Phase I Clinical and Pharmacokinetic Study of Oral S-1 in Patients With Advanced Solid Tumors

Abstract

The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m(2) bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m(2) bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment.

EORTC Early Clinical Studies Group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer

“…In a NorthAmerican phase I study the MTD of S-1 was determined to be even lower: 30 mg m À2 b.i.d., again with diarrhoea as the DLT . Although the dose-limiting toxicity in an earlier European phase I study also was diarrhoea (van Groeningen et al, 2000), the dose-limiting toxicity in an earlier Japanese study on the contrary was myelosuppression (Taguchi et al, 1997). The reason for these differences in toxicity is unknown.…”

“…The plasma pharmacokinetics of 5-FU after oral administration of S-1 were linear and almost similar to that of continuous intravenous infusion of 5-FU (Hirata et al, 1999). A statistically significant relation was observed between the severity of diarrhoea and pharmacokinetic parameters of 5-FU (van Groeningen et al, 2000). On the basis of these results, the recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients was 40 mg m À2 b.i.d.…”

“…The doselimiting toxicity was myelosuppression in a Japanese (Taguchi et al, 1997), and diarrhoea in a European and a North-American phase I study van Groeningen et al, 2000). The plasma pharmacokinetics of 5-FU after oral administration of S-1 were linear and almost similar to that of continuous intravenous infusion of 5-FU (Hirata et al, 1999).…”

“…In heavily pretreated patients, the recommended dose was 35 mg m À2 b.i.d. (van Groeningen et al, 2000).…”

Comparative pharmacology of oral fluoropyrimidines: a focus on pharmacokinetics, pharmacodynamics and pharmacomodulation

“…For instance, Van Groeningen et al (2000) noted, for S-1, that among 5-FU plasma concentrations measured during the 28 days of oral treatment, only the level just before drug intake in week 2 was significantly related to grade 3-4 diarrhoea. A confirmation of this interesting observation during phase II -III trials would be useful in order to identify a 5-FU threshold concentration at risk for toxicity with a possibility for dose adjustment during the treatment course.…”