A randomised, phase II trial of the DNA-hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in combination with carboplatin vs carboplatin alone in patients with recurrent, partially platinum-sensitive ovarian cancer.

R M Glasspool, R Brown, M E Gore, G J S Rustin, I A McNeish, R H Wilson, S Pledge, J Paul, M Mackean, G D Hall, H Gabra, S E R Halford, J Walker, K Appleton, R Ullah, S Kaye

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Abstract

Background: Our previous laboratory and clinical data suggested that one mechanism underlying the development of platinum resistance in ovarian cancer is the acquisition of DNA methylation. We therefore tested the hypothesis that the DNA hypomethylating agent 5-aza-2'-deoxycytodine (decitabine) can reverse resistance to carboplatin in women with relapsed ovarian cancer.

Methods: Patients progressing 6-12 months after previous platinum therapy were randomised to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone. The primary objective was response rate in patients with methylated hMLH1 tumour DNA in plasma.

Results: After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination. Responses by GCIG criteria were 9 out of 14 vs 3 out of 15 and by RECIST were 6 out of 13 vs 1 out of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%).

Conclusions: With this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver. Patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.
Original languageEnglish
Pages (from-to)1923-1929
Number of pages7
JournalBritish Journal of Cancer
Volume110
Early online date18 Mar 2014
DOIs
Publication statusPublished - 18 Mar 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Glasspool, R. M., Brown, R., Gore, M. E., Rustin, G. J. S., McNeish, I. A., Wilson, R. H., Pledge, S., Paul, J., Mackean, M., Hall, G. D., Gabra, H., Halford, S. E. R., Walker, J., Appleton, K., Ullah, R., & Kaye, S. (2014). A randomised, phase II trial of the DNA-hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in combination with carboplatin vs carboplatin alone in patients with recurrent, partially platinum-sensitive ovarian cancer. British Journal of Cancer, 110, 1923-1929. https://doi.org/10.1038/bjc.2014.116