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.
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.
Authors: Andrew K L Goey; Irma Meijerman; Hilde Rosing; Jacobus A Burgers; Marja Mergui-Roelvink; Marianne Keessen; Serena Marchetti; Jos H Beijnen; Jan H M Schellens Journal: Br J Clin Pharmacol Date: 2013-09 Impact factor: 4.335
Authors: Catherine A Burkhart; Fujiko Watt; Jayne Murray; Marina Pajic; Anatoly Prokvolit; Chengyuan Xue; Claudia Flemming; Janice Smith; Andrei Purmal; Nadezhda Isachenko; Pavel G Komarov; Katerina V Gurova; Alan C Sartorelli; Glenn M Marshall; Murray D Norris; Andrei V Gudkov; Michelle Haber Journal: Cancer Res Date: 2009-08-04 Impact factor: 12.701
Authors: Wayne L Furman; Fariba Navid; Najat C Daw; M Beth McCarville; Lisa M McGregor; Sheri L Spunt; Carlos Rodriguez-Galindo; John C Panetta; Kristine R Crews; Jianrong Wu; Amar J Gajjar; Peter J Houghton; Victor M Santana; Clinton F Stewart Journal: J Clin Oncol Date: 2009-08-17 Impact factor: 44.544