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A Cancer Research (UK) randomized phase II study of idoxifene in patients with locally advanced/metastatic breast cancer resistant to tamoxifen

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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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Acknowledgements

This study was conducted by the Cancer Research Campaign. We acknowledge the support of Judith Bliss from the Institute of Cancer Research in the analysis of data and statistical support. The pharmacokinetic, endocrine and lipid analyses were supported by a separate programme grant from the Cancer Research Campaign to the CRC Centre for Cancer Therapeutics and the Department of Academic Biochemistry at the Institute of Cancer Research and Royal Marsden Hospital. Dr. Ray McCague and Dr. Ian Hardcastle from the CRC Centre for Cancer Therapeutics isolated and synthesized the metabolites of idoxifene. Idoxifene was subsequently licensed to SmithKline Beecham Pharmaceuticals through the British Technology Group.

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Authors and Affiliations

  1. Cancer Research UK, Lincoln’s Inn Fields, London, WC2A 3PX, UK

    S. R. D. Johnston, L. A. Gumbrell, T. R. J. Evans, R. E. Coleman, I. E. Smith, C. J. Twelves, M. Soukop, D. W. Rea, H. M. Earl, A. Howell, A. Jones, P. Canney, T. J. Powles, B. P. Haynes, B. Nutley, R. Grimshaw, M. Jarman, G. W. Halbert, M. Brampton, J. Haviland, M. Dowsett & R. C. Coombes

  2. Cancer Cell Biology Section, Department of Cancer Medicine, Division of Medicine, Faculty of Medicine , Imperial College, Hammersmith Hospital, 6th Floor, MRC Cyclotron Building, Du Cane Road, London, W12 0NN, UK

    R. C. Coombes

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  1. S. R. D. Johnston
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  2. L. A. Gumbrell
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  3. T. R. J. Evans
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  4. R. E. Coleman
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  5. I. E. Smith
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  6. C. J. Twelves
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  7. M. Soukop
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  9. H. M. Earl
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  10. A. Howell
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  11. A. Jones
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  12. P. Canney
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  13. T. J. Powles
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  17. M. Jarman
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  20. J. Haviland
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  21. M. Dowsett
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  22. R. C. Coombes
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Corresponding author

Correspondence to R. C. Coombes.

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This work is presented on behalf of the Cancer Research UK Phase I/II Committee.

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Johnston, S.R.D., Gumbrell, L.A., Evans, T.R.J. et al. A Cancer Research (UK) randomized phase II study of idoxifene in patients with locally advanced/metastatic breast cancer resistant to tamoxifen. Cancer Chemother Pharmacol 53, 341–348 (2004). https://doi.org/10.1007/s00280-003-0733-6

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  • DOI: https://doi.org/10.1007/s00280-003-0733-6

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