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Phase I Clinical and Pharmacogenetic Study of Weekly TAS-103 in Patients With Advanced Cancer

From the Committee on Clinical Pharmacology, Section of Pediatric Hematology-Oncology, Department of Pediatrics; Section of Hematology-Oncology, Department of Medicine; Department of Human Genetics and Cancer Research Center, University of Chicago, Chicago, IL; Covance Laboratory, Madison, WI; and ClinTrials Res Inc, Morrisville, NC.

Address reprint requests to Lalitha Iyer, PhD, Department of Medicine and Committee on Clinical Pharmacology, University of Chicago, 5841 South Maryland Ave, MC 2115, Chicago, IL 60637; email: liyer{at}medicine.bsd.uchicago.edu

PURPOSE: TAS-103 is an inhibitor of both topoiso-merase I and II enzymes with broad antitumor activity. It is metabolized to TAS-103-glucuronide (TAS-103-G) predominantly by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of TAS-103 when administered on a weekly schedule to patients with advanced cancer. In addition, we evaluated the influence of UGT1A1 genotype on the pharmacokinetics and toxicity of TAS-103.

PATIENTS AND METHODS: Thirty-two patients were treated with escalating doses (50 to 200 mg/m²) of TAS-103, administered intravenously over 1 hour each week for 3 weeks. Pharmacokinetic analysis was performed at the 130-, 160-, and 200-mg/m² dose levels. UGT1A1 genotypes were determined using reverse-transcription polymerase chain reaction techniques.

RESULTS: DLT (grade 3 neutropenia) was observed in 5 of 12 patients at 160 mg/m² and in 3 of 6 patients at 200 mg/m². At 160 mg/m², there was a significant correlation between areas under the curve (AUCs) for TAS-103 and TAS-103-G (r = 0.76, P < .05) and an apparent relationship between TAS-103 AUC and D 15 absolute neutrophil count (r = -0.63, P < .05, n = 11, one outlier excluded). UGT1A1 genotype did not influence clearance of TAS-103.

CONCLUSION: We recommend a dose of 130 to 160 mg/m², or 250 to 300 mg administered using the above weekly schedule for phase II studies. Further studies to characterize the pharmacodynamics and pharmacogenetics of TAS-103 are warranted.

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