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

Christopher Sweeney, Glenn Liu, Constantin Yiannoutsos, Jill Kolesar, Dorothea Horvath, Mary Jane Staab, Karen Fife, Victoria Armstrong, Anthony Treston, Carolyn Sidor, George Wilding

Research output: Contribution to journalArticle

139 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6625-6633
Number of pages9
JournalClinical Cancer Research
Volume11
Issue number18
DOIs
StatePublished - Sep 15 2005

Fingerprint

Capsules
Prostatic Neoplasms
Prostate-Specific Antigen
Pharmacokinetics
Hormones
Safety
Sex Hormone-Binding Globulin
Transaminases
Venous Thrombosis
Biological Availability
Research Design
2-methoxyestradiol
Liver
Therapeutics
Pharmaceutical Preparations
2-methoxyestrone

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Sweeney, Christopher; Liu, Glenn; Yiannoutsos, Constantin; Kolesar, Jill; Horvath, Dorothea; Staab, Mary Jane; Fife, Karen; Armstrong, Victoria; Treston, Anthony; Sidor, Carolyn; Wilding, George.

In: Clinical Cancer Research, Vol. 11, No. 18, 15.09.2005, p. 6625-6633.

Research output: Contribution to journalArticle

Sweeney, Christopher ; Liu, Glenn ; Yiannoutsos, Constantin ; Kolesar, Jill ; Horvath, Dorothea ; Staab, Mary Jane ; Fife, Karen ; Armstrong, Victoria ; Treston, Anthony ; Sidor, Carolyn ; Wilding, George. / 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. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 18. pp. 6625-6633.
@article{c48b131503e74fd585939fd4d1844264,
title = "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",
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.",
author = "Christopher Sweeney and Glenn Liu and Constantin Yiannoutsos and Jill Kolesar and Dorothea Horvath and Staab, {Mary Jane} and Karen Fife and Victoria Armstrong and Anthony Treston and Carolyn Sidor and George Wilding",
year = "2005",
month = "9",
day = "15",
doi = "10.1158/1078-0432.CCR-05-0440",
language = "English",
volume = "11",
pages = "6625--6633",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

TY - JOUR

T1 - 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

AU - Sweeney, Christopher

AU - Liu, Glenn

AU - Yiannoutsos, Constantin

AU - Kolesar, Jill

AU - Horvath, Dorothea

AU - Staab, Mary Jane

AU - Fife, Karen

AU - Armstrong, Victoria

AU - Treston, Anthony

AU - Sidor, Carolyn

AU - Wilding, George

PY - 2005/9/15

Y1 - 2005/9/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=25144452785&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=25144452785&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-05-0440

DO - 10.1158/1078-0432.CCR-05-0440

M3 - Article

C2 - 16166441

AN - SCOPUS:25144452785

VL - 11

SP - 6625

EP - 6633

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 18

ER -