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

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/m(2)) of TAS-103, administered intravenously over 1 hour each week for 3 weeks. Pharmacokinetic analysis was performed at the 130-, 160-, and 200-mg/m(2) 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/m(2) and in 3 of 6 patients at 200 mg/m(2). At 160 mg/m(2), 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/m(2), 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.

• Authors: R B Ewesuedo, L Iyer, S Das, A Koenig, S Mani, N J Vogelzang, R L Schilsky, W Brenckman, M J Ratain
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 19 Issue 7 Pg. 2084-90 (Apr 01 2001) ISSN: 0732-183X [Print] United States
• PMID: 11283142 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminoquinolines
• Antineoplastic Agents
• Indenes
• Topoisomerase II Inhibitors
• UGT1A1 enzyme
• Glucuronosyltransferase
• 6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one

Topics

• Adult
• Aged
• Aminoquinolines (administration & dosage, pharmacokinetics, pharmacology)
• Antineoplastic Agents (administration & dosage, pharmacokinetics, pharmacology)
• Female
• Genotype
• Glucuronosyltransferase (genetics)
• Humans
• Indenes (administration & dosage, pharmacokinetics, pharmacology)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Pharmacogenetics
• Salvage Therapy (methods)
• Topoisomerase II Inhibitors