title: Phase I trial of 2-methoxyestradiol NanoCrystal dispersion in advanced solid malignancies.
abstract: OBJECTIVE
  2-methoxyestradiol (2ME2; Panzem) is an endogenous, estradiol-17beta metabolite that at pharmacologic doses exerts antimitotic and antiangiogenic activities. Studies with a 2ME2 capsule formulation showed limited oral bioavailability. We report the results of a phase I study using a NanoCrystal Dispersion formulation of 2ME2 (2ME2 NCD).
  
  
  METHODS
  Patients with refractory solid tumors received 2ME2 NCD orally. Patients received drug either every 6 hours (part A) or every 8 hours (part B). Doses were escalated in successive cohorts until the maximum tolerated dose (MTD) was identified. The primary objective was identifying the MTD. Secondary objectives were to evaluate the plasma pharmacokinetics of 2ME2 and efficacy.
  
  
  RESULTS
  In part A, 16 patients received a median of 4 cycles of 2ME2 NCD. Dose-limiting toxicities (DLT) included fatigue (2), hypophosphatemia (2), increased alanine aminotransferase (1), and muscle weakness (1). Trough levels at steady-state reached the minimum effective concentration in all cohorts. The MTD was determined to be 1,000 mg orally every 6 hours. In part B, 10 patients received a median of 1 cycle. DLTs included elevated gamma-glutamyltransferase (1), hyponatremia (1), fatigue (1), and anorexia (1). An MTD could not be defined for part B because 4 of 10 patients had DLTs at the initial dose level and dose reduction was not pursued. Thirteen patients had stable disease (A, 11; B, 2); there were no confirmed responses.
  
  
  CONCLUSIONS
  For 2ME2 NCD, the MTD and recommended phase II regimen is 1,000 mg orally every 6 hours. Treatment was generally well-tolerated.
authors.affiliation: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center Madison, Wisconsin 53792, USA.
authors.forename: Amye J
authors.initials: AJ
authors.lastname: Tevaarwerk
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Holen
authors.forename: Dona B
authors.initials: DB
authors.lastname: Alberti
authors.forename: Carolyn
authors.initials: C
authors.lastname: Sidor
authors.forename: Jamie
authors.initials: J
authors.lastname: Arnott
authors.forename: Check
authors.initials: C
authors.lastname: Quon
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
mesh_terms: D000077584:2-Methoxyestradiol; D000368:Aged; D000369:Aged, 80 and over; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D053758:Nanoparticles / Q000008:administration & dosage*; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D004958:Estradiol; D000077584:2-Methoxyestradiol