially with an oral drug. Because the study was not powered to determine time-dependent pharmacokinetics and given the high variability and small sample size, it is not possible to draw a definitive conclusion about time independent pharmacokinetics.
There is currently no validated surrogate marker for the activity of LY293111. Preclinical models indicate that LY29311 is a PPAR As an inhibitor of LTB4 receptor and the lipoxygenase pathway, LY23111 represents the first drug of its class to enter clinical trial. Pancreatic cancer cells that express the LTB4 receptor are susceptible to the antiproliferative effects of the drug.20 In addition, the expression of the receptor has been reported to be increased in pancreatic cancer tissue but not in normal pancreatic ductal cells.20 However, whether expression of the LTB4 receptor is an absolute requirement for the drug's activity is unknown and requires further exploration. From the preclinical studies in xenografts, it appears that at a LY293111 dose of 100 mg/kg/day, a Cmax of at least 1.8 µmol/L is required to maximally inhibit tumor growth in at least one pancreatic xenograft model. However, the preclinical models also indicate that 250 mg/kg/day may result in even greater degrees of tumor inhibition without significant toxicity. In addition, it has been shown that there are no interspecies differences in protein binding for this drug between mouse and man (Eli Lilly, unpublished data). Our pharmacokinetic data indicates that we can achieve a mean Cmax of > 2 µM, and, in fact, at our recommended phase II dose of 600 mg BID, we achieve a mean Cmax of 4.4 µM. Thus, though single-agent activity was low, these PK assessments, across species, indicate that drug levels of LY293111 can be achieved with oral dosing in humans that should be sufficient to inhibit the putative targets in vivo. In addition, this effect can be achieved at doses that are not associated with significant toxicity. Preclinical studies also indicate that this agent potentiates the effect of gemcitabine, as well as that of other cytotoxic agents.21,22 In view of its single agent activity against pancreatic cancer cells both in vitro and in vivo, and the high expression of the LTB4 receptor in patients with pancreatic cancer, a clinical trial is underway evaluating LY23111 in patients with advanced pancreatic cancer.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar amount codes: (A) < $10,000 (B) $10,000-99,999 (C)
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.
1. Tang DG, Chen YQ, Honn KV: Arachidonate lipoxygenases as essential regulators of cell survival and apoptosis. Proc Natl Acad Sci USA 93:5241-5246, 1996 2. Teicher BA, Korbut TT, Menon K, et al: Cyclooxygenase and lipoxygenase inhibitors as modulators of cancer therapies. Cancer Chemother Pharmacol 33:515-522, 1994[Medline] 3. Teicher BA, Holden SA, Herman TS, et al: Modulation of [cisdiamminedichloroplatinum(II)/hyperthermia] therapy by inhibitors of arachidonic acid metabolism. Int J Onoco 4:17-22, 1994 4. Ara G, Teicher BA: Cyclooxygenase and lipoxygenase inhibitors in cancer therapy. Prostaglandins Leukot Essent Fatty Acids 54:3-16, 1996[CrossRef][Medline] 5. Bortuzzo C, Hanif R, Kashfi K, et al: The effect of leukotrienes B and selected HETEs on the proliferation of colon cancer cells. Biochim Biophys Acta 1300:240-246, 1996[Medline] 6. el-Hakim I, Langdon JD, Zakrzowski JT, et al: Leukotriene Bgamma and oral cancer. Br J Oral Maxillofac Surg 28:155-157, 1990[CrossRef][Medline] 7. Ding XZ, Iversen P, Cluck MW, et al: Lipoxygenase inhibitors abolish proliferation of human pancreatic cancer cells. Biochem Biophys Res Commun 261:218-223, 1999[CrossRef][Medline]
8. Ghosh J, Myers CE: Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells. Proc Natl Acad Sci USA 95:13182-13187, 1998
9. Rioux N, Castonguay A: Inhibitors of lipoxygenase: A new class of cancer chemopreventive agents. Carcinogenesis 19:1393-1400, 1998. 10. Varian J, Filial SEG, Perinea P: Directional motility in strongly malignant murine tumor cells. Int J Cancer 35:558-560, 1985 11. Marder P, Spaethe SM, Froelich LL, et al: Inhibition of ex vivo neutrophil activation by oral LY293111, a novel leukotriene B 4 receptor antagonist. Br J Clin Pharmacol 42:457-464, 1996[CrossRef][Medline] 12. Jackson WT, Fleisch JH: Development of novel anti-inflammatory agents: A pharmacologic perspective on leukotrienes and their receptor. Prog Drug Res 46:115-168, 1996[Medline] 13. Sawyer JS, Bach NJ, Baker R, et al: Synthetic and structure/ activity studies on acid-substituted 2-arylphenols: Discovery of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]- propoxy]phenoxy]benzoic acid, a high-affinity leukotriene B4 receptor antagonist. J Med Chem 38:4411-4432, 1995[CrossRef][Medline]
14. Jackson WT, Froelich LL, Boyd RJ, et al: Pharmacologic actions of the second-generation leukotriene B4 receptor antagonist LY293111: in vitro studies. J Pharmacol Exp Ther 288:286-294, 1999
15. Tong WG, Ding XZ, Hennig R, et al: Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Clin Cancer Res 8:3232-3242, 2002
16. Marshall M, Diaz HB, Brozinick J, et al: LY293111 inhibits tumor cell growth in vitro through an apparent PPAR 17. Smith BP, Vandenhende VR, DeSante KA, et al: Confidence interval criteria for assessment of dose proportionality. Pharm Res 17:1278-1283, 2000[CrossRef][Medline] 18. Buechler C, Ritter M, Duong CQ, et al: Adipophilin is a sensitive marker for lipid loading in human blood monocytes. Biochim Biophys Acta 1532:97-104, 2001[Medline] 19. Tontonoz P, Nagy L, Alvarez J, et al: PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93:241-252, 1998[CrossRef][Medline]
20. Hennig R, Ding XZ, Tong WG, et al: 5-Lipoxygenase and leukotriene B(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue. Am J Pathol 161:421-428, 2002 21. Hennig R, Ding XZ, Tong WG, et al: Effect of LY293111 in combination with gemcitabine in colonic cancer. Cancer Lett 210:41-46, 2004[Medline] 22. Budman DR, Calabro A: Studies of synergistic and antagonistic combinations of conventional cytotoxic agents with the multiple eiconsanoid pathway modulator LY293111. Anticancer Drugs 15:1-5, 2004[Medline] Submitted October 26, 2004; accepted March 24, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10.9% and ± 2.9%, respectively. For the low range assay, the overall precision and accuracy for sample analysis using the high range assay was 
(area under the plasma concentration time curve from 0 to infinity) were calculated by a combination of the linear and logarithmic trapezoidal methods. The linear trapezoidal method was employed up to tmax and then log trapezoidal rule was used. AUC was calculated according to the following equation: 
AUC
