Phase I study to evaluate multiple regimens of intravenous 5-fluorouracil administered in combination with weekly gemcitabine in patients with advanced solid tumors: a potential broadly active regimen for advanced solid tumor malignancies.

BACKGROUND The purpose of this study was to determine the maximum tolerated dose and toxicity profile of gemcitabine given on a weekly schedule with continuous infusion 5-fluorouracil. PATIENTS AND METHODS Eligible patients with advanced solid tumors received escalating doses of gemcitabine 200 and 300 mg/m2 weekly as a 30-minute infusion on Days 1, 8, and 15 every 4 weeks (schedule 1) or 450, 600, 800, 1000, 1250, 1500, 1800, and 2200 mg/m2 on Days 1 and 8 (schedule 2) every 3 weeks, respectively. At the completion of gemcitabine infusion (Day 1), patients received fixed dose continuous infusion of 5-fluorouracil at either 300 mg/m2 (Days 1–21) or 200 mg/m2 (Days 1–21; schedule 1) every 4 weeks or 200 mg/m2 (Days 1–14; schedule 2] every 3 weeks, respectively. Toxicity assessments were performed weekly on study, and efficacy measurements were performed every 6–8 weeks. RESULTS Seventy patients with advanced solid malignancies received a total of 220 cycles of combination chemotherapy. Eleven (14.3%) patients received no more than 1 treatment cycle of combination therapy. Schedule 1 maximum tolerated dose of gemcitabine was 600 mg/m2/week when combined with 5-fluorouracil (5-FU) at 200 mg/m2/day (Days 1–21) repeated every 4 weeks. The schedule 2 maximum tolerated dose of gemcitabine was 2200 mg/m2/week when combined with 5-FU dosed at 200 mg/m2/day (Days 1–14) repeated every 3 weeks. In schedule 1, the limiting factor for gemcitabine delivery was the Day 15 dose that often was omitted because of myelosuppression and/or mucositis. In schedule 1 cycle 1, nonhematologic toxicity was common and included Grade 3–4 toxicities: mucositis (8 patients), fatigue (2 patients), and anorexia (1 patient). One patient had Grade 3–4 neutropenia at dose level 5 (maximum tolerated dose). In schedule 2 cycle 1, hematologic toxicities were more common than nonhematologic toxicity and included Grade 3 anemia (3 patients), Grade 3 neutropenia (4 patients), and Grade 3 thrombocytopenia (2 patients). The nonhematologic toxicities included Grade 3 mucositis (3 patients), Grade 3 fatigue (2 patients), and Grade 3 dehydration (1 patient). Overall, antitumor activity was observed in seven patients. Three of 30 patients with cytokine refractory renal cell carcinoma (RCC; relative risk [RR] 10 %; 95% confidence interval [CI], 0.82–22%) had a partial response. Of the remaining 27 patients with RCC, 4 patients had a minor response, and 10 patients had stable disease lasting a median of 6.4 (range, 4–12) months. The remaining 5 responses occurred in 40 patients (RR, 12.5%; 95% CI, 4.2–26.8%): 2 patients with 5-FU refractory colon carcinoma, 1 patient with hepatoma, 1 patient with paclitaxel-cisplatin–resistant ovarian carcinoma, and 1 patient with cisplatin-resistant head and neck squamous cell carcinoma had a partial response. CONCLUSIONS For Phase II development, gemcitabine 450–600 mg/m2 on Days 1, 8, and 15 can be safely combined with 5-FU 200 mg/m2 given as a continuous infusion (Days 1–21) of a 28-day cycle or gemcitabine 1800 mg/m2 Days 1 and 8 given with 5-FU 200 mg/m2 as a continuous infusion (Days 1–14) of a 21-day cycle. The observed antitumor activity in several solid tumors, especially in renal cell carcinoma, warrants broad Phase II evaluation. Cancer 2001;92:1567–76. © 2001 American Cancer Society.