Abstract
4617 Background: The E/D combination is used widely to treat metastatic HRPC. Imatinib mesylate inhibits the platelet-derived growth factor receptor which is overexpressed in HRPC, and is synergistic with docetaxel in preclinical models. A phase I trial of E/D was therefore undertaken to determine the maximum tolerated dose of docetaxel in this combination. Methods: Metastatic HRPC patients with progressive disease by Consensus Criteria and no prior chemotherapy or investigational therapy were treated in a standard phase I design. All patients received therapy every 21 days consisting of fixed doses of estramustine phosphate, (280 mg po tid D 1–5) dexamethasone (8 mg po bid D 1–3), warfarin (2 mg po qd) and imatinib (400 mg po qd D 1–21). Docetaxel on day 1 was dose-escalated by cohort from 50 to 60 to 70 mg/m2 iv. Results: A total of 13 patients were treated. On dose level 3 (400 mg qd imatinib, 70 mg/m2 docetaxel), 2 patients experienced grade 3 elevated prothrombin times attributed to the interaction between imatinib and warfarin, so an additional 3 patients were treated at an intermediate level utilizing 300 mg qd imatinib and 60 mg/m2 docetaxel. While this dose level was initially established as the recommended phase II level, overall in the entire study, 5/13 patients had unacceptable toxicity as defined by the protocol, which exceeded pre-specified boundaries, mandating study closure. These events were thromboembolic in nature and included 2 cerebrovascular accidents, 1 myocardial infarct, 1 mesenteric ischemia and 1 deep vein thrombosis. Conclusions: The combination of estramustine, docetaxel and imatinib results in excessive thromboembolic toxicity, potentially due to interactions between estramustine, a known thrombogenic agent, and imatinib. This toxicity precludes the use of this combination in HRPC patients. No significant financial relationships to disclose.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
