Phase I and pharmacokinetic study of two sequences of gemcitabine and docetaxel administered weekly to patients with advanced cancer

Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxic ity (DLT), and effect of drug sequence on toxicities and pharmacokinetics o f the combination of gemcitabine and docetaxel. Methods: A total of 34 pati ents with advanced cancers were treated with gemcitabine and docetaxel on d ays 1 and 8 of each 21-day cycle according to the following dose escalation schedule: level 1, 800 and 30 mg/m(2), respectively; level 2, 800 and 40 m g/m(2); level 3, 1000 and 40 mg/m(2); and level 4, 1250 and 40 mg/m(2). At each dose level, at least three patients were assigned to one of the two se quences of drug administration: gemcitabine --> docetaxel or docetaxel --> gemcitabine. Once the MTD had been reached, six additional patients, who ha d received no more than one chemotherapy regimen, were enrolled to dose lev els 3 and 4 (gemcitabine --> docetaxel) to determine the MTD in minimally p retreated patients. Results: Neutropenia was the most frequent DLT with an overall incidence of 23.5%. Grade 3/4 neutropenia occurred in 62% of patien ts (8/13) who had received two or more prior chemotherapy regimens, but not at all (0/15) in patients who had received no more than one prior chemothe rapy regimens (P < 0.001). Additional DLTs included grade 4 diarrhea and gr ade 4 stomatitis in one patient each. The MTD was determined to be gemcitab ine 800 mg/m(2) and docetaxel 40 mg/m(2) in patients who had received two o r more prior chemotherapy regimens. However, minimally pretreated patients (no more than one prior chemotherapy regimen) were able to tolerate higher doses with an MTD of gemcitabine 1250 mg/m(2) and docetaxel 40 mg/m(2). The re were no significant differences in toxicities or pharmacokinetics betwee n the two sequences of administration. Partial and minor responses were obs erved in 23.5% of patients: non-small-cell lung (two of eight), gastric (tw o of three), head and neck (one of two), bladder (two of four) and hepatoce llular cancer (one of one). Conclusions: The combination of gemcitabine and docetaxel administered on days 1 and 8 every 21 days was feasible and well tolerated in patients with advanced malignancies. The sequence of administ ration had no significant effect on the toxicity or pharmacokinetics of eit her drug. Minimally pretreated patients tolerated higher doses of this comb ination without significant toxicities. This schedule and combination demon strated activity in a variety of solid tumors, and merits further evaluatio n.