Phase I study with pharmacokinetics of S-1 on an oral daily schedule for 28 days in patients with solid tumors.
OBJECTIVE
Our purpose in the study was to determine the maximum tolerated dose and dose-limiting toxicity and investigate the clinical pharmacology of S-1, a combination of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate.


METHODS
Eligible patients had advanced solid tumors, adequate organ function, and no anticancer therapy in the preceding 4 weeks. Dose level 1 was 30 mg/m(2)/dose, level 2 was 40 mg/m(2)/dose, and level 3 was 35 allmg/m(2)/dose, all of the levels comprising two daily doses. S-1 was administered as a single dose at each level, and its pharmacology was studied. The first course was begun 3 days later and consisted of 28 consecutive treatment days, followed by a 1-week rest.


RESULTS
Sixteen patients were enrolled; toxicity could be assessed in all of the 16 and response in 15. At dose level 1, two of nine patients developed grade 3 hyperbilirubinemia or diarrhea. Dose-limiting toxicity (diarrhea) occurred in all three of the patients at dose level 2. The protocol was, therefore, amended to include an intermediate dose level (level 3), which caused grade 3 or 4 diarrhea or hyperbilirubinemia in three of four patients. Dose level 1 was thus considered as the maximum tolerated dose. Other grade 3 or 4 toxic effects at dose level 2 or 3 were granulocytopenia, nausea, and vomiting. The pharmacology of tegafur, CDHP, potassium oxonate, and fluorouracil (a metabolite of tegafur) was characterized by rapid absorption and was consistent with first-order kinetics. One patient with colorectal cancer had a durable partial response.


CONCLUSIONS
The recommended S-1 dose for future studies is 30 mg/m(2) twice daily, and diarrhea is the most frequent toxic effect. Additional trials of S-1 in the treatment of patients with solid tumors are warranted.
Hoff
Paulo M
PM
Department of Gastrointestinal Medical Oncology, The University of Texas, M D Anderson Cancer Center, Houston, Texas, USA.
Saad
Everardo D
ED
Ajani
Jaffer A
JA
Lassere
Yvonne
Y
Wenske
Cynthia
C
Medgyesy
Diana
D
Dwivedy
Sunita
S
Russo
Mark
M
Pazdur
Richard
R
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000009:adverse effects / Q000493:pharmacokinetics*; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics*; D005641:Tegafur / Q000009:adverse effects / Q000493:pharmacokinetics*; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid