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A Phase II Multicenter, Randomized, Double-Blind, Safety Trial Assessing the Pharmacokinetics, Pharmacodynamics, and Efficacy of Oral 2-Methoxyestradiol Capsules in Hormone-Refractory Prostate Cancer

Authors' Affiliations: Divisions of ¹ Hematology-Oncology and ² Biostatistics, Department of Medicine, Indiana University, Indianapolis, Indiana; ³ Department of Oncology, University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin; and ⁴ EntreMed, Rockville, Maryland

Requests for reprints: Christopher Sweeney, Department of Medicine, Indiana University, 535 Barnhill Drive, Room 473, Indianapolis, IN 46202. Phone: 317-274-3515; Fax: 317-274-3646; E-mail: chsweene{at}iupui.edu.

Purpose: To determine whether the preclinical antitumor and antiangiogenic activity of 2-methoxyestradiol can be translated to the clinic.

Experimental Design: Men with hormone-refractory prostate cancer were enrolled into this phase II randomized, double-blind trial of two doses of oral 2-methoxyestradiol capsules (400 and 1,200 mg/d) given in 4-week cycles. Pharmacokinetic sampling was done on day 1 of cycles 1 and 2 and trough samples were obtained weekly.

Results: Thirty-three men were accrued between February and September 2001. The notable toxicity related to therapy was one grade 2 and two grade 3 episodes of liver transaminase elevation, which resolved with continued treatment in two patients. There were two cases of deep venous thromboses. The drug had nonlinear pharmacokinetic, rapid conversion to 2-methoxyestrone and 85% conjugation. Trough plasma levels of unconjugated 2-methoxyestradiol and 2-methoxyestrone were 4 and 40 ng/mL, respectively. Prostate-specific antigen declines between 21% and 40% were seen in seven patients in the 1,200 mg group and in one patient in the 400 mg group. The higher-dose group showed significantly decreased prostate-specific antigen velocity (P = 0.037) and compared with the 400 mg dose had a longer median time to prostate-specific antigen progression (109 versus 67 days; P = 0.094) and time on study (126 versus 61 days; P = 0.024). There was a 2.5- and 4-fold increase in sex hormone-binding globulin for the 400 and 1,200 mg dose levels, respectively, at days 28 and 56.

Conclusion: 2-Methoxyestradiol is well tolerated and, despite suboptimal plasma levels and limited oral bioavailability with this capsule formulation, still showed some anticancer activity at 1,200 mg/d.

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