Faculty Collaboration Database

Phase I study of docetaxel in combination with the P-glycoprotein inhibitor, zosuquidar, in resistant malignancies. Clin Cancer Res 2004 Nov 01;10(21):7220-8

Date

11/10/2004

Pubmed ID

15534095

DOI

10.1158/1078-0432.CCR-04-0452

Scopus ID

2-s2.0-8444251671 (requires institutional sign-in at Scopus site)   69 Citations

Abstract

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/m2. Zosuquidar was escalated from 100 to 300 mg/m2 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/m2 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/m2 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.

Author List

Fracasso PM, Goldstein LJ, de Alwis DP, Rader JS, Arquette MA, Goodner SA, Wright LP, Fears CL, Gazak RJ, Andre VA, Burgess MF, Slapak CA, Schellens JH

Author

Janet Sue Rader MD Chair, Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Administration, Oral
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
Area Under Curve
Dibenzocycloheptenes
Dose-Response Relationship, Drug
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms
Quinolines
Taxoids
Time Factors