Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors
- 5 June 2008
- journal article
- Published by Springer Science and Business Media LLC in Investigational New Drugs
- Vol. 26 (5), 445-454
- https://doi.org/10.1007/s10637-008-9142-3
Abstract
This study was designed to determine the safety and optimal dosing of TAS-102, a novel oral combination of ααα-trifluorothymidine (FTD) and an inhibitor of thymidine phoshorylase, in patients with solid tumors. Patients who met the eligibility criteria were treated with one of two different TAS-102 regimens: once per day on either days 1–5 and 8–12 every 4 weeks (schedule A) or days 1–5 every 3 weeks (schedule B). The primary objectives were the determination of the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose. Pharmacokinetic analysis was conducted during courses 1 and 2. Sixty-three patients received a total of 172 courses of therapy with the median number of courses delivered on both schedules being 2. DLTs were observed in three patients on schedule A, 70 mg/m2/day (1) and 110 mg/m2/day (2); and in five patients on schedule B, 120 mg/m2/day (1), 170 mg/m2/day (2), 180 mg/m2/day (2). Granulocytopenia was the DLT in seven of the eight cases. The most frequent toxicities were nausea, fatigue, granulocytopenia, anemia, diarrhea, and abdominal pain. Twelve patients, 6 on schedule A and 6 on schedule B, were treated at the recommended phase II dose, with good tolerance. No objective responses were seen in this heavily pretreated, 5-FU-refractory population. The pharmacokinetic parameters of FTD are a T max of 0.53 to 3.15 h, t 1/2 of 1.46 to 4.20 h, volume of distribution of 0.0526 to 0.483 l/kg, and clearance of 0.0194 to 0.197 1/h/kg. The recommended phase II doses for TAS-102 are 100 mg/m2/day on schedule A and 160 mg/m2/day on schedule B. Future development of TAS-102 should focus upon multiple daily dosing schedules.Keywords
This publication has 20 references indexed in Scilit:
- Therapeutic potential of the dual‐targeted TAS‐102 formulation in the treatment of gastrointestinal malignanciesCancer Science, 2007
- Phase I study to determine the safety and pharmacokinetics of oral administration of TAS‐102 in patients with solid tumorsCancer, 2006
- Potentiation of the antitumor activity of α, α, α-trifluorothymidine by the co-administration of an inhibitor of thymidine phosphorylase at a suitable molar ratio in vivoInternational Journal of Oncology, 2005
- Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cellsCancer Chemotherapy and Pharmacology, 2005
- Determinants of trifluorothymidine sensitivity and metabolism in colon and lung cancer cellsAnti-Cancer Drugs, 2005
- A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA.International Journal of Oncology, 2004
- Thymidine phosphorylase and fluoropyrimidines efficacy: a Jekyll and Hyde story.Current Medicinal Chemistry - Anti-Cancer Agents, 2004
- 5-Fluorouracil: mechanisms of action and clinical strategiesNature Reviews Cancer, 2003
- Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patientsCancer Chemotherapy and Pharmacology, 2000
- Preliminary study on the optimal dosage schedule for oral tegafur/uracil (UFT) chemotherapyInternational Journal of Clinical Oncology, 1998