Phase I study of orally administered S-1 in combination with epirubicin and oxaliplatin in patients with advanced solid tumors and chemotherapy-naïve advanced or metastatic esophagogastric cancer

Abstract

Background This phase I study investigated the safety and the maximum tolerated dose (MTD) of the oral fluoropyrimidine S-1 when combined with epirubicin and oxaliplatin (EOS). Methods Patients aged C18 years with advanced or metastatic solid tumors were enrolled in a 3 ? 3 design with S-1 dose escalation (two planned cohorts) performed according to the occurrence of dose-limiting toxicity (DLT). On day 1 of each 21-day cycle, patients received epirubicin 50 mg/m 2 followed by oxaliplatin 130 mg/m 2 (maximum 8 cycles) and then S-1 [20 mg/m 2 (cohort 1) or 25 mg/m 2 (cohort 2), twice daily]: first dose, evening of day 1; subsequent administration on days 2-14, twice daily; last dose, morning of day 15 (unlimited number of S-1 cycles). After protocol amendment, enrollment in a third cohort was restricted to patients with chemotherapynaïve advanced or metastatic esophagogastric cancer. Results DLT was reported for two of the five patients in cohort 2, defining 20 mg/m 2 twice daily as the MTD of S-1 combined with epirubicin and oxaliplatin in heavily pretreated patients. Thirteen patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer were subsequently enrolled and treated at an S-1 dose level of 25 mg/m 2 twice daily; no DLTs were reported; median overall survival was 13.1 months. Of the 11 evaluable patients, three (27 %) had partial responses and seven (64 %) had stable disease. The safety profile was in line with expectations. Conclusions The promising activity of EOS (S-1 dose level, 25 mg/m 2 twice daily) and acceptable safety profile support further clinical development of this combination for the first-line treatment of patients with advanced or metastatic esophagogastric cancer.

S-1 in combination with docetaxel and oxaliplatin in patients with advanced gastro-esophageal adenocarcinoma: two parallel phase 1/2a studies

“…Non-hematological toxicities were very infrequent at the RD levels (3A and 2B). The RD of S-1 is in line with the S-1 dose commonly recommended for Caucasian patients [5,23,24], but lower than doses used in East Asian patients; which we believe is due to more effective bioactivation of tegafur to 5-FU caused by higher activity of CYP2A6 in Caucasian patients [25].…”

Correlation between Immunohistochemical Markers in Hepatocellular Carcinoma Cells and In Vitro High-Throughput Drug Sensitivity Screening

“…For example, the FOLFOX4 regimen, containing L-OHP and 5-FU, has passed the certification of a large-scale phase III clinical study [ 42 ], and the GEMOX regimen containing L-OHP and gemcitabine achieved an objective response rate of 22% and overall survival of 11 months [ 43 ]. The combination of L-OHP and EPI is often used in research into gastric cancer chemotherapy [ 44 , 45 ]. However, its mechanism of action is still not clear, and it is rarely used for the treatment of liver cancer.…”

New Perspectives in the Treatment of Advanced Gastric Cancer: S-1 as a Novel Oral 5-FU Therapy in Combination with Cisplatin

“…So far, enzyme assays for the routine screening of cancer patients prior to 5-FU administration are not available [50]. Known DPD deficiency as well as treatment with DPD inhibitors within 4 weeks before study entry, including sorivudine or its chemically related analogues such as brivudine, are contraindications for any 5-FU-based chemotherapy [49]. …”

“…Cisplatin should be discontinued after six cycles without withdrawal of S-1. If cisplatin is discontinued before completion of the scheduled six cycles, S-1 can be resumed as a monotherapy when the criteria for treatment resumption are met [49]. …”