Phase I and pharmacokinetic study of docetaxel, irinotecan, and celecoxib in patients with advanced non-small cell lung cancer.
OBJECTIVE
We studied the toxicities, potential pharmacokinetic interactions, and preliminary antitumor activity of the combination of docetaxel and irinotecan with celecoxib, a selective cyclooxygenase-2 inhibitor.


METHODS
Eligible patients had advanced non-small lung cancer (NSCLC) with measurable disease, good performance status, and adequate end organ function. Docetaxel and irinotecan were administered intravenously on days 1 and 8, every 21 days, and their doses were escalated on successive patient cohorts at three dose levels: 30/50, 30/60, and 35/60 (doses in mg/m2). Celecoxib was administered at a starting dose of 400 mg orally twice daily without interruption, beginning on day 2 of cycle 1. Pharmacokinetic studies were performed on day 1 of cycle 1 and day 1 of cycle 2.


RESULTS
Seventeen patients with advanced NSCLC were enrolled and collectively received 78 cycles of therapy. Diarrhea was the most common toxicity; it was noted in 13 patients (76%). Dose-limiting toxicities occurred at dose level 1 (myocardial infarction in a patient with multiple coronary artery disease risk factors) and dose level 3 (grade 4 neutropenia with fatal urosepsis). Other major toxicities were: grade 3 neutropenia (2 patients); grade 3/4 diarrhea (3/1); grade 3 nausea (2); grade 2 rash (1); and grade 3 pneumonitis (1). The maximum tolerated dose was at dose level 3, i.e., docetaxel 35 mg/m2 and irinotecan 60 mg/m2 on days 1 and 8, plus celecoxib 400 mg twice daily, repeated every 21 days. Five of 15 evaluable patients achieved an objective response. The pharmacokinetics of docetaxel were not altered by celecoxib. However, we observed an 18% increase in the average elimination clearance of irinotecan coincident with the addition of celecoxib.


CONCLUSIONS
The addition of celecoxib to docetaxel and irinotecan was generally well tolerated but unpredictable fatal toxicity occurred. Diarrhea was the most common toxicity. Antitumor activity was promising. The alteration of irinotecan pharmacokinetic parameters observed may not be clinically relevant.
Argiris
Athanassios
A
Division of Hematology-Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA.
Kut
Victoria
V
Luong
Lynn
L
Avram
Michael J
MJ
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism*; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077143:Docetaxel; D004347:Drug Interactions; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
D000972:Antineoplastic Agents, Phytogenic; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D043823:Taxoids; D000077143:Docetaxel; D000077146:Irinotecan; D000068579:Celecoxib; D002166:Camptothecin