Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 24, No 18S (June 20 Supplement), 2006: 2053
© 2006 American Society of Clinical Oncology

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Abstract

A phase I trial of TAS-102 administered on a three times a day schedule in patients with solid tumors

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

2053

Background: TAS-102 consists of trifluorothymidine (FTD) and an inhibitor of thymidine phosphorylase (TP). FTD, like 5-fluorouracil, is an inhibitor of thymidylate synthase. However, when orally administered, FTD is rapidly degraded to an inactive form, primarily by TP. Co-administration of FTD with an inhibitor of TP elevates FTD concentrations. Since tumor xenograft models demonstrated greater anti-tumor activity with divided daily dosing of TAS-102, and a phase I trial of once-daily TAS-102 showed a short FTD half-life, this trial was designed to explore a three times a day dosing schedule. Methods: Patients with advanced solid tumors having received prior therapy, with adequate organ function, and performance status Zubrod 0–2, were eligible. TAS-102 was administered orally three times a day for 5 days a week for two weeks, followed by two weeks off. Courses were repeated every 4 weeks. Results: A total of 15 patients (8 female, age 37–72 years) were enrolled into the study; three at 60 mg/m²/day, 6 each at 70 mg/m²/day and 80 mg/m²/day. Nine patients had colorectal cancer, 2 carcinoma of unknown primary, 2 pancreatic cancer, one each medullary thyroid cancer and cholangiocarcinoma. Toxicity was assessed throughout all courses of therapy. Grade 3 and 4 hematological toxicities were the most common, including 3 episodes of grade 3 neutropenia at 60 mg/m²/day, 5 at 70 mg/m²/day, 5 at 80 mg/m²/day with only 1 instance of grade 3 thrombocytopenia at 80 mg/m²/day. Non-hematological grade 3 toxicities included nausea/vomiting (1 at 70 mg/m²/day), colitis, gout, and hematuria (1 each at 70 mg/m²/day), and fatigue (1 at 70 mg/m²/day and 2 at 80 mg/m²/day) Two episodes of dose-limiting toxicity were observed at 80 mg/m²/day: grade 3 fatigue and grade 4 neutropenia. Although there were no objective responses, nine patients (60%) maintained stable disease with a median duration of disease stabilization of 4.3 months (range, 1.9 to 8.6 months). Conclusions: TAS-102 is well tolerated with manageable hematologic toxicity and few non-hematological toxicities. The most common grade 3 or 4 toxicity was neutropenia. The suggested phase II dose of TAS-102 is 70 mg/m²/day when administered orally three times a day for 5 days a week for two weeks followed by two weeks off every 4 weeks.

Author Disclosure

Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Taiho Pharmaceutical Co, Ltd Eli Lilly sanofi-aventis

Abstract presentation from the 2006 ASCO Annual Meeting