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.
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.
Quincy Siu-Chung
QS
Chu
Lisa A
LA
Hammond
Garry
G
Schwartz
Leonel
L
Ochoa
Sun-Young
SY
Rha
Louis
L
Denis
Kathleen
K
Molpus
Brian
B
Roedig
Stephen P
SP
Letrent
Bharat
B
Damle
Arthur P
AP
DeCillis
Eric K
EK
Rowinsky
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