Phase I and Pharmacokinetic Study of Escalating Dose of Docetaxel Administered with Granulocyte Colony-stimulating Factor Support in Adult Advanced Solid Tumors

Purpose: The purpose of our study was to assess the feasibility, toxicity, and pharmacokinetics of an escalating dose of docetaxel when administered with granulocyte colony-stimulating factor (G-CSF) support every 3 weeks. Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of docetaxel as a 1-h infusion every 3 weeks, supported by s.c. administration of human recombinant glycosilated G-CSF Granocyte (lenograstim), 5 μg/kg/day (from day 4 until neutrophil count >0.5–10 g /liter for two consecutive days). Plasma sampling was performed to characterize the pharmacokinetics of docetaxel at the new recommended high-dose level. Results: Forty-seven patients were treated with 116 courses of docetaxel at eight dose levels ranging from 100–185 mg/m 2 . Dose-limiting toxicities were nonhematologic and included mucositis and dermatitis. Severe skin toxicity observed at 185 mg/m 2 led to discontinuing the study, and 175 mg/m 2 was selected as the recommended dose of docetaxel + G-CSF for future Phase II studies. Analysis of multiple courses revealed dermatitis, mucositis, arthralgia/myalgia, and neuropathy as the main dose-related toxic events. At 175 mg/m 2 mean ± SD values for docetaxel plasmatic peak, area under the curve, clearance, volume of distribution, and terminal half-life were 6.7 ± 1.7 μg/ml, 9.7 ± 4 μg·h/ml, 34.2 ± 12 liters/h, and 122.7 ± 124 liters, respectively. Of the 16 patients treated at 175 mg/m 2 , 8 patients responded (7 breast cancer and 1 lung cancer patients) including one complete response (1 breast cancer patient). Conclusions: Using G-CSF support allows substantial dose escalation of docetaxel. Whether such a dose increase improves the response rate warrants further investigation. At the highest dose level studied, pharmacokinetic parameters seem to maintain a linear profile.