Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours.
BACKGROUND
TAS-102 consists of α, α, α-trifluorothymidine (TFT) and an inhibitor of thymidine phosphorylase (TPI). We conducted a dose-escalation phase I study in Japanese patients with advanced solid tumours.


METHODS
TAS-102 was administered twice daily on days 1-5 and days 8-12 in a 28-day cycle to patients with solid tumours refractory to standard chemotherapy, to determine its maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). MTD was evaluated in cycle 1.


RESULTS
Safety and PKs were evaluated in 21 patients treated with TAS-102 at 30, 40, 50, 60, or 70 mg m(-2) per day. DLTs, such as grade 4 leucopenia, grade 4 neutropenia, and grade 4 thrombocytopenia, were observed in two patients at doses of 30 and 70 mg m(-2). α, α, α-trifluorothymidine and TPI exposures increased dose dependently, and the percentage of decrease in neutrophil count and TFT exposure were significantly correlated. The disease control rate was 50.0% with a median progression-free survival of 2.4 months in 18 colorectal cancer patients. The dose of TAS-102 was not increased above 70 mg m(-2) per day because of the increased tendency for grade 3 and 4 neutropenia, and 70 mg m(-2) per day was the recommended dose for phase II studies.


CONCLUSIONS
TAS-102 at 70 mg m(-2) per day was tolerated in Japanese patients with advanced solid tumours. Phase II studies are ongoing in patients with colorectal cancer.
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. tdoi@east.ncc.go.jp
T
T
Doi
A
A
Ohtsu
T
T
Yoshino
N
N
Boku
Y
Y
Onozawa
A
A
Fukutomi
S
S
Hironaka
W
W
Koizumi
T
T
Sasaki
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D044466:Asian People; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; 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* / Q000378:metabolism; D011759:Pyrrolidines; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors*; D013941:Thymine; D014271:Trifluridine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014498:Uracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D004338:Drug Combinations; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D013939:Thymidine Phosphorylase; D013941:Thymine; D014271:Trifluridine