Phase I Study of Docetaxel in Combination with the P-Glycoprotein Inhibitor, Zosuquidar, in Resistant Malignancies

• Published in: Clinical cancer research 2004-11, Vol.10 (21), p.7220-7228
• Main Authors: FRACASSE, Paula M, GOLDSTEIN, Lori J, BURGESS, Michael F, SLAPAK, Christopher A, SCHELLENS, Jan H. M, DE ALWIS, Dinesh P, RADER, Janet S, ARQUETTE, Matthew A, GOODNER, Sherry A, WRIGHT, Lisa P, FEARS, Carole L, GAZAK, Robert J, ANDRE, Valerie A. M
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Area Under Curve; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; Biological and medical sciences; Dibenzocycloheptenes - administration & dosage; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Neoplasms - pathology; Pharmacology. Drug treatments; Quinolines - administration & dosage; Taxoids - administration & dosage; Time Factors; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-0452

Purpose: To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of docetaxel infused over 1 hour when given in combination with oral zosuquidar to patients with resistant solid tumors. Experimental Design: In cycle 1, patients received docetaxel alone. In subsequent cycles, zosuquidar was administered with docetaxel, which was escalated from 75 to 100 mg/m 2 . Zosuquidar was escalated from 100 to 300 mg/m 2 every 8 hours on days 1 to 3 for a total of 7 doses, or from 400 to 500 mg every 12 hours for 2 doses administered 2 hours before docetaxel. The pharmacokinetics of docetaxel with and without zosuquidar administration were obtained. Results: Thirty-six of 41 patients completed at least one cycle of docetaxel and zosuquidar. The maximum tolerated dose was docetaxel 100 mg/m 2 and zosuquidar 500 mg every 12 hours for 2 doses. The most common toxicity was neutropenia. In 35 patients, zosuquidar produced minimal increases in the docetaxel peak plasma concentrations and area under the curve. Dosing over 3 days with zosuquidar (7 doses) did not show benefit over the 1-day dosing. Of the 36 patients, one patient had a partial response, and 14 patients had disease stabilization. Conclusions: Docetaxel at 75 or 100 mg/m 2 and zosuquidar 500 mg 2 hours before docetaxel and 12 hours later is well tolerated. Zosuquidar minimally alters the pharmacokinetics of docetaxel, allowing full dose docetaxel to be given with this P-glycoprotein modulator. A Phase II study with this combination in advanced breast carcinoma is underway.