Phase I and pharmacokinetic study of escalating dose of docetaxel administered with granulocyte colony-stimulating factor support in adult advanced solid tumors.
OBJECTIVE
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.


METHODS
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 microg/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 microg/ml, 9.7 +/- 4 microg.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.
Gonçalves
Anthony
A
Department of Medicine, Institut Paoli-Calmettes, 13273 Marseille, France. oncomed@marseille.fnclcc.fr
Viret
Frederic
F
Ciccolini
Joseph
J
Genre
Dominique
D
Gravis
Gwenaelle
G
Giovanini
Marc
M
Camerlo
Jacques
J
Catalin
Jacques
J
Maraninchi
Dominique
D
Viens
Patrice
P
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000494:pharmacology; D001943:Breast Neoplasms / Q000628:therapy; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000493:pharmacokinetics*; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D043823:Taxoids; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; D017239:Paclitaxel