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 tolerate d 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 d oses of gemcitabine 200 and 300 mg/m(2) weekly as a 30-minute infusion on D ays 1, 8, and 15 every 4 weeks (schedule 1) or 450, 600, 800, 1000, 1250, 1 500, 1800, and 2200 mg/m(2) on Days 1 and 8 (schedule 2) every 3 weeks, res pectively. At the completion of gemcitabine infusion (Day 1), patients rece ived fixed dose continuous infusion of 5-fluorouracil at either 300 mg/m2 ( Days 1-21) or 200 mg/m(2) (Days 1-21; schedule 1) every 4 weeks or 200 mg/m 2 (Days 1-14; schedule 2] every 3 weeks, respectively. Toxicity assessments were performed weekly on study, and efficacy measurements were performed e very 6-8 weeks. RESULTS. Seventy patients with advanced solid malignancies received a total of 220 cycles of combination chemotherapy. Eleven (14.3%) patients receive d no more than 1 treatment cycle of combination therapy. Schedule I maximum tolerated dose of gemcitabine was 600 mg/m(2)/week when combined with 5-fl uorouracil (5-FU) at 200 mg/m(2)/day (Days 1-21) repeated every 4 weeks. Th e schedule 2 maximum tolerated dose of gemcitabine was 2200 mg/m(2)/week wh en combined with 5-FU dosed at 200 mg/m(2)/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 muco sitis. In schedule I cycle 1, nonhematologic toxicity was common and includ ed Grade 3-4 toxicities: mucositis (8 patients), fatigue (2 patients), and anorexia (I patient). One patient had Grade 3-4 neutropenia at dose level 5 (maximum tolerated dose). In schedule 2 cycle 1, hematologic toxicities we re 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 pa tients), Grade 3 fatigue (2 patients), and Grade 3 dehydration (I patient). Overall, antitumor activity was observed in seven patients. Three of 30 pa tients with cytokine refractory renal cell carcinoma (RCC; relative risk [R R] 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 1 0 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, I patient with hep atoma, I patient with paclitaxel-cisplatin-resistant ovarian carcinoma, and I patient with cisplatin- resistant head and neck squamous cell carcinoma had a partial response. CONCLUSIONS. For Phase II development, gemcitabine 450-600 mg/m(2) on Days 1, 8, and 15 can be safely combined with 5-FU 200 mg/m2 given as a continuo us infusion (Days 1-21) of a 28-day cycle or gemcitabine 1800 mg/m(2) Days I and 8 given with 5-FU 200 mg/m(2) as a continuous infusion (Days 1-14) of a 21-day cycle. The observed antitumor activity in several solid tumors, e specially in renal cell carcinoma, warrants broad Phase II evaluation. (C) 2001 American Cancer Society.