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Br J Cancer. 2014 Apr 15;110(8):1923-9. doi: 10.1038/bjc.2014.116. Epub 2014 Mar 18.

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.

Author information

1
The Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK.
2
Department Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
3
Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.
4
Mount Vernon Cancer Centre, Northwood, Middlesex HA6 2RN, UK.
5
St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK.
6
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7AB, N. Ireland, UK.
7
Sheffield Weston Park Hospital, Whitham Road, Sheffield, South Yorkshire S10 2SJ, UK.
8
Edinburgh Western General Hospital, Crewe Road S, Edinburgh EH4 2XU, UK.
9
St James's Institute of Oncology, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
10
Drug Development Office Cancer Research UK, Angel Building, 407 Street, John Street, Islington, London EC1V 4AD, UK.
11
Analytical Services Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1QH, UK.

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.

PMID:
24642620
PMCID:
PMC3992493
DOI:
10.1038/bjc.2014.116
[Indexed for MEDLINE]
Free PMC Article

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