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.

Abstract

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.

• Authors: Lisa A Hammond-Thelin, Melanie B Thomas, Michiko Iwasaki, James L Abbruzzese, Yvonne Lassere, Christina A Meyers, Paulo Hoff, Johann de Bono, Jody Norris, Hitoshi Matsushita, Akira Mita, Eric K Rowinsky
• Journal: Investigational new drugs (Invest New Drugs) Vol. 30 Issue 1 Pg. 316-26 (Feb 2012) ISSN: 1573-0646 [Electronic] United States
• PMID: 20839029 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(3-C-ethynylribopentofuranosyl)cytosine
• Antineoplastic Agents
• Enzyme Inhibitors
• Cytidine
• RNA Polymerase II
• RNA Polymerase I
• RNA Polymerase III

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Area Under Curve
• Biotransformation
• Cytidine (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• Drug Administration Schedule
• Enzyme Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Feasibility Studies
• Female
• Half-Life
• Humans
• Infusions, Intravenous
• Kaplan-Meier Estimate
• Male
• Maximum Tolerated Dose
• Metabolic Clearance Rate
• Middle Aged
• Neoplasms (drug therapy, enzymology, genetics, pathology)
• RNA Polymerase I (antagonists & inhibitors, metabolism)
• RNA Polymerase II (antagonists & inhibitors, metabolism)
• RNA Polymerase III (antagonists & inhibitors, metabolism)
• Texas
• Treatment Outcome