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

Abstract.

Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and effect of drug sequence on toxicities and pharmacokinetics of the combination of gemcitabine and docetaxel. Methods: A total of 34 patients with advanced cancers were treated with gemcitabine and docetaxel on days 1 and 8 of each 21-day cycle according to the following dose escalation schedule: level 1, 800 and 30 mg/m², respectively; level 2, 800 and 40 mg/m²; level 3, 1000 and 40 mg/m²; and level 4, 1250 and 40 mg/m². At each dose level, at least three patients were assigned to one of the two sequences of drug administration: gemcitabine→docetaxel or docetaxel→gemcitabine. Once the MTD had been reached, six additional patients, who had received no more than one chemotherapy regimen, were enrolled to dose levels 3 and 4 (gemcitabine→docetaxel) to determine the MTD in minimally pretreated patients. Results: Neutropenia was the most frequent DLT with an overall incidence of 23.5%. Grade 3/4 neutropenia occurred in 62% of patients (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 chemotherapy regimens (P<0.001). Additional DLTs included grade 4 diarrhea and grade 4 stomatitis in one patient each. The MTD was determined to be gemcitabine 800 mg/m² and docetaxel 40 mg/m² in patients who had received two or 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/m² and docetaxel 40 mg/m². There were no significant differences in toxicities or pharmacokinetics between the two sequences of administration. Partial and minor responses were observed in 23.5% of patients: non-small-cell lung (two of eight), gastric (two of three), head and neck (one of two), bladder (two of four) and hepatocellular 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 administration had no significant effect on the toxicity or pharmacokinetics of either drug. Minimally pretreated patients tolerated higher doses of this combination without significant toxicities. This schedule and combination demonstrated activity in a variety of solid tumors, and merits further evaluation.