Phase I and pharmacokinetic study of the oral fluoropyrimidine S-1 on a once-daily-for-28-day schedule in patients with advanced malignancies.
OBJECTIVE
The oral fluoropyrimidine S-1, which consists of a mixture of a 5-fluorouracil (5-FU) prodrug (tegafur), a dihydropyrimidine dehydrogenase inhibitor [5-chloro-2,4-dihydroxypyrimidine (CDHP)], and an inhibitor of orotate phosphoribosyltransferase [potassium oxonate (oxonic acid)], was developed to increase the feasibility and therapeutic index of 5-FU administered orally. The principal objective of this study was to assess the feasibility of administering S-1 on a once-daily-for-28-day schedule every 5 weeks, determine the maximum tolerated dose, characterize the pharmacokinetics of S-1, and seek evidence of anticancer activity.


METHODS
Patients with advanced solid malignancies were treated with escalating doses of S-1 on a once-daily oral schedule for 28 days every 5 weeks. The maximum tolerated dose was defined as the highest dose in which fewer than two of the first six new patients experienced dose-limiting toxicity. The pharmacokinetic profiles of the tegafur, CDHP, and oxonic acid constituents were characterized.


RESULTS
Twenty patients were treated with 72 courses of S-1 at three dose levels ranging from 50 to 70 mg/m(2)/day. Diarrhea, which was often associated with abdominal discomfort and cramping, was the principal dose-limiting toxicity of S-1 on this protracted schedule. Nausea, vomiting, mucositis, fatigue, and cutaneous effects were also observed but were rarely severe. Myelosuppression was modest and uncommon. A partial response and a 49% reduction in tumor size were observed in patients with fluoropyrimidine- and irinotecan-resistant colorectal carcinoma. The pharmacokinetic data suggested potent inhibition of 5-FU clearance by CHDP, with resultant 5-FU exposure at least 10-fold higher than that reported from equitoxic doses of tegafur modulated by uracil in the oral fluoropyrimidine UFT.


CONCLUSIONS
The recommended dose for Phase II studies of S-1 administered once daily for 28 consecutive days every 5 weeks is 50 mg/m(2)/day. The pharmacokinetic data indicate substantial modulation of 5-FU clearance by CDHP. Based on these pharmacokinetic data, the predictable toxicity profile of S-1, and the low incidence of severe adverse effects at the recommended Phase II dose, evaluations of S-1 on this schedule are warranted in malignancies that are sensitive to the fluoropyrimidines.
Chu
Quincy Siu-Chung
QS
Institute for Drug Development, Cancer Therapy and Research Center and The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
Hammond
Lisa A
LA
Schwartz
Garry
G
Ochoa
Leonel
L
Rha
Sun-Young
SY
Denis
Louis
L
Molpus
Kathleen
K
Roedig
Brian
B
Letrent
Stephen P
SP
Damle
Bharat
B
DeCillis
Arthur P
AP
Rowinsky
Eric K
EK
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009962:Orotate Phosphoribosyltransferase / Q000037:antagonists & inhibitors; D010094:Oxonic Acid / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013274:Stomach Neoplasms / Q000188:drug therapy; D005641:Tegafur / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors
C417063:5-chlorodihydroxypyridine; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C029269:5-fluoropyrimidine; D009962:Orotate Phosphoribosyltransferase