Phase I clinical and pharmacokinetic trial of docetaxel and irinotecan administered on a weekly schedule.
BACKGROUND
Docetaxel and irinotecan are synergistic agents with a broad spectrum of activity but overlapping myelosuppression. The study was designed to maintain dose intensity while limiting myelosuppression. The objectives of this study were to determine the maximal tolerated dose (MTD) of the combination of docetaxel and irinotecan administered weekly for four consecutive weeks every 42 days, to describe toxicities of this regimen, and to perform a pharmacokinetic analysis to evaluate changes in drug disposition as a function of dose as well as repeated dosing.


METHODS
Adult patients with advanced solid tumors were treated with docetaxel followed by irinotecan. Doses of 30/50, 35/50, 35/66, 30/57, 30/65, 30/80 mg/m(2), respectively, were studied. Pharmacokinetics of docetaxel, irinotecan and SN-38 in plasma were determined on days 1 and 22 by a high-performance liquid chromatography (HPLC) assay.


RESULTS
A total of 35 patients were treated. The MTD was docetaxel 30 mg/m(2) plus irinotecan 65 mg/m(2). Diarrhea was the dose-limiting toxicity; myelosuppression and other non-hematological toxicities were uncommon and mild. There were no significant differences in pharmacokinetic parameters between day 1 and day 22 (n=20). Five objective responses (breast, stomach and unknown primary) were observed among 30 evaluable patients. In addition, eight patients achieved stable disease.


CONCLUSIONS
The combination of weekly docetaxel and irinotecan is a well tolerated regimen and should be explored in phase II trials. This schedule maintains dose intensity and has limited myelosuppression.
Garcia
Agustin A
AA
Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Pujari
Mahesh
M
Jeffers
Susan
S
Iqbal
Syma
S
Lenz
Heinz-Josef
HJ
Beringer
Paul
P
Louie
Stan
S
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D043823:Taxoids / Q000008:administration & dosage
D043823:Taxoids; D000077143:Docetaxel; D000077146:Irinotecan; D002166:Camptothecin