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Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors.

Publication ,  Journal Article
Overman, MJ; Varadhachary, G; Kopetz, S; Thomas, MB; Fukushima, M; Kuwata, K; Mita, A; Wolff, RA; Hoff, PM; Xiong, H; Abbruzzese, JL
Published in: Invest New Drugs
October 2008

This study was designed to determine the safety and optimal dosing of TAS-102, a novel oral combination of alphaalphaalpha-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/m(2)/day (1) and 110 mg/m(2)/day (2); and in five patients on schedule B, 120 mg/m(2)/day (1), 170 mg/m(2)/day (2), 180 mg/m(2)/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/m(2)/day on schedule A and 160 mg/m(2)/day on schedule B. Future development of TAS-102 should focus upon multiple daily dosing schedules.

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Published In

Invest New Drugs

DOI

ISSN

0167-6997

Publication Date

October 2008

Volume

26

Issue

5

Start / End Page

445 / 454

Location

United States

Related Subject Headings

  • Uracil
  • Trifluridine
  • Thymine
  • Pyrrolidines
  • Oncology & Carcinogenesis
  • Neoplasms
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Humans
 

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Overman, M. J., Varadhachary, G., Kopetz, S., Thomas, M. B., Fukushima, M., Kuwata, K., … Abbruzzese, J. L. (2008). Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors. Invest New Drugs, 26(5), 445–454. https://doi.org/10.1007/s10637-008-9142-3
Overman, Michael J., Gauri Varadhachary, Scott Kopetz, Melanie B. Thomas, Masakazu Fukushima, Keizo Kuwata, Akira Mita, et al. “Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors.Invest New Drugs 26, no. 5 (October 2008): 445–54. https://doi.org/10.1007/s10637-008-9142-3.
Overman MJ, Varadhachary G, Kopetz S, Thomas MB, Fukushima M, Kuwata K, et al. Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors. Invest New Drugs. 2008 Oct;26(5):445–54.
Overman, Michael J., et al. “Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors.Invest New Drugs, vol. 26, no. 5, Oct. 2008, pp. 445–54. Pubmed, doi:10.1007/s10637-008-9142-3.
Overman MJ, Varadhachary G, Kopetz S, Thomas MB, Fukushima M, Kuwata K, Mita A, Wolff RA, Hoff PM, Xiong H, Abbruzzese JL. Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors. Invest New Drugs. 2008 Oct;26(5):445–454.
Journal cover image

Published In

Invest New Drugs

DOI

ISSN

0167-6997

Publication Date

October 2008

Volume

26

Issue

5

Start / End Page

445 / 454

Location

United States

Related Subject Headings

  • Uracil
  • Trifluridine
  • Thymine
  • Pyrrolidines
  • Oncology & Carcinogenesis
  • Neoplasms
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Humans