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: OBJECTIVE
  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).
  
  
  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/m(2) 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.
  
  
  CONCLUSIONS
  2ME2, alone or in combination with docetaxel, was well tolerated in patients with MBC but systemic exposure remained below the expected therapeutic range.
authors.affiliation: Department of Medicine, Indiana University, Indianapolis, IN, USA.
authors.forename: Jehana
authors.initials: J
authors.lastname: James
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Murry
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Treston
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Storniolo
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.forename: Carolyn
authors.initials: C
authors.lastname: Sidor
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Miller
mesh_terms: D000077584:2-Methoxyestradiol; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077143:Docetaxel; D004334:Drug Administration Schedule; D004958:Estradiol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006207:Half-Life; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D043823:Taxoids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D016482:Urinalysis; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000652:urine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D050257:Tubulin Modulators; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D000077143:Docetaxel; D004958:Estradiol; D000077584:2-Methoxyestradiol; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9