Journal article
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
Clinical cancer research, Vol.11(18), pp.6625-6633
09/15/2005
DOI: 10.1158/1078-0432.ccr-05-0440
PMID: 16166441
Abstract
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.
Details
- Title: Subtitle
- 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
- Creators
- Christopher Sweeney - Indiana University IndianapolisGlenn Liu - University of Wisconsin Carbone Cancer CenterGeorge Wilding - University of Wisconsin Carbone Cancer CenterConstantin Yiannoutsos - Indiana University – Purdue University IndianapolisJill Kolesar - University of Wisconsin Carbone Cancer CenterDorothea Horvath - University of Wisconsin Carbone Cancer CenterMary Jane Staab - University of Wisconsin Carbone Cancer CenterKaren Fife - Indiana University IndianapolisVictoria Armstrong - Indiana University IndianapolisAntliofiy Treston - EntieMiad, Rockville, Maryland, United StatesCarolyn Sidor - CASI Pharmaceuticals
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.11(18), pp.6625-6633
- Publisher
- American Association for Cancer Research
- DOI
- 10.1158/1078-0432.ccr-05-0440
- PMID
- 16166441
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Language
- English
- Date published
- 09/15/2005
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984695796002771
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