A phase I trial of docetaxel/estramustine/imatinib in patients with hormone-refractory prostate cancer

Amy M. Lin, Brian I. Rini, Mika K. Derynck, Vivian Weinberg, Margaret Park, Charles J. Ryan, Jonathan E. Rosenberg, Glenn Bubley, Eric J. Small

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Background: Docetaxel/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 Methods: A 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. Results: On 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. Conclusion: The high incidence of thromboembolic events observed when imatinib was combined with docetaxel/estramustine precludes further exploration of this regimen.

Original languageEnglish (US)
Pages (from-to)323-328
Number of pages6
JournalClinical Genitourinary Cancer
Volume5
Issue number5
DOIs
StatePublished - Jun 2007
Externally publishedYes

Keywords

  • Dose-limiting toxicities
  • Platelet-derived growth factor receptor
  • Prostate-specific antigen

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