A phase I study of doxifluridine combined with weekly paclitaxel for metastatic gastric cancer

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.

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.

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.

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.