Phase I study of 8-Cl-adenosine in CLL (IND 68,229)

描述(由申请人提供)： 核苷类似物在血液系统恶性肿瘤的治疗中发挥了关键作用。虽然第一个类似物是在50多年前使用的，但在过去的五年里，四个新的同系物被批准用于治疗。这些临床使用的类似物的一个共同特征是，它们都是DNA导向的；专门影响RNA的类似物还没有进入临床。8-氯腺苷是一种新的、唯一的核苷类似物，在临床上是第一个被测试的类别。首先，与其他临床使用的类似物不同，这种药物含有核糖。其次，8-氯-腺苷是由腺苷激酶磷酸化的，腺苷激酶在癌细胞中具有高比活性，而脱氧胞苷酶则激活目前使用的类似物。第三，8-氯三磷酸腺苷(8-Cl-ATP)被掺入到RNA中，对DNA合成没有任何影响。第四，8-氯-三磷酸腺苷也被掺入转录本的聚(A)尾部，从而抑制了多聚腺苷化和mRNA的合成。作为对信使核糖核酸合成作用的结果，短命转录本的耗尽。第五，生化研究和分子模拟数据表明，8-氯腺苷二磷酸(8-Cl-ADP)是线粒体ATP合成酶的底物，8-Cl-ATP是线粒体ATP合成酶的抑制剂，线粒体ATP合成酶是氧化磷酸化途径的顶端酶，导致细胞生物能量的耗尽。总体而言，这些功能使这款模拟器在同类产品中是第一款。基于这一背景，研究人员假设8-氯-腺苷将对不生长或惰性的恶性细胞产生新的药效学反应。研究人员表示，8-氯-腺苷的独特性得到了该领域同行的认可，因为他们获得了国家癌症研究所的两个奖项，食品和药物管理局的研究药物申请(IND)，以及在慢性淋巴细胞性白血病患者中进行第一阶段临床研究的药物材料。为了实现他们的总体目标并检验他们的假设，研究人员计划追求以下三个目标。目的1.使用已建立的指南评价8-氯-腺苷的毒性。在慢性淋巴细胞性白血病受试者中进行1期临床试验，以确定血液毒性和非血液毒性，并确定MTD和DLT。目的2.使用已建立的指南评价8-氯-腺苷的疗效。在慢性淋巴细胞性白血病患者中进行第一阶段临床试验，以确定该药物的临床益处。确定完全缓解、部分缓解和血液学改善。目的3.使用明确的生物标志物，评价8-氯-腺苷在慢性淋巴细胞性白血病患者1/2期临床试验中的药代动力学和药效学。研究人员表示，这些目标将建立8-氯-腺苷在CLL中的用途，为第二阶段研究提供剂量，并为该药物的单独和联合最佳使用提供知识。

DESCRIPTION (provided by applicant): Nucleoside analogues have played a pivotal role in the treatment of hematological malignancies. While the first analogue was used more than 50 years ago, during the last five years, four new congeners were approved for therapy. A common feature among these clinically used analogues is that they are all DNA-directed; analogues that are exclusively affecting RNA have not been brought to the clinic. 8-chloro-adenosine is a novel and unique nucleoside analogue that is first in its class to be tested in the clinic. First, in contrast to other clinically used analogues, this agent has a ribose sugar. Second, 8-Cl-Ado is phosphorylated by adenosine kinase which is present in high specific activity in cancer cells as opposed to deoxycytidine kinase which activates currently used analogues. Third, 8-chloro-adenosine triphosphate (8-Cl-ATP) is incorporated into RNA without any effect on DNA synthesis. Fourth, 8-Cl-ATP is also incorporated into poly(A) tail of transcripts resulting in inhibition of polyadenylation and mRNA synthesis. As a consequence of the actions on mRNA synthesis, there is a depletion of short-lived transcripts. Fifth, biochemical studies and molecular modeling data have suggested that 8-chloro-adenosine diphosphate (8-Cl-ADP) is a substrate and 8-Cl-ATP is an inhibitor for mitochondrial ATP synthase, the apical enzyme of the oxidative phosphorylation pathway which results in a depletion of cellular bioenergy. Collectively these features make this analogue a first in its class. Based on this background, the investigators hypothesized that 8-Cl-Ado will elicit novel pharmacodynamic responses to non-growing or indolent malignant cells. The investigators state that the uniqueness of 8-Cl-Ado was recognized by peers in this field as they have obtained two awards from the National Cancer Institute, an investigational drug application (IND) from the Food and Drug Administration, and drug