Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors.
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.
Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston Texas, 1515 Holcombe Blvd., Houston, TX, 77030, USA. moverman@mdanderson.org
Michael J
MJ
Overman
Gauri
G
Varadhachary
Scott
S
Kopetz
Melanie B
MB
Thomas
Masakazu
M
Fukushima
Keizo
K
Kuwata
Akira
A
Mita
Robert A
RA
Wolff
Paulo M
PM
Hoff
Henry
H
Xiong
James L
JL
Abbruzzese
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011759:Pyrrolidines; D013941:Thymine; D014271:Trifluridine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014498:Uracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000970:Antineoplastic Agents; D004338:Drug Combinations; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D013941:Thymine; D014271:Trifluridine