Phase1/11 study of 5-aza-2'-deoxycytidine and valproic *

描述(由申请人提供)：成人白血病患者的治疗选择仍然不是最优的，因此需要新的合理设计的治疗方法。两个表观遗传学改变目前是密集研究的焦点：启动子CpG岛的DNA甲基化，以及与不同水平的染色质压缩和基因表达相关的组蛋白密码的变化。这是因为：1)它们在白血病患者中被观察到的频率很高；2)它们都在基因表达中发挥作用，并且密切相关；3)它们可以通过低甲基化药物和具有临床前和临床活性的组蛋白去乙酰酶抑制剂(HDACi)来调节。低甲基化药物5-氮杂-2‘-脱氧胞苷(地西他滨)的I期研究结果表明，地西他滨在每天15 mg/m2×10天的剂量下具有显著的活性。丙戊酸是一种口服抗惊厥剂，在生理剂量下具有很强的HDACi活性，也具有极好的安全性。基于此，我们提出了一个假设，即地西他滨和丙戊酸的组合将具有良好的耐受性，并将具有显著的抗白血病活性。为了验证这一假设，我们提出了以下目标：进行一项低剂量地西他滨与递增剂量丙戊酸的I/II期研究。这项研究将监测毒性、临床反应以及组蛋白乙酰化、DNA甲基化和基因表达的变化。这项研究将具有重要的意义，因为它将提供关于DNA去甲基化试剂和HDACi组合的临床和体内分子意义的基础知识。SuperGen(R)将慷慨地提供地西他滨。丙戊酸是FDA批准的抗惊厥药物。

DESCRIPTION (provided by applicant): Treatment options for adult patients with leukemia remain sub-optimal, and therefore new rationally designed therapies are needed. Two epigenetic alterations are currently the focus of intense investigation: DNA methylation of promoter CpG islands, and changes in the histone code associated with distinct levels of chromatin compaction and gene expression. These are of interest because: 1) they are observed at high frequency in patients with leukemia; 2) both have a role in gene expression and are intimately associated; and 3) can be modulated using hypomethylating agents and histone deacetylase inhibitors (HDACI) with preclinical and clinical activity. Results of a phase I study of low-dose 5-aza-2'-deoxycytidine (decitabine), a hypomethylating agent, performed at our institution, have shown that decitabine has significant activity at doses of 15 mg/m2 daily X 10 days. Valproic acid is an oral anti-convulsant agent with potent HDACI activity at physiological doses, also with an excellent safety profile. Based on this, we propose the hypothesis that the combination of decitabine and valproic acid will be well tolerated and will have significant antileukemia activity. To test this hypothesis, we propose the following aim: to conduct a phase I/II study of low-dose decitabine with escalating doses of valproic acid. The study will be monitored for toxicity, clinical response, and changes in histone acetylation, DNA methylation and gene expression. This study will have important implications, as it will provide fundamental knowledge regarding the clinical and molecular implications in vivo of the combination of a DNA hypomethylating agent and a HDACI. Decitabine will be generously provided by SuperGen (r). Valproic acid is an FDA approved anti-convulsant.