A phase I trial of docetaxel/estramustine/imatinib in patients with hormone-refractory prostate cancer |
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Authors: | Lin Amy M Rini Brian I Derynck Mika K Weinberg Vivian Park Margaret Ryan Charles J Rosenberg Jonathan E Bubley Glenn Small Eric J |
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Affiliation: | a University of California, San Francisco b The Cleveland Clinic Foundation, OH c Beth Israel Deaconess Medical Center, Boston, MA |
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Abstract: | BackgroundDocetaxel/estramustine was a commonly used regimen to treat metastatic hormone-refractory prostate cancer. Imatinib inhibits the platelet-derived growth factor receptor that is expressed in prostate cancer and is synergistic with taxanes in preclinical prostate cancer models.Patients and MethodsA phase I trial of docetaxel/estramustine/imatinib was undertaken to determine the safety and maximum tolerated dose of this combination. Patients with progressive, metastatic, hormone-refractory prostate cancer were treated every 21 days with fixed doses of estramustine (280 mg orally 3 times a day on days 1-5), imatinib (400 mg orally daily on days 1-21), dexamethasone (8 mg orally twice daily on days 1-3), and prophylactic warfarin (2 mg orally daily on days 1-21). Cohorts of 3-6 patients were enrolled to receive escalating doses of docetaxel on day 2 from 50 mg/m2 to 60 mg/m2 to 70 mg/m2. Thirteen patients were treated.ResultsOn dose level 3 (docetaxel 70 mg/m2 and imatinib 400 mg daily), 2 patients experienced grade 3 elevations in prothrombin time, attributed to the interaction between imatinib and warfarin. The protocol was amended to include an intermediate dose level (docetaxel 60 mg/m2 and imatinib 300 mg daily). However, in the overall study, there were 5 unacceptable toxicities (2 cerebrovascular accidents, 1 myocardial infarction, 1 mesenteric ischemia, and 1 deep venous thrombosis) in 13 patients; 2 of those toxicities resulted in death. The study was closed early to further accrual.ConclusionThe high incidence of thromboembolic events observed when imatinib was combined with docetaxel/estramustine precludes further exploration of this regimen. |
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Keywords: | Dose-limiting toxicities Platelet-derived growth factor receptor Prostate-specific antigen |
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