Phase I/II Study of MS-275 and 5-Azacytidine in Patients with Advanced Non-Small

描述（由申请人提供）：非小细胞肺癌（NSCLC）是美国最常见的癌症死亡原因，大多数NSCLC患者在初次治疗后死于复发性进展性疾病。对于与长期无病生存相关的复发性肺癌，尚无可用的治疗方法。对于非小细胞肺癌，特别是复发性疾病的新疗法，是一个迫切的需求。通过异常DNA甲基化和组蛋白去乙酰化介导的表观遗传基因沉默是肺癌发生的关键因素。我们小组的临床前研究表明，DNA甲基转移酶（DNMT）和组蛋白去乙酰化酶（HDAC）的联合抑制可协同诱导肿瘤中表观遗传沉默的肿瘤抑制基因的重新表达。在我们的机构中，DNMT抑制剂5AC与HDAC抑制剂苯基丁酸酯或MS- 275联合用于血液恶性肿瘤的临床研究已经产生了显著的临床活性，与逆转这些疾病中沉默的关键肿瘤抑制基因的表观遗传变化相关。我们建议在晚期复发性非小细胞肺癌患者中使用5AC和MS-275联合表观遗传靶向治疗的疗效，该方案在血液系统恶性肿瘤患者中具有良好的耐受性和显著的活性。该试验将包括相关分析，旨在评估治疗是否与我们发现肺癌中常见的表观遗传沉默基因的重新表达相关。目的：1 .评估5AC联合MS-275治疗复发性晚期NSCLC患者的安全性、毒性特征，并确定MS-275的最大耐受剂量。SA2：确定5AC和MS-275在复发性NSCLC患者中的客观有效率。SA3：确定5AC和MS-275在复发性NSCLC患者中的药代动力学特征。SA4：通过血液、痰和组织活检分析，评估5AC和MS-275对复发性NSCLC患者DNA甲基化、组蛋白乙酰化和基因再表达的药效学影响。肺癌是男性和女性癌症死亡的最常见原因，每年在美国造成超过16万人死亡。该项目将研究肺癌患者的一种新的治疗策略，基于逆转癌症中调节基因的异常沉默。如果成功，这种方法可以改变患有这种疾病的个体的不良预后。

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is the most common cause of cancer death in the U.S. Most NSCLC patients die of recurrent progressive disease after primary therapy. There are no available therapies for recurrent lung cancer associated with long-term disease-free survival. New therapies for NSCLC, particularly for recurrent disease, are a critical need. Epigenetic gene silencing mediated through aberrant DNA methylation and histone deacetylation is a key contributor to lung carcinogenesis. Preclinical studies by our group have shown that combined inhibition of DNA methyl transferases (DNMT) and of histone deacetylases (HDAC) synergistically induces re-expression of tumor suppressor genes epigenetically silenced in cancer. Clinical studies at our institution of the DNMT inhibitor 5AC in combination with HDAC inhibitors phenylbutyrate or MS- 275 in hematologic malignancies have resulted in remarkable clinical activity associated with reversal of epigenetic changes in key tumor suppressor genes silenced in these diseases. We propose to test the efficacy of combined epigenetic targeting in patients with advanced, recurrent NSCLC using 5AC and MS-275 on a schedule shown to be well-tolerated and associated with significant activity in patients with hematologic malignancies. The trial will include correlative analyses designed to evaluate whether therapy is associated with re-expression of genes we have found to be frequently epigenetically silenced in lung cancer. The aims of this project include the following: SA1: To assess safety, characterize toxicities, and determine the maximum tolerated dose of 5AC with MS-275 in patients with recurrent advanced NSCLC. SA2: To determine the objective response rate of 5AC and MS-275 in patients with recurrent NSCLC. SA3: To determine the pharmacokinetic profile of 5AC and MS-275 in patients with recurrent NSCLC. SA4: To assess the pharmacodynamic effects of 5AC and MS-275 on DNA methylation, histone acetylation, and gene re-expression in patients with recurrent NSCLC through analysis of blood, sputum and tissue biopsies. Lung cancer is the most common cause of cancer death in both men and women, responsible for over 160,000 deaths annually in the U.S. This project will study a novel therapeutic strategy in patients with lung cancer, based on reversing the aberrant silencing of regulatory genes in cancers. If successful, this approach could alter the poor prognosis of individuals with this disease.