Background: Gefitinib, which is an orally active epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated activity against hormone-refractory prostate cancer (HRPC) in preclinical studies. In this pilot Phase I trial, the authors evaluated the tolerability, efficacy, and pharmacokinetics of gefitinib combined with estramustine and docetaxel in patients with HRPC.
Methods: Patients received gefitinib (at a dose of 250 mg/day or 500 mg/day) on each day of a 21-day treatment cycle. Docetaxel (at a dose of 60 mg/m(2)) was administered on Day 1, and estramustine (at a dose of 280 mg) was administered 3 times daily on Days 1 through 5.
Results: Fifteen patients were recruited at each gefitinib dose level. The most common adverse events observed were consistent with the known profiles of gefitinib, docetaxel, and estramustine. No dose-limiting toxicity was observed. Adverse events considered to be gefitinib related included diarrhea (n = 23 patients), rash (n = 8 patients), nausea (n = 7 patients), dry skin (n = 6 patients), and emesis (n = 6 patients). Overall, 9 of 22 evaluable patients (40.9%) experienced a pain response. and 9 of 30 patients (30%) had a prostate-specific antigen response. A partial objective tumor response was demonstrated in 1 of 13 evaluable patients (7.7%) in each dose group; the median time to progression for both doses combined was 185 days (range, 28-233 days). Data comparisons within individual patients suggested that docetaxel and estramustine had no effect on gefitinib steady-state levels. Gefitinib had no effect on docetaxel exposure at the 250-mg dose but decreased exposure at the 500-mg dose. However, gefitinib may increase exposure to estramustine, particularly at the 500 mg/day dose.
Conclusions: The results of the current study demonstrated that gefitinib combined with estramustine and docetaxel had acceptable and predictable tolerability. However, it is unclear whether gefitinib provides an additional clinical benefit over docetaxel and estramustine alone.