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. doi: 10.1007/s10637-008-9142-3. Epub 2008 Jun 5.

Abstract

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Drug Administration Schedule
  • Drug Combinations
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Pyrrolidines
  • Thymine
  • Trifluridine / administration & dosage
  • Trifluridine / adverse effects
  • Trifluridine / pharmacokinetics
  • Trifluridine / therapeutic use*
  • Uracil / administration & dosage
  • Uracil / adverse effects
  • Uracil / analogs & derivatives*
  • Uracil / pharmacokinetics
  • Uracil / therapeutic use

Substances

  • Antineoplastic Agents
  • Drug Combinations
  • Pyrrolidines
  • trifluridine tipiracil drug combination
  • Uracil
  • Thymine
  • Trifluridine