Phase I safety, pharmacokinetic and pharmacodynamic studies of 2-methoxyestradiol alone or in combination with docetaxel in patients with locally recurrent or metastatic breast cancer

Jehana James, Daryl J. Murry, Anthony M. Treston, Anna Maria Storniolo, George W. Sledge, Carolyn Sidor, Kathy Miller

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Abstract

Purpose: We report the first phase I trials of 2-methoxyestradiol (2ME2, Panzem® Capsules, EntreMed, Rockville, MD), alone and in combination with docetaxel, in patients with metastatic breast cancer (MBC). Patients and methods: In Trial 001, 2ME2 monotherapy was administered orally once (200-1000 mg/d, cohorts 1-5) or twice daily (200-800 mg/q12h, cohorts 6-9) for 28 days followed by a 14-day observation period, continuously thereafter. In Trial 002, docetaxel 35 mg/m2 was administered weekly for four of six weeks for a maximum six cycles; 2ME2 (200-1000 mg/d) was given orally once daily for 28 days followed by a 13-day observation period in cycle one, continuously thereafter. In both trials, responding or stable patients continued 2ME2 until progression. Results: Trial 001 enrolled 31 patients; there were no objective responses. Trial 002 enrolled 15 patients; ORR was 20% including one CR. There were no Grade IV toxicities; MTD was not reached in either study. When combined with docetaxel, three patients had significant transaminase elevations that returned to normal with continued treatment (in two of three patients). There was significant inter-patient variability and extensive metabolism to 2-methoxyestrone (2ME1). Steady-state AUC and trough concentrations of 2ME2 increased linearly up to 400-600 mg/d; doses above 400-600 mg/d did not increase 2ME2 levels. The target trough concentration (3-25 ng/mL) was not attained. Combined administration did not alter docetaxel or 2ME2 pharmacokinetics. Conclusion: 2ME2, alone or in combination with docetaxel, was well tolerated in patients with MBC but systemic exposure remained below the expected therapeutic range.

Original languageEnglish
Pages (from-to)41-48
Number of pages8
JournalInvestigational New Drugs
Volume25
Issue number1
DOIs
StatePublished - Feb 2007

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docetaxel
Pharmacokinetics
Breast Neoplasms
Safety
Observation
2-methoxyestradiol
Transaminases

Keywords

  • Angiogenesis
  • Breast cancer
  • Clinical trial

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Phase I safety, pharmacokinetic and pharmacodynamic studies of 2-methoxyestradiol alone or in combination with docetaxel in patients with locally recurrent or metastatic breast cancer. / James, Jehana; Murry, Daryl J.; Treston, Anthony M.; Storniolo, Anna Maria; Sledge, George W.; Sidor, Carolyn; Miller, Kathy.

In: Investigational New Drugs, Vol. 25, No. 1, 02.2007, p. 41-48.

Research output: Contribution to journalArticle

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title = "Phase I safety, pharmacokinetic and pharmacodynamic studies of 2-methoxyestradiol alone or in combination with docetaxel in patients with locally recurrent or metastatic breast cancer",
abstract = "Purpose: We report the first phase I trials of 2-methoxyestradiol (2ME2, Panzem{\circledR} Capsules, EntreMed, Rockville, MD), alone and in combination with docetaxel, in patients with metastatic breast cancer (MBC). Patients and methods: In Trial 001, 2ME2 monotherapy was administered orally once (200-1000 mg/d, cohorts 1-5) or twice daily (200-800 mg/q12h, cohorts 6-9) for 28 days followed by a 14-day observation period, continuously thereafter. In Trial 002, docetaxel 35 mg/m2 was administered weekly for four of six weeks for a maximum six cycles; 2ME2 (200-1000 mg/d) was given orally once daily for 28 days followed by a 13-day observation period in cycle one, continuously thereafter. In both trials, responding or stable patients continued 2ME2 until progression. Results: Trial 001 enrolled 31 patients; there were no objective responses. Trial 002 enrolled 15 patients; ORR was 20{\%} including one CR. There were no Grade IV toxicities; MTD was not reached in either study. When combined with docetaxel, three patients had significant transaminase elevations that returned to normal with continued treatment (in two of three patients). There was significant inter-patient variability and extensive metabolism to 2-methoxyestrone (2ME1). Steady-state AUC and trough concentrations of 2ME2 increased linearly up to 400-600 mg/d; doses above 400-600 mg/d did not increase 2ME2 levels. The target trough concentration (3-25 ng/mL) was not attained. Combined administration did not alter docetaxel or 2ME2 pharmacokinetics. Conclusion: 2ME2, alone or in combination with docetaxel, was well tolerated in patients with MBC but systemic exposure remained below the expected therapeutic range.",
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AU - Treston, Anthony M.

