Phase I Study of Combination Therapy with S-1 and Docetaxel (TXT) for Advanced or Recurrent Gastric Cancer

Abstract

Background: S-1, an oral fluorouracil antitumor drug, and docetaxel have both been identified as effective agents for the treatment of gastric cancer. The two drugs have incompletely overlapping principal toxicities, which constitute the rationale for evaluating the effects of a combination of S-1 and docetaxel in this phase I study. The aim of this phase I study was to determine the maximum-tolerated dose (MTD) and the recommended dose of docetaxel with a fixed dose of S-1 in patients with advanced or recurrent gastric cancer. Patients and Methods: The pharmacokinetics of both drugs were evaluated on Day 1 of treatment. Patients with a performance status (PS) of 0 to 2 received docetaxel at the starting dose of 40 mg/m² by i.v. infusion over 1 hour on Day 1 and S-1 at the full dose of 80 mg/m² daily for two weeks every three weeks. Nine patients were treated with increasing dose levels of docetaxel as follows: (docetaxel/S-1, mg/m²): 40/80 (Level 1), 50/80 (Level 2) and 60/80 (Level 3) and all the cases were found to be assessable for drug safety, while 7 were assessable for response. Colony-stimulating factor (CSF) was not used in this study. The adverse effects of the treatment were analyzed according to NCI-CTC, version 2, and the response was assessed according to the Japanese Classification of Gastric Cancer, 13th Ed. Results: The MTD was reached at the 50/80 mg/m² dose level in three patients out of six, who experienced a dose-limiting toxicity (DLT). The DLTs were neutropenia and allergic reactions. No hematological or non-hematological adverse effects (more severe than Grade 2) were observed in any of the Level 1 patients. However, among the Level 2 patients, 50% developed neutropenia (more severe than Grade 2), 33% developed loss of appetite, 17% developed diarrhea, 33% developed stomatitis and 17% developed allergic reactions. On the other hand, partial response was achieved in 5 (71.4%) of the 7 patients with evaluable lesions. The pharmacokinetics of docetaxel were not altered as compared to that in the historical controls by the administration of S-1. These results indicate that the recommended doses of the two drugs in the combination therapy would be 40 mg/m² for docetaxel and 80 mg/m² for S-1. Conclusion: The drug combination showed a good safety profile, with neutropenia being a common but manageable adverse reaction. Moreover, the responses observed in the study suggest that the drug combination shows a high degree of efficacy in patients with advanced and or recurrent gastric cancer.