Platinum resistance is a major obstacle in the treatment of epithelial ovarian cancer (EOC). It has been demonstrated that aberrations in DNA methylation play a significant role in this phenomenon by silencing expression of tumor suppressor and pro-apoptotic genes. We showed in EOC cells resistant to chemotherapy that decitabine, an effective epigenetic modulator, restores sensitivity to platinum. Based on these data we hypothesized that reversal of DNA methylation by decitabine allows re-expression of silenced tumor suppressors and re-sensitizes ovarian tumors to platinum. We propose to address this hypothesis in a phase I/II clinical trial designed to test whether low dose decitabine induces DNA demethylation in vivo and re-sensitizes recurrent EOC to platinum. We will examine both clinical and pharmacodynamic correlates, by pursuing three aims:
Aim 1. Determine whether a biologically active dose of decitabine administered i.v. qd for 5 days before carboplatin is tolerated in patients with recurrent, platinum-resistant or -refractory EOC. This will be addressed in a limited dose escalation phase I trial.
Aim 2. Determine the clinical efficacy of decitabine and carboplatin in patients with platinum-resistant or -refractory EOC. The primary endpoint is the rate of objective responses.
Aim 3. Determine the pharmacodynamic activity of decitabine in-vivo. To evaluate the biological activity of decitabine, we will examine global and gene-specific DNA methylation changes induced by decitabine in peripheral blood and tumor biopsies. In summary, successful completion of this clinical trial will provide critical information regarding the role of epigenetic modulation with low dose decitabine in restoring sensitivity to platinum in patients with EOC. Both clinical and biological correlates will be studied.
This clinical trial proposes a novel treatment intervention for women with ovarian cancer who have failed standard chemotherapy and now have resistant tumors. We will use a new drug, called decitabine, to reverse resistance to chemotherapy. During this trial we will monitor clinical response to treatment, as well as changes in the processing of specific genes involved in drug resistance. Successful completion of this study will provide a novel opportunity for treatment for these patients who have otherwise very limited options.
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