Phase I Study of a Combination of S-1 and Weekly Paclitaxel in Patients with Advanced or Recurrent Gastric Cancer

Abstract

Objective: A phase I study of weekly intravenous paclitaxel combined with a fixed dose of S-1, a dihydropyrimidine-dehydrogenase-inhibitory oral fluoropyrimidine, was conducted for patients with advanced or recurrent gastric cancer (ARGC). Endpoints of this study were to examine the toxicity profile of this regimen and to determine the recommended dose (RD) of paclitaxel. Methods: S-1 was fixed at a dose of 80 mg/m² per day and was administered for 2 weeks (days 1–14) followed by a 2-week rest. Two dose levels of paclitaxel (level 1: 60 mg/m², level 0: 50 mg/m²) were studied. Paclitaxel was infused over 1 h on days 1, 8, and 15. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of paclitaxel in some patients. Fifteen patients were enrolled (6 patients in level 1, and 9 patients in level 0). Dose-limiting toxicities were defined as grade 4 hematological (including grade 3 febrile neutropenia) and grade 3 non-hematological (except anorexia, nausea, vomiting and depilation) toxicities. Results: Three of 6 patients in level 1 developed grade 4 neutropenia or grade 3 febrile neutropenia, and 1 of them also showed grade 3 diarrhea, which settled the maximum-tolerated dose at this level. At level 0, 2 of 9 patients developed grade 4 neutropenia or grade 3 febrile neutropenia, and the RD of paclitaxel for this protocol was set at this level. Pharmacologic studies demonstrated the persistence of significant serum paclitaxel levels over 24 h after drug administration at both levels. Objective responses according to Response Evaluation Criteria in Solid Tumors were observed in 3 of 6 patients who had measurable disease. Conclusion: A combination of S-1 and weekly paclitaxel was feasible and well tolerated, and is suggested to produce a worthwhile response in ARGC. These results warrant further investigation, and a phase II study has already been started.

A multi-center phase II study of S-1 plus paclitaxel as first-line therapy for patients with advanced or recurrent unresectable gastric cancer

“…The gastrointestinal toxicities of the current regimen were tolerable, with less than 5% of cases with grade 3 diarrhea and stomatitis. In the Japanese phase I/II trial, reported by Ueda et al [23], febrile neutropenia developed in one (17%) patient with 40.0 mg/m 2 per week of paclitaxel and in one (11%) patient with 33.3 mg/ m 2 per week of paclitaxel . In the current study, febrile neutropenia developed in four (7%) patients with 46.7 mg/m 2 per week of paclitaxel.…”

“…In Korean trial, the dose was Wnely adjusted compared with Japanese trials in which S-1 dose by body surface area (BSA) was roughly divided into three levels. The actual dose was nearly same in patients with BSA between 1.4-1.7 m 2 of two nations paclitaxel 50-60 mg/m 2 , weekly [6,7,9,13,17,20,23]. The most common dose limiting toxicities were grade 3 diarrhea or grade 4 neutropenia.…”

“…Paclitaxel has synergistic antitumor eVects with 5-Xuorouracil (5-FU) according to clinical trials as well as preclinical studies, and a diVerent spectrum of side eVects [12,18]. Several clinical trials of S-1 and paclitaxel combination therapy have been conducted in Japan [6,7,9,13,17,20,23]. The response rate has been reported to be 40-60% with the schedule of S-1 80 mg/m 2 for 14 days plus weekly paclitaxel 50-60 mg/m 2 on days 1 and 8.…”

Multicenter phase II study of weekly paclitaxel plus S-1 combination chemotherapy in patients with advanced gastric cancer

“…The response rate has been reported to be 40%-60% with the schedule of S-1 80 mg/m 2 for 14 days plus paclitaxel 50-60 mg/m 2 on days 1 and 8 or days 1 and 15. We have also conducted a phase I clinical trial of 2 weeks S-1 plus weekly paclitaxel on days 1, 8, and 15 of a 4-week cycle [34]. Based on the data from that trial, a multicenter phase II study was conducted by the Kyoto Gastrointestinal Cancer Chemotherapy Study Group in order to assess the effi cacy of S-1 and weekly paclitaxel administered every 4 weeks as fi rstline treatment for patients with advanced or metastatic gastric cancer.…”

Recent advances in the treatment of peritoneal dissemination of gastrointestinal cancers by nucleoside antimetabolites

“…At present, clinical studies of TS-1 combined with taxanes or cisplatin in patients with advanced gastric cancer have been evaluated. (9,59,60) It has been reported that docetaxel and S-1 combination therapy are highly active and well tolerated in advanced or recurrent gastric cancer. (57) Capecitabine is an orally administered fluoropyrimidine anticancer drug used in the treatment of metastatic breast and Sakamoto et al reported that the administration of capecitabine for the treatment of chemotherapy-naive patients with unresectable advanced or metastatic gastric cancer showed promising activity and was well tolerated as a first-line therapy for advanced and metastatic gastric cancer.…”