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Clinical Trial
. 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

R M Glasspool  1 , R Brown  2 , M E Gore  3 , G J S Rustin  4 , I A McNeish  5 , R H Wilson  6 , S Pledge  7 , J Paul  1 , M Mackean  8 , G D Hall  9 , H Gabra  2 , S E R Halford  10 , J Walker  11 , K Appleton  11 , R Ullah  11 , S Kaye  3 ; Scottish Gynaecological Trials Group
Affiliations
Clinical Trial

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 et al. Br J Cancer. .

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.

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Figures

Figure 1
Figure 1
Progression-free survival.
Figure 2
Figure 2
Changes in global methylation levels. Cycle 1 ratios of 5-methyl-2'-deoxycytidine to total cytidine in peripheral blood cells of patients receiving (A) 90 mg m−2 decitabine; (B) 45 mg m−2; and (C) carboplatin alone. The line represents the mean ratio in healthy volunteers.
See this image and copyright information in PMC

References

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