Phase I and pharmacokinetic study of S-1 administered for 14 days in a 21-day cycle in patients with advanced upper gastrointestinal cancer.
OBJECTIVE
S-1 is a novel oral fluoropyrimidine that combines tegafur with CDHP and oxonic acid. To decrease the incidence of late onset, severe diarrhea observed in a previous study, a phase I study was conducted to determine the maximum tolerated dose (MTD) of S-1 utilizing a 14-day schedule, repeated every 21 days, in patients with chemotherapy-refractory upper gastrointestinal malignancies.


METHODS
S-1 was administered orally, twice-daily, at an initial dose level of 30 mg/m2/dose; doses were escalated by 5 mg/m2 at each level. A minimum of three patients were enrolled at each dose level. S-1 toxicity, antitumor activity, and pharmacokinetics were assessed. The MTD was based on the dose limiting toxicity (DLT) during the first treatment cycle.


RESULTS
At 30 mg/m2 no DLT was observed in the first three evaluable patients. Two of the first three patients at the 35 mg/m2 dose level developed DLTs (grade 3 rash and dehydration). An additional nine patients were subsequently treated at 30 mg/m2 without DLT and this dose was established as the MTD. Common toxicities at 30 mg/m2 included diarrhea, nausea, skin rash, anorexia, and fatigue. No grade 4 toxicities were observed. One partial response was seen in a patient with gemcitabine-refractory pancreatic adenocarcinoma and ten patients with pancreatic, gastric, or gallbladder carcinomas achieved stable disease as their best response to therapy. The AUC(0-8) of 5-FU at the 30 and 35 mg/m2 dose levels were 875 +/- 212 and 894 +/- 151 h ng/ml, respectively.


CONCLUSIONS
In a 14-day dosing schedule, the MTD of S-1 was 30 mg/m2 and preliminary evidence of antitumor activity was seen in a North American population with refractory upper gastrointestinal malignancies.
Zhu
Andrew X
AX
Massachusetts General Hospital, 100 Blossom Street, Cox 640, Boston, MA 02114, USA. azhu@partners.org
Clark
Jeffrey W
JW
Ryan
David P
DP
Meyerhardt
Jeffrey A
JA
Enzinger
Peter C
PC
Earle
Craig C
CC
Fuchs
Charles S
CS
Regan
Eileen
E
Anbe
Hiroshi
H
Houghton
Michele
M
Zhang
Joshua
J
Urrea
Peter
P
Kulke
Matthew H
MH
D000284:Administration, Oral; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010094:Oxonic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005641:Tegafur / Q000008:administration & dosage / Q000493:pharmacokinetics*; D041742:Upper Gastrointestinal Tract / Q000473:pathology
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid