Cancer Research UK Phase I/II Committee. A Cancer Research (UK) randomised phase II study of idoxifene in patients with locally advanced / metastatic breast cancer resistant to tamoxifen

Johnston, S.R., Gumbrell, L.A., Evans, T.R., Coleman, R.E., Smith, I.E., Twelves, C.J., Soukop, M., Rea, D.W., Earl, H.M., Howell, A., Jones, A., Canney, P., Powels, T.J., Haynes, B.P., Nutley, B., Grimshaw, R., Jarman, Megan, Halbert, G.W., Brampton, M., Haviland, J.S., Dowsett, M. and Coombes, R.C. (2004) Cancer Research UK Phase I/II Committee. A Cancer Research (UK) randomised phase II study of idoxifene in patients with locally advanced / metastatic breast cancer resistant to tamoxifen. Cancer Chemotherapy and Pharmacology, 53 (4), 341-348. (doi:10.1007/s00280-003-0733-6).

Abstract

Idoxifene is a novel selective oestrogen receptor modulator (SERM) which had greater binding affinity for the oestrogen receptor (ER) and reduced agonist activity compared with tamoxifen in preclinical studies. In a randomized phase II trial in 56 postmenopausal patients with progressive locally advanced/metastatic breast cancer we assessed whether idoxifene showed evidence of activity compared with an increased 40 mg/day dose of tamoxifen in patients who had previously demonstrated resistance to the standard 20 mg/day dose of tamoxifen. Of 47 patients eligible for response (25 idoxifene, 22 tamoxifen), two partial responses and two disease stabilizations (SD) for >6 months were seen with idoxifene (overall clinical benefit rate 16%, 95% CI 4.5–36.1%). The median duration of clinical benefit was 9.8 months. In contrast, no objective responses were seen with the increased 40 mg/day dose of tamoxifen, although two patients had SD for 7 and 14 months (clinical benefit rate 9%, 95% CI 1.1–29.2%). Idoxifene was well tolerated and the reported possible drug-related toxicities were similar in frequency to those with tamoxifen (hot flushes 13% vs 15%, mild nausea 20% vs 15%). Endocrine and lipid analysis in both groups showed a similar significant fall in serum follicle-stimulating hormone and luteinizing hormone after 4 weeks, together with a significant rise in sex hormone binding globulin levels and 11% reduction in serum cholesterol levels. In conclusion, while idoxifene was associated with only modest evidence of clinical activity in patients with tamoxifen-resistant breast cancer, its toxicity profile and effects on endocrine/lipid parameters were similar to those of tamoxifen

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