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

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. PATIENTS AND 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. CONCLUSION: 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.