title: A phase I dose-escalation, safety and pharmacokinetic study of the 2-methoxyestradiol analog ENMD-1198 administered orally to patients with advanced cancer.
abstract: BACKGROUND
  2-methoxyestradiol (2ME2) is an estradiol-17β metabolite with antiproliferative and antiangiogenic activities. ENMD-1198 is an analog of 2ME2 which was developed to decrease the metabolism and increase both the bioavailability and antitumor activities of the parent molecule. This first-in-human phase I study evaluated the tolerability, pharmacokinetics and preliminary evidence of activity of ENMD-1198 in advanced cancer patients.
  
  
  METHODS
  Eligible patients received ENMD-1198 orally once daily in Part A (standard 3 + 3 dose escalation design), or in Part B (accelerated dose escalation design). Cycle 1 consisted of 28 days daily dosing followed by a 14-(Part A) or 7-(Part B) day observation period, then continuously in 28 day cycles thereafter.
  
  
  RESULTS
  A total of 29 patients were enrolled in 12 dose cohorts (5 to 550 mg/m²)/d). The most common drug-related toxicities were Grade 1/2 fatigue (55%), nausea and vomiting (37%), and constipation (34%). Two DLTs (Grade 4 neutropenia) occurred at 550 mg/m²/day, and 425 mg/m²/d was declared the maximum tolerated dose. ENMD-1198 was absorbed rapidly with a T(max) of 1-2 h. Exposure to ENMD-1198 (C(max) and AUC₀₋₂₄ hr increased linearly with dose. The mean terminal half-life was 15 h. A 3-fold accumulation was found after multiple doses. Five patients achieved stabilization of disease for at least 2 cycles, three of whom (with neuroendocrine carcinoma of pancreas, prostate cancer and ovarian cancer) demonstrated prolonged stabilization ranging from 8-24.5 cycles.
  
  
  CONCLUSIONS
  ENMD-1198 is well-tolerated with a pharmacokinetic exposure profile compatible with once daily dosing. The recommended phase II dose of ENMD-1198 is 425 mg/m²/d. Early evidence of prolonged disease stabilization in pre-treated patients suggests ENMD-1198 is worthy of additional investigation.
authors.affiliation: Developmental Therapeutics Program, Division of Medical Oncology, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Daniel
authors.initials: D
authors.lastname: Gustafson
authors.forename: Sujatha
authors.initials: S
authors.lastname: Nallapareddy
authors.forename: Sami
authors.initials: S
authors.lastname: Diab
authors.forename: Stephen
authors.initials: S
authors.lastname: Leong
authors.forename: Karl
authors.initials: K
authors.lastname: Lewis
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Treston
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: Carolyn
authors.initials: C
authors.lastname: Sidor
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
mesh_terms: D000077584:2-Methoxyestradiol; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003710:Demography; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004963:Estrenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D051381:Rats; D013045:Species Specificity
chemical_list: C530263:2-methoxyoestra-1,3,5(10),16-tetraene-3-carboxamide; D000970:Antineoplastic Agents; D004963:Estrenes; D004958:Estradiol; D000077584:2-Methoxyestradiol