Japanese early phase II study of droloxifene in the treatment of advanced breast cancer. Preliminary dose-finding study.

Droloxifene, a new tamoxifen (TAM)-derived compound, has excellent antiestrogenic activity. This compound exhibits less endogenously estrogenic but higher antiestrogenic activity, with better tolerability than TAM in experimental models. Two phase II studies of droloxifene were performed in 47 Japanese institutions to assess the optimal dose. The first was a randomized comparative study using 20, 40, and 80 mg, respectively, once a day. The other was a pilot study using 120 mg once a day. The subjects of both studies were women with primary or recurrent advanced breast cancer, regardless of estrogen receptor status and menopausal status. Of 94 patients enrolled in the comparative study, 22, 26, and 23 were evaluable in the 20-, 40-, and 80-mg groups, respectively. Of the 71 evaluable patients, 14 (19.7%) were negative for estrogen receptor, and 36 (50.7%) had a previous history of TAM therapy. The response rate complete response + partial response (CR + PR) was 13.6% for 20 mg, 15.4% for 40 mg, and 17.4% for 80 mg. The rate of no change (NC) was 31.9%, 46.1%, and 47.8%, and that of progressive disease (PD) was 54.5%, 38.5% and 34.8%, respectively, in the 20-, 40-, and 80-mg groups. In the other study, 16 patients were enrolled in the pilot study with 120 mg of droloxifene, of whom 14 were evaluable. The response rate was slightly higher: four responders (28.6%) were assessed as CR + PR, six (42.9%) as NC, and four (28.6%) as PD. These results suggest that the response rate may be dose-dependent and that PD rates seem lower in the higher doses. No serious side effects were encountered, and droloxifene was well tolerated even in the higher doses. At present, a final randomized dose-finding study with 80 mg/day and 120 mg/day is being carried out.