Phase II trial of exemestane in combination with fulvestrant in postmenopausal women with hormone responsive advanced breast cancer: no evidence of a pharmacokinetic interaction between exemestane and fulvestrant.

Abstract

Abstract Abstract #6131 Background: Treatment options for postmenopausal women (PW) with hormone responsive breast cancer (HRBC) involve blocking estrogen receptor (ER) with anti-estrogens or inhibiting estrogen synthesis with aromatase inhibitors (AI). A mouse xenograft model showed that combination of the pure estrogen antagonist fulvestrant (FUL) and an AI was more effective in suppressing tumor growth than either treatment alone. We hypothesized this combination would have an enhanced anti-tumor activity in PW with HRBC. To test this hypothesis a phase II trial of FUL and the steroidal AI exemestane (EXE) was designed.
 Materials & Methods: Eligible PW may have received prior adjuvant chemotherapy (CT), treatment with tamoxifen, anastrazole or letrozole in the adjuvant or advanced disease setting. EXE at a dose of 25 mg daily was started on Day 1. On day 8, FUL was added and administered as an IM injection of 250 mg every 28 days. Response was assessed every 2 cycles by physical examination and imaging studies. The steady-state pharmacokinetics of EXE when administered alone (Day 7) and in combination with FUL (Day 120) was assessed in a subset of PW. Plasma samples were obtained before and 1, 2, 4, 6, 8, and 24 hours after dosing on each occasion. Plasma concentrations of EXE and 17-hydroxyEXE were analyzed using a validated liquid chromatographic method with mass spectrometric detection. Serum concentrations of insulin growth factor I (IGF-I) were determined prior to dosing, on Day 7 and Day 120. The primary clinical endpoint is the proportion of patients free of progressive disease at 6 months. A Fleming single-stage design (with P0 =0.5, P1= 0.7, α=0.10 and β=0.10) requires a sample size of 40 women. If 24 of the 40 PW are progression-free at 6-months, this treatment will be worthy of future study.
 Results: Nineteen women were enrolled. The median age was 64 years (range 48-83 years); 42% had prior adjuvant CT, 53% had prior hormonal therapy; and 47% had visceral metastases. Nine (47%) had a PFS ≥ 6 months (range 6 to 20 months) with 8 still on treatment; 8 (42%) progressed prior to 6 mo; and 2 (11%) have been on treatment for < 2 mo. Only 1 (5%) developed grade 3 arthralgias that required treatment discontinuation; 2 (11%) had grade 3 fatigue; and 2 (11%) had grade 3 bone pain. Steady-state EXE plasma concentration-time profiles were determined in 9 women on both Day 7 (EXE alone) and Day 120 (EXE+FUL). Mean EXE Cmax, AUC, and half-life values determined on Day 120 were within 12% of values determined on Day 7. The median serum concentrations of IGF-I prior to therapy were 112 ng/ml (range 85-172); on day 7 were 134 ng/ml (range 86-174); and on day 120 were 129 ng/ml (range 73-216) Discussion: Co-administration of FUL does not result in clinically relevant changes in EXE plasma concentrations. This combined therapy is well tolerated and active. Accrual is ongoing. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6131.