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

Department of Medicine, Institut Paoli-Calmettes, 13273 Marseille, France [A. G., F. V., D. G., G. G., M. G., J. Cam., D. M., P. V.]; Pharmacokinetic and Toxicokinetic Laboratory, School of Pharmacy, Marseille, France [J. Ci., J. Cat.]; and Université Méditerranée, IFR57 Marseille, France [J. Cat., D. M., P. V.]

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/m². Dose-limiting toxicities were nonhematologic and included mucositis and dermatitis. Severe skin toxicity observed at 185 mg/m² led to discontinuing the study, and 175 mg/m² 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/m² 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/m², 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.

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