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Investigational New Drugs

, Volume 25, Issue 1, pp 41–48 | Cite as

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 D. MillerEmail author
PHASE I STUDIES

Summary

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.

Keywords

Angiogenesis Breast cancer Clinical trial 

Notes

Acknowledgments

Supported by the American Cancer Society grant # CRTG-00-199-01-CCE (KDM) a Career Development Award from the American Society of Clinical Oncology (KDM), Breast Cancer Research Foundation (GWS, KDM) and research supported by EntreMed, Inc.

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Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Jehana James
    • 1
  • Daryl J. Murry
    • 2
  • Anthony M. Treston
    • 3
  • Anna Maria Storniolo
    • 4
  • George W. Sledge
    • 4
  • Carolyn Sidor
    • 3
  • Kathy D. Miller
    • 4
    Email author
  1. 1.Department of MedicineIndiana UniversityIndianapolisUSA
  2. 2.School of PharmacyPurdue UniversityWest LafayetteUSA
  3. 3.EntreMed, Inc.RockvilleUSA
  4. 4.Division of Hematology and OncologyIndiana University Cancer PavilionIndianapolisUSA

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