Phase I clinical and pharmacogenetic study of weekly TAS-103 in patients with advanced cancer

Purpose: TAS-103 is an inhibitor of both topoisomerase 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.