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

R. B. Ewesuedo, L. Iyer, S. Das, A. Koenig, Sridhar Mani, N. J. Vogelzang, R. L. Schilsky, W. Brenckman, M. J. Ratain

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2084-2090
Number of pages7
JournalJournal of Clinical Oncology
Volume19
Issue number7
StatePublished - Apr 1 2001
Externally publishedYes

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Glucuronosyltransferase
Uridine Diphosphate
Neoplasms
Protein Isoforms
Genotype
Glucuronides
Area Under Curve
Appointments and Schedules
Pharmacokinetics
Pharmacogenomic Testing
6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one
Clinical Studies
Topoisomerase I Inhibitors
Topoisomerase II Inhibitors
Maximum Tolerated Dose
Pharmacogenetics
Neutropenia
Reverse Transcription
Neutrophils
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ewesuedo, R. B., Iyer, L., Das, S., Koenig, A., Mani, S., Vogelzang, N. J., ... Ratain, M. J. (2001). Phase I clinical and pharmacogenetic study of weekly TAS-103 in patients with advanced cancer. Journal of Clinical Oncology, 19(7), 2084-2090.

Phase I clinical and pharmacogenetic study of weekly TAS-103 in patients with advanced cancer. / Ewesuedo, R. B.; Iyer, L.; Das, S.; Koenig, A.; Mani, Sridhar; Vogelzang, N. J.; Schilsky, R. L.; Brenckman, W.; Ratain, M. J.

In: Journal of Clinical Oncology, Vol. 19, No. 7, 01.04.2001, p. 2084-2090.

Research output: Contribution to journalArticle

Ewesuedo, RB, Iyer, L, Das, S, Koenig, A, Mani, S, Vogelzang, NJ, Schilsky, RL, Brenckman, W & Ratain, MJ 2001, 'Phase I clinical and pharmacogenetic study of weekly TAS-103 in patients with advanced cancer', Journal of Clinical Oncology, vol. 19, no. 7, pp. 2084-2090.
Ewesuedo RB, Iyer L, Das S, Koenig A, Mani S, Vogelzang NJ et al. Phase I clinical and pharmacogenetic study of weekly TAS-103 in patients with advanced cancer. Journal of Clinical Oncology. 2001 Apr 1;19(7):2084-2090.
Ewesuedo, R. B. ; Iyer, L. ; Das, S. ; Koenig, A. ; Mani, Sridhar ; Vogelzang, N. J. ; Schilsky, R. L. ; Brenckman, W. ; Ratain, M. J. / Phase I clinical and pharmacogenetic study of weekly TAS-103 in patients with advanced cancer. In: Journal of Clinical Oncology. 2001 ; Vol. 19, No. 7. pp. 2084-2090.
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abstract = "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.",
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AU - Ewesuedo, R. B.

AU - Iyer, L.

AU - Das, S.

AU - Koenig, A.

AU - Mani, Sridhar

AU - Vogelzang, N. J.

AU - Schilsky, R. L.

AU - Brenckman, W.

AU - Ratain, M. J.

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