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
| Autor: | Stan B. Kaye, Robert S. Brown, Hani Gabra, Rosalind Glasspool, G.J.S. Rustin, James Paul, Martin Gore, K. Appleton, Richard H. Wilson, J Walker, Melanie Mackean, Geoffrey Hall, R. Ullah, Sarah Halford, Iain A. McNeish, Pledge S |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
5-aza-2′-deoxycytidine
Oncology Cancer Research medicine.medical_specialty endocrine system diseases Azacitidine Decitabine Neutropenia Pharmacology Carboplatin RC0254 chemistry.chemical_compound Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Adaptor Proteins Signal Transducing Aged Platinum Ovarian Neoplasms drug resistance DNA methylation business.industry Nuclear Proteins Middle Aged Interim analysis medicine.disease female genital diseases and pregnancy complications Clinical trial ovarian cancer chemistry Hypomethylating agent Drug Resistance Neoplasm Clinical Study Female Neoplasm Recurrence Local MutL Protein Homolog 1 business Ovarian cancer medicine.drug |
| Zdroj: | British Journal of Cancer |
| ISSN: | 0007-0920 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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