Phase I and pharmacokinetic study of the oral fluoropyrimidine S-1 on a once-daily-for-28-day schedule in patients with advanced malignancies

Quincy Siu Chung Chu, Lisa A. Hammond, Garry Schwartz, Leonel Ochoa, Sun Young Rha, Louis Denis, Kathleen Molpus, Brian Roedig, Stephen P. Letrent, Bharat Damle, Arthur P. DeCillis, Eric K. Rowinsky

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Abstract

Purpose: 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. Experimental Design: 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/m2/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 fluoropyrhnidine- and irinotecan-resistant colorectal carcinoma. The pharmalokinetic 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/m2/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.

Original languageEnglish
Pages (from-to)4913-4921
Number of pages9
JournalClinical Cancer Research
Volume10
Issue number15
DOIs
Publication statusPublished - 2004 Aug 1

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Fluorouracil
Appointments and Schedules
Tegafur
Pharmacokinetics
Oxonic Acid
irinotecan
Maximum Tolerated Dose
Neoplasms
Orotate Phosphoribosyltransferase
Dihydrouracil Dehydrogenase (NADP)
Mucositis
Uracil
Prodrugs
Nausea
Vomiting
Fatigue
Colorectal Neoplasms
Diarrhea
Research Design
Skin

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Chu, Quincy Siu Chung ; Hammond, Lisa A. ; Schwartz, Garry ; Ochoa, Leonel ; Rha, Sun Young ; Denis, Louis ; Molpus, Kathleen ; Roedig, Brian ; Letrent, Stephen P. ; Damle, Bharat ; DeCillis, Arthur P. ; Rowinsky, Eric K. / Phase I and pharmacokinetic study of the oral fluoropyrimidine S-1 on a once-daily-for-28-day schedule in patients with advanced malignancies. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 15. pp. 4913-4921.
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title = "Phase I and pharmacokinetic study of the oral fluoropyrimidine S-1 on a once-daily-for-28-day schedule in patients with advanced malignancies",
abstract = "Purpose: 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. Experimental Design: 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/m2/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 fluoropyrhnidine- and irinotecan-resistant colorectal carcinoma. The pharmalokinetic 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/m2/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.",
author = "Chu, {Quincy Siu Chung} and Hammond, {Lisa A.} and Garry Schwartz and Leonel Ochoa and Rha, {Sun Young} and Louis Denis and Kathleen Molpus and Brian Roedig and Letrent, {Stephen P.} and Bharat Damle and DeCillis, {Arthur P.} and Rowinsky, {Eric K.}",
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doi = "10.1158/1078-0432.CCR-04-0469",
language = "English",
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Chu, QSC, Hammond, LA, Schwartz, G, Ochoa, L, Rha, SY, Denis, L, Molpus, K, Roedig, B, Letrent, SP, Damle, B, DeCillis, AP & Rowinsky, EK 2004, 'Phase I and pharmacokinetic study of the oral fluoropyrimidine S-1 on a once-daily-for-28-day schedule in patients with advanced malignancies', Clinical Cancer Research, vol. 10, no. 15, pp. 4913-4921. https://doi.org/10.1158/1078-0432.CCR-04-0469

Phase I and pharmacokinetic study of the oral fluoropyrimidine S-1 on a once-daily-for-28-day schedule in patients with advanced malignancies. / Chu, Quincy Siu Chung; Hammond, Lisa A.; Schwartz, Garry; Ochoa, Leonel; Rha, Sun Young; Denis, Louis; Molpus, Kathleen; Roedig, Brian; Letrent, Stephen P.; Damle, Bharat; DeCillis, Arthur P.; Rowinsky, Eric K.

In: Clinical Cancer Research, Vol. 10, No. 15, 01.08.2004, p. 4913-4921.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase I and pharmacokinetic study of the oral fluoropyrimidine S-1 on a once-daily-for-28-day schedule in patients with advanced malignancies

AU - Chu, Quincy Siu Chung

AU - Hammond, Lisa A.

AU - Schwartz, Garry

AU - Ochoa, Leonel

AU - Rha, Sun Young

AU - Denis, Louis

AU - Molpus, Kathleen

AU - Roedig, Brian

AU - Letrent, Stephen P.

AU - Damle, Bharat

AU - DeCillis, Arthur P.

AU - Rowinsky, Eric K.

PY - 2004/8/1

Y1 - 2004/8/1

N2 - Purpose: 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. Experimental Design: 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/m2/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 fluoropyrhnidine- and irinotecan-resistant colorectal carcinoma. The pharmalokinetic 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/m2/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.

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