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
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-methoxyes...
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| Published in: | Clinical cancer research Vol. 11; no. 18; pp. 6625 - 6633 |
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| Main Authors: | , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Philadelphia, PA
American Association for Cancer Research
15-09-2005
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | 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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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 1078-0432 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-05-0440 |