A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers

Abstract

While tamoxifen use is associated with clear benefits in the treatment of hormone-sensitive breast cancer, it also exhibits partial oestrogen agonist activity that is associated with adverse events, including endometrial cancer. Fulvestrant ("Faslodex") is a new oestrogen receptor antagonist that downregulates the oestrogen receptor and has no known agonist effect. This single-centre, double-blind, randomised, parallel-group trial was conducted to determine the direct effects of fulvestrant on the female endometrium when given alone and in combination with the oestrogen, ethinyloestradiol. Following a 14-day, pretrial screening period, 30 eligible postmenopausal volunteers were randomised to receive fulvestrant 250 mg, fulvestrant 125 mg or matched placebo administered as a single intramuscular injection. Two weeks postinjection, volunteers received 2-weeks concurrent exposure to ethinyloestradiol 20 microg day(-1). Endometrial thickness was measured before and after the 14-day screening period with further measurements predose (to confirm a return to baseline) and on days 14, 28 and 42 post-treatment with fulvestrant. Pharmacokinetic and safety assessments were performed throughout the trial. Fulvestrant at a dose of 250 mg significantly (P=0.0001) inhibited the oestrogen-stimulated thickening of the endometrium compared with placebo. Neither the 125 mg nor 250 mg doses of fulvestrant demonstrated oestrogenic effects on the endometrium over the initial 14-day assessment period. Fulvestrant was well tolerated and reduced the incidence of ethinyloestradiol-related side effects. At the same dose level that is being evaluated in clinical trials of postmenopausal women with advanced breast cancer, fulvestrant (250 mg) is an antioestrogen with no evidence of agonist activity in the endometrium of healthy postmenopausal women.

Figure 1

Study design. N.B. Fulvestrant administered as a single intramuscular injection, which provided continuous exposure over at least a 28-day period.

Figure 2

Mean endometrial thickness from premedical examination to trial day 42. Abbreviations: Pre=premedical examination; D14=after 14 days of ethinyloestradiol treatment; T1=treatment day 1 immediately before patients received either placebo or fulvestrant (125 mg or 250 mg); T14=day 14 when volunteers received their second challenge with ethinyloestradiol; T28=day 28 post-treatment at the end of the second ethinyloestradiol challenge; T42=day 42 post-treatment.

Figure 3

Geometric mean (s.d.) plasma concentrations of fulvestrant. Day 1 concentration was taken 2 h after dosing; day 14 concentration was taken pre-inflation of cuff.