AU - Storniolo, Anna Maria

AU - Sledge, George W.

AU - Sidor, Carolyn

AU - Miller, Kathy

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N2 - Purpose: We report the first phase I trials of 2-methoxyestradiol (2ME2, Panzem® Capsules, EntreMed, Rockville, MD), alone and in combination with docetaxel, in patients with metastatic breast cancer (MBC). Patients and methods: In Trial 001, 2ME2 monotherapy was administered orally once (200-1000 mg/d, cohorts 1-5) or twice daily (200-800 mg/q12h, cohorts 6-9) for 28 days followed by a 14-day observation period, continuously thereafter. In Trial 002, docetaxel 35 mg/m2 was administered weekly for four of six weeks for a maximum six cycles; 2ME2 (200-1000 mg/d) was given orally once daily for 28 days followed by a 13-day observation period in cycle one, continuously thereafter. In both trials, responding or stable patients continued 2ME2 until progression. Results: Trial 001 enrolled 31 patients; there were no objective responses. Trial 002 enrolled 15 patients; ORR was 20% including one CR. There were no Grade IV toxicities; MTD was not reached in either study. When combined with docetaxel, three patients had significant transaminase elevations that returned to normal with continued treatment (in two of three patients). There was significant inter-patient variability and extensive metabolism to 2-methoxyestrone (2ME1). Steady-state AUC and trough concentrations of 2ME2 increased linearly up to 400-600 mg/d; doses above 400-600 mg/d did not increase 2ME2 levels. The target trough concentration (3-25 ng/mL) was not attained. Combined administration did not alter docetaxel or 2ME2 pharmacokinetics. Conclusion: 2ME2, alone or in combination with docetaxel, was well tolerated in patients with MBC but systemic exposure remained below the expected therapeutic range.

AB - Purpose: We report the first phase I trials of 2-methoxyestradiol (2ME2, Panzem® Capsules, EntreMed, Rockville, MD), alone and in combination with docetaxel, in patients with metastatic breast cancer (MBC). Patients and methods: In Trial 001, 2ME2 monotherapy was administered orally once (200-1000 mg/d, cohorts 1-5) or twice daily (200-800 mg/q12h, cohorts 6-9) for 28 days followed by a 14-day observation period, continuously thereafter. In Trial 002, docetaxel 35 mg/m2 was administered weekly for four of six weeks for a maximum six cycles; 2ME2 (200-1000 mg/d) was given orally once daily for 28 days followed by a 13-day observation period in cycle one, continuously thereafter. In both trials, responding or stable patients continued 2ME2 until progression. Results: Trial 001 enrolled 31 patients; there were no objective responses. Trial 002 enrolled 15 patients; ORR was 20% including one CR. There were no Grade IV toxicities; MTD was not reached in either study. When combined with docetaxel, three patients had significant transaminase elevations that returned to normal with continued treatment (in two of three patients). There was significant inter-patient variability and extensive metabolism to 2-methoxyestrone (2ME1). Steady-state AUC and trough concentrations of 2ME2 increased linearly up to 400-600 mg/d; doses above 400-600 mg/d did not increase 2ME2 levels. The target trough concentration (3-25 ng/mL) was not attained. Combined administration did not alter docetaxel or 2ME2 pharmacokinetics. Conclusion: 2ME2, alone or in combination with docetaxel, was well tolerated in patients with MBC but systemic exposure remained below the expected therapeutic range.

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