title: Early phase II study of the new aromatase inhibitor YM511 in postmenopausal patients with breast cancer. Difficulty in clinical dose recommendation based on preclinical and phase I findings.
abstract: BACKGROUND
  A phase II study of a non-steroidal selective aromatase inhibitor, YM511, 4-[N-bromobenzyl]-N-(4H-1,2,4-triazol-4-yl)amino) benzonitrile, was conducted to evaluate the anti-tumor response, dose-dependence of response rate and tolerability in postmenopausal patients with advanced breast cancer.
  
  
  METHODS
  Patients were randomly allocated to a dose of 0.3, 1, 3, 10 or 30 mg after stratification according to PS, previous therapy and ER, and were administered the drug orally once a day.
  
  
  RESULTS
  Of 98 eligible patients, 6 achieved complete response (CR) and 14 partial response (PR), resulting in an objective response rate of 20.4%. In addition, 13 patients achieved NC lasting more than 24 weeks (L-NC), resulting in an overall success rate of 33.7%. However, no clear dose-dependence of response rate was observed. Significant reduction of serum estradiol level was observed at all doses. Median time to progression of disease was 61-233 days. Toxicity was mild or moderate in severity. Fifty-five adverse events were reported in 38 patients, the most common being gastrointestinal disorders such as nausea, vomiting and anorexia (18 events) and constitutional symptoms such as asthenia, hot flushes and common cold syndrome (14 events). The frequency of drug-related adverse events was not dose-related. Abnormalities in hematological laboratory values and blood biochemistry, which were probably drug-related, were less than 5% in frequency except for cholesterol level, and were light or moderate in severity.
  
  
  CONCLUSIONS
  YM511 appeared to be effective and safe in postmenopausal patients with breast cancer. Dose-dependent increase in response rate was not clearly observed at doses from 0.3 mg/day to 30 mg/day. The recommended dose of YM511 for further studies is 0.3 mg or less than 0.3 mg.
authors.affiliation: Breast Cancer Center, Toyosu Hospital, Showa University School of Medicine, 1-18, Toyosu 4-chome, Koutou-ku, Tokyo 135-8577, Japan. watana_y@yamanouchi.co.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tominaga
authors.forename: Takaichiro
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000368:Aged; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D004958:Estradiol / Q000097:blood; D004970:Estrone / Q000097:blood; D005260:Female; D006801:Humans; D017698:Postmenopause / Q000097:blood; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D014230:Triazoles; C096486:YM 511; D004970:Estrone; D004958:Estradiol