Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 2556
© 2007 American Society of Clinical Oncology

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Abstract

Phase I study to determine the safety and pharmacokinetics of 4-hour intravenous infusion of TAS-106 on a once per week for 3 consecutive weeks every 28-day schedule in patients with solid tumors

M. D. Anderson Cancer Center, Houston, TX; Taiho Pharmaceutical Co.,Ltd., Tokyo, Japan

2556

Background: Most solid tumors are slow growing so the S-phase-specific anti-tumor drugs have limited efficacy. The antitumor nucleoside 3’-C-ethynylcytidine (ECyd, TAS-106) inhibits RNA synthesis by blocking RNA polymerases. In vitro, TAS-106 has demonstrated cytotoxicity 300 times greater than that of 5-FU against human lung, colorectal, gastric, pancreas and breast cancer cells. This trial was based on a previous clinical trial, in which study drug was administered as a bolus injection wkly for 3 consecutive weeks every 28- days and TAS-106 caused reversible dose-limiting peripheral neuropathy, and the safety dose was 1.32 mg/m²/dose. Methods: Objectives of this study were to determine the recommended phase II dose (RP2D) and the dose-limiting toxicity of TAS-106 administered by 4-hour IV infusion wkly for 3 consecutive weeks every 28-days; to investigate the clinical pharmacokinetics and pharmacodynamics of TAS-106, and document any antitumor activity observed. Results: A total of 18 patients (pts) were treated in the study; 16 pts were evaluable. The med age was 59; 11 female. A total of 44 courses of therapy were initiated by pts during the study; 39 courses (88.6%) were completed. Six pts had best tumor responses of stable disease (SD) and 9 pts had best tumor responses of progressive disease (PD); no pts had a complete or partial response. The mean duration of SD was 103.7 days. Median time to treatment failure was 57.0 days. At the RP2D (2.04 mg/m²/dose), 2 of 8 pts had best tumor response of SD with a mean duration of 132.0 days and three of the 8 pts had PD. For 12 pts (66.7%), adverse events (AEs) were considered to be related to TAS-106; the most commonly reported drug-related AEs were tremor (8 pts, 44.4%), neuropathy (4 pts, 22.2%), and peripheral neuropathy and fatigue (3 pts, 16.7% each) . No Grade 4 drug-related AEs were reported. Plasma concentrations increased with increasing dose, and at 2.04 mg/m², the Cmax was 47.6±1.3 ng/mL. Conclusions: The safety profile of TAS-106 administered via wkly 4-hour IV infusion appears to be similar to the toxicity profile of TAS-106 when administered as a wkly bolus. In wkly 4-hour IV infusion, peripheral neuropathy was acceptable at the RP2D.

No significant financial relationships to disclose.

Abstract presentation from the 2007 ASCO Annual Meeting