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Investigational New Drugs

, Volume 26, Issue 5, pp 445–454 | Cite as

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

  • Michael J. OvermanEmail author
  • Gauri Varadhachary
  • Scott Kopetz
  • Melanie B. Thomas
  • Masakazu Fukushima
  • Keizo Kuwata
  • Akira Mita
  • Robert A. Wolff
  • Paulo M. Hoff
  • Henry Xiong
  • James L. Abbruzzese
PHASE I STUDIES

Summary

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

TAS-102 5-Flourouracil Phase 1 Solid tumor Colorectal cancer 

Notes

Acknowledgments

Financial support for this research was provided by Taiho Pharmaceuticals. A partial presentation of this material was given at the 2001 American Society of Clinical Oncology meeting, abstract no. 386, and the 2002 American Association of Cancer Research meeting, abstract no. 2754

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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Michael J. Overman
    • 1
    Email author
  • Gauri Varadhachary
    • 1
  • Scott Kopetz
    • 1
  • Melanie B. Thomas
    • 1
  • Masakazu Fukushima
    • 3
  • Keizo Kuwata
    • 3
  • Akira Mita
    • 3
  • Robert A. Wolff
    • 1
  • Paulo M. Hoff
    • 4
  • Henry Xiong
    • 2
  • James L. Abbruzzese
    • 1
  1. 1.Department of Gastrointestinal Medical OncologyThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  2. 2.The Center for Cancer and Blood DisordersForthWorthUSA
  3. 3.Taiho Pharmaceutical Co. LTD.TokyoJapan
  4. 4.Centro Oncológico de Hospital Sirio-LibanésSao PauloBrazil

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