Phase I trial of intramuscular estradiol valerate (I/M-E) in hormone refractory prostate cancer

Abstract

4726 Introduction. We evaluated the safety of I/M–E depots administered every two weeks, in hormone refractory prostate cancer patients receiving chemotherapy. Due to high incidence of thrombo-embolic (TE) events associated with oral estrogens, sensitive markers of coagulation activation were monitored during I/M–E treatments to guide initiation of anticoagulant prophylaxis. The primary goal was to establish maximal tolerated dose (MTD) using 3 I/M–E doses (10mg, 20mg and 40 mg). Methods: Patients with no history of TE events were enrolled after consenting and screening for thrombosis. Treatment was delivered in cohorts of three, at the 3 dose levels. Three doses of I/M–E depots were given every two weeks. Prior to each dose, markers of coagulation activation were measured. These included thrombin anti-thrombin complex (TAT; reference range:1.0–4.1μ/l) and quantitative DDimers (QDD; range:0–250ng/ml). Patients with levels above reference ranges were also given daily prophylaxis with 60mg of LMWH. Dose limiting toxicity was defined as two consecutive dosing periods during which TAT/QDD levels remained elevated despite LMWH prophylaxis. Results: 9 patients have completed study on three dose levels (3 each). Study treatment durations varied between 6 and 8 weeks for each patient. All patients received variable duration of prophylaxis with LMWH due to increase in baseline TAT/QDD levels after receiving study drug. No study related TE/hemorrhagic event is seen. Grade 2 toxicities include gynacomastia (1/9), fluid retention (4/9) and local bruises at LMWH injection site (4/9). Anti–Xa activity in patients receiving prophylactic LMWH varied between 0.0–0.4U/ml. Conclusions: MTD is reached at 40mg of I/M–E with prophylactic LMWH in this patient population and is found safe and well tolerated. Where-as oral estramustine and estrogens share a high incidence of TE events, IM–E/LMWH combination appears a safe alternative in advanced prostate cancer. Efficacy trials will be conducted of this combination in prostate cancer patients on chemotherapy. Potential anti cancer effects of LMWH in advanced prostate cancer will also be explored in these future trials. No significant financial relationships to disclose.