Phase I and pharmacokinetic study of 3'-C-ethynylcytidine (TAS-106), an inhibitor of RNA polymerase I, II and III,in patients with advanced solid malignancies.

Journal Article (Journal Article)

BACKGROUND: TAS-106 is a novel nucleoside analog that inhibits RNA polymerases I, II and II and has demonstrated robust antitumor activity in a wide range of models of human cancer in preclinical studies. This study was performed to principally evaluate the feasibility of administering TAS-106 as a bolus intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of TAS-106 as a single bolus IV infusion every 3 weeks. Plasma and urine sampling were performed during the first course to characterize the pharmacokinetic profile of TAS-106 and assess pharmacodynamic relationships. RESULTS: Thirty patients were treated with 66 courses of TAS-106 at eight dose levels ranging from 0.67-9.46 mg/m(2). A cumulative sensory peripheral neuropathy was the principal dose-limiting toxicity (DLT) of TAS-106 at the 6.31 mg/m(2) dose level, which was determined to be the maximum tolerated dose (MTD). Other mild-moderate drug-related toxicities include asthenia, anorexia, nausea, vomiting, myelosuppression, and dermatologic effects. Major objective antitumor responses were not observed. The pharmacokinetics of TAS-106 were dose-proportional. The terminal elimination half-life (t(1/2)) averaged 11.3 ± 3.3 h. Approximately 71% of TAS-106 was excreted in the urine as unchanged drug. Pharmacodynamic relationships were observed between neuropathy and: C(5min;) AUC(0-inf;) and dermatologic toxicity. CONCLUSIONS: The recommended phase II dose of TAS-106 is 4.21 mg/m(2). However, due to a cumulative drug-related peripheral sensory neuropathy that proved to be dose-limiting, further evaluation of this bolus every 21 day infusion schedule will not be pursued and instead, an alternate dosing schedule of TAS-106 administered as a continuous 24-hour infusion will be explored to decrease C(max) in efforts to minimize peripheral neuropathy and maximize antitumor activity.

Full Text

Duke Authors

Cited Authors

  • Hammond-Thelin, LA; Thomas, MB; Iwasaki, M; Abbruzzese, JL; Lassere, Y; Meyers, CA; Hoff, P; de Bono, J; Norris, J; Matsushita, H; Mita, A; Rowinsky, EK

Published Date

  • February 2012

Published In

Volume / Issue

  • 30 / 1

Start / End Page

  • 316 - 326

PubMed ID

  • 20839029

Electronic International Standard Serial Number (EISSN)

  • 1573-0646

Digital Object Identifier (DOI)

  • 10.1007/s10637-010-9535-y


  • eng

Conference Location

  • United States