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[Phase I study of S-1. S-1 Study Group]
T Taguchi1, Y Inuyama, R Kanamaru
1Osaka University, Japan Society for Cancer Chemotherapy.
Abstract:
We have conducted Phase I study of a novel oral antitumor agent of fluorinated pyrimidines, S-1, in which tegafur (FT) is combined with two classes of modulator, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio of FT:CDHP:Oxo = 1:0.4:1 as a multi-center study with 16 institutions nationwide. Two administration methods, once and twice daily administrations, were evaluated. As a result, MAD was determined as 150 mg/body/day approximately 200 mg/body/day and 75 mg/body x2/day approximately 100 mg/body x2/day, respectively. DLF was myelosuppression, mainly consisting of leukopenia in the two administrations. Most adverse reactions observed, including myelosuppression, disappeared by discontinuation of administration, and recovery was in about 2 weeks. Adverse reactions other than myelosuppression which induced the discontinuation were rash and vomiting. Other adverse reactions observed were anorexia, malaise, diarrhea and stomatitis. Diarrhea and stomatitis were mild (Grade 1), except those observed at a dose of 200 mg/body/day, and did not induce discontinuation of administration. Based on these findings and pharmacokinetic evaluation, the recommended dose and administration for Early Phase II studies were determined as twice daily administration of 75 mg/body for 28 consecutive days with 14 days rest (1 course).
Insights
This Phase I study evaluated S-1, an oral antitumor agent. The recommended dose for further studies is 75 mg twice daily, with myelosuppression as the main dose-limiting toxicity.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- S-1 is a novel oral antitumor agent comprising tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo).
- Fluoropyrimidines are a critical class of chemotherapeutic agents used in cancer treatment.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) and safety profile of S-1 in cancer patients.
- To establish the recommended dose and administration schedule for Phase II clinical trials.
Main Methods:
- A multi-center Phase I clinical trial involving 16 institutions nationwide.
- Evaluation of two administration schedules: once daily and twice daily.
- Assessment of dose-limiting toxicities (DLTs) and adverse events.
Main Results:
- The maximum tolerated dose (MTD) was established at approximately 150-200 mg/day for once-daily dosing and 75-100 mg twice daily for twice-daily dosing.
- Myelosuppression, primarily leukopenia, was the main dose-limiting toxicity for both administration schedules.
- Adverse events like rash and vomiting necessitated treatment discontinuation in some cases, while others like diarrhea and stomatitis were generally mild.
Conclusions:
- Twice-daily administration of S-1 at 75 mg/body for 28 consecutive days with a 14-day rest period was determined as the recommended dose and schedule for Phase II studies.
- S-1 demonstrates a manageable safety profile, with myelosuppression being the primary concern.
- Further investigation in Phase II trials is warranted to evaluate the efficacy of S-1.