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

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/m2. A cumulative sensory peripheral neuropathy was the principal dose-limiting toxicity (DLT) of TAS-106 at the 6.31 mg/m2 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 (t1/2) 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: C5min; AUC0-inf; and dermatologic toxicity. Conclusions The recommended phase II dose of TAS-106 is 4.21 mg/m2. 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 Cmax in efforts to minimize peripheral neuropathy and maximize antitumor activity.