PURPOSE: Based on the synergistic effect in preclinical studies, a phase I clinical trial for the combination of paclitaxel and doxifluridine (an intermetabolite of capecitabine) was performed to determine the recommended dose for the treatment of patients with metastatic gastric cancer. METHODS: The dose of paclitaxel was increased from 60 mg/m2 at level 1 to 90 mg/m2 at level 5. It was administered as a 1-h infusion on days 1 and 8. The dose of doxifluridine was fixed at 600 mg/m2 per day up to level 3, and escalated to 800 mg/m2 per day at levels 4 and 5. It was administered orally for 2 weeks. The treatment was repeated every 3 weeks. RESULTS: A total of 28 patients were enrolled. No dose-limiting toxicity (DLT) was observed at levels 1 and 2 (paclitaxel 70 mg/m2). A DLT of grade 4 neutropenia lasting for more than 4 days was observed in one patient at level 3 (paclitaxel 80 mg/m2). In addition, the first five of six patients in this group experienced grade 3 neutropenia during the first treatment cycle. A further six patients were added in order to confirm the safety of this dosage level, and no more DLTs except for grade 3 nausea in one patient were observed in the second cohort. No DLT was seen in three patients at level 4 (paclitaxel 80 mg/m2). DLTs (grade 3 neuropathy in one patient and a treatment delay of the second cycle for more than 1 week due to grade 3 neutropenia in another) were observed in two out of six patients at level 5 (paclitaxel 90 mg/m2), and this dose level was determined as the maximum tolerated dose. The tumor response rate was 42% (95% confidence interval 20-67%) in 19 patients with measurable lesions. CONCLUSIONS: The recommended dose was determined as 80 mg/m2 of paclitaxel (days 1 and 8) and 800 mg/m2) of doxifluridine (days 1-14) every 3 weeks. The results of this phase I study are encouraging and a phase II trial is thus warranted.
PURPOSE: Based on the synergistic effect in preclinical studies, a phase I clinical trial for the combination of paclitaxel and doxifluridine (an intermetabolite of capecitabine) was performed to determine the recommended dose for the treatment of patients with metastatic gastric cancer. METHODS: The dose of paclitaxel was increased from 60 mg/m2 at level 1 to 90 mg/m2 at level 5. It was administered as a 1-h infusion on days 1 and 8. The dose of doxifluridine was fixed at 600 mg/m2 per day up to level 3, and escalated to 800 mg/m2 per day at levels 4 and 5. It was administered orally for 2 weeks. The treatment was repeated every 3 weeks. RESULTS: A total of 28 patients were enrolled. No dose-limiting toxicity (DLT) was observed at levels 1 and 2 (paclitaxel 70 mg/m2). A DLT of grade 4 neutropenia lasting for more than 4 days was observed in one patient at level 3 (paclitaxel 80 mg/m2). In addition, the first five of six patients in this group experienced grade 3 neutropenia during the first treatment cycle. A further six patients were added in order to confirm the safety of this dosage level, and no more DLTs except for grade 3 nausea in one patient were observed in the second cohort. No DLT was seen in three patients at level 4 (paclitaxel 80 mg/m2). DLTs (grade 3 neuropathy in one patient and a treatment delay of the second cycle for more than 1 week due to grade 3 neutropenia in another) were observed in two out of six patients at level 5 (paclitaxel 90 mg/m2), and this dose level was determined as the maximum tolerated dose. The tumor response rate was 42% (95% confidence interval 20-67%) in 19 patients with measurable lesions. CONCLUSIONS: The recommended dose was determined as 80 mg/m2 of paclitaxel (days 1 and 8) and 800 mg/m2) of doxifluridine (days 1-14) every 3 weeks. The results of this phase I study are encouraging and a phase II trial is thus warranted.