*2.2. Treatment and Dose Escalation Schedules in the Phase I Study*

On day 1 of each cycle, docetaxel (Sanofi-aventis K.K., Tokyo, Japan) diluted with 500 mL of normal saline was administered as a 90-min infusion. S-1 (Taiho Pharmaceutical Company, Tokyo, Japan) was orally administered twice daily on days 1–14. The dose of S-1 was determined according to the patient's body surface area as follows: <1.25 m2, 40 mg; 1.25–1.50 m2, 50 mg; and >1.5 m2, 60 mg. Combination chemotherapy was repeated every 3 weeks until progressive disease (PD) occurred.

In the phase I study, the starting dose of docetaxel was 45 mg/m<sup>2</sup> (level 1). Docetaxel dose escalation was performed as follows: in the patient cohorts containing at least 3 patients at each dose level, if none of the patients treated at a given dose level experienced dose limiting toxicity (DLT) as defined below, patients were entered at the next dose level (50 mg/m2 at level 2, 60 mg/m2 at level 3, and 70 mg/m<sup>2</sup> at level 4). If 1 or 2 of the 3 patients in the cohort experienced DLT, 3 additional patients were entered at the same level. MTD was then fixed and dose escalation was discontinued if all 3 patients in the 3-patient cohorts or ≥3 patients in the 6-patient cohorts experienced DLT. Adverse events were assessed in the first two cycles of the phase I study.

In the phase II study, the recommended dose of docetaxel determined in phase I was used in combination with S-1 in the same manner. The treatment regimen was repeated every 21 days until PD, patient withdrawal, or the occurrence of a serious adverse event. Granulocyte colony-stimulating factor (G-CSF) could be administered when either fever ≥38 ◦C with grade 3 or 4 neutropenia occurred. DLT was defined as: grade 4 neutropenia lasting for ≥4 days, grade 3 febrile neutropenia lasting ≥72 h, grade 3 thrombocytopenia, ≥grade 3 nonhematologic toxicity (besides nausea, vomiting, fatigue, and alopecia), ≥grade 2 interstitial pneumonia, or interruption of the S-1 medication for ≥7 days. If a patient experienced DLT, the docetaxel dose was reduced by one level in the subsequent cycle. To receive a subsequent cycle of chemotherapy, patients had to have leukocyte counts <sup>≥</sup>3000/mm3, neutrophil counts <sup>≥</sup>1500/mm3, platelets <sup>≥</sup>100,000/mm3, serum creatinine <sup>&</sup>lt;1.5 mg/dL, and reduction in any treatment-related nonhematologic toxicity to <grade 1 (besides alopecia and neuropathy).
