Phase I and pharmacokinetic study of irinotecan and docetaxel in patients with advanced solid tumors: Preliminary evidence of clinical activity

Purpose: The goals of this study were to determine the maximum-tolerated do se and describe the toxicities of the combination of irinotecan and docetax el administered every 3 weeks to patients with advanced malignancies and, a lso, ta evaluate the effect of irinotecan on the disposition of docetaxel a nd describe preliminary evidence of antitumor activity. Patients and Methods: Eighteen patients received 85 courses (median, two co urses; range, one to 15 courses) of treatment with irinotecan, administered over 90 minutes by intravenous infusion, followed by docetaxel, administer ed over 60 minutes by intravenous infusion. Four escalating dose levers of irinotecan/docetaxel (160/50 mg/m(2), 160/65 mg/m(2), 200/65 mg/m(2), and 2 00/75 mg/m(2)) were studied. Pharmacokinetic analyses were performed to eva luate the effect of irinotecan on the disposition of docetaxel, Results: The most common and dose-limiting toxicity was myelosuppression, w hich consisted of neutropenia that was severe (National Cancer Institute co mmon toxicity criteria [NCI CTC] grade 4) but brief (<5 days) in 11 patient s, with three episodes of febrile neutropenia, Nonhematologic toxicities of anorexia, nausea, and stomatitis were mild to moderate (NCI CTC grades 1 a nd 2), but there was one incidence each of both CTC grade 3 anorexia and na usea, All patients had total alopecia. Diarrhea war dose-dependent and seve re in four patients who failed to take adequate antidiarrhea therapy. Five out of 16 assessable patients, one with cholangiocarcinoma, one with leiomy osarcoma, and three with nan-small-cell lung cancer, achieved partial remis sions. Conclusion: The combination of irinotecan and docetaxel causes significant reversible myelosuppression, which was dose limiting but led to no serious sequelae, There was no evidence of a clinically significant interaction usi ng these two agents in this sequence. The combination showed antitumor acti vity at all the dose levels tested and should be further studied in a numbe r of tumor types, The recommended phase II dose on this schedule is irinote can 160 mg/m(2) and docetaxel 65 mg/m(2). J Clin Oncol 18:1116-1123. (C) 20 00 by American Society of Clinical Oncology.