Abstract
2005 Background: There is increasing evidence that DNA hypermethylation of CpG islands at key genes is associated with chemo resistance. For instance, methylation of a CpG-island at the hMLH1 promoter may be a major mechanism for loss of MLH1 expression associated with chemo resistance. Decitabine (5-Aza-2'-deoxycytidine) is a demethylating agent which has been shown in in vivo studies to reactivate MLH1 expression leading to sensitisation of chemo resistant tumours to a range of cytotoxic drugs. This Phase I study investigated the feasibility of delivering a dose of decitabine which would cause demethylation and hence potential sensitisation without causing prohibitive myelosuppression in combination with carboplatin. Methods: Pts with a variety of malignancies were enrolled. The starting dose of decitabine (on Day 1) was 45mg/m2. This was escalated in steps of 45mg/m2. Carboplatin at a fixed dose of AUC5 was given on Day 8. The interval between decitabine and carboplatin was 8 days which was within the optimal time for demethylation from xenograft studies. Treatment was repeated every 4 weeks. Results: 14 heavily-pretreated pts have been enrolled to date (6M/8F). Median age: 55; mean PS (ECOG): 1. Pts have been treated at 3 dose levels of decitabine: 45, 90 and 135mg/m2. Median number of cycles: 2 (range 0.5–6). 13/14 patients were evaluable for toxicity. MTD was identified as decitabine 135mg/m2 with grade 4 febrile neutropenia (1 pt), and grade 4 neutropenia necessitating delay of cycle 2 for >7 days (1 pt). Other possible treatment-related toxicities included: nausea, vomiting, diarrhoea, fatigue, anorexia, anaemia (all ≤grade 2 and easily manageable). PD studies showed reduction in 5-methylcytosine to total cytosine ratios in DNA isolated from peripheral mononuclear cells at all dose levels, and was maximal between Days 8 and 12 following decitabine infusion Conclusion: This study confirms that the combination of decitabine and carboplatin is feasible. Futher patients are being accrued to assess PD effects in tumour as well as peripheral blood and buccal smears. No significant financial relationships to disclose.
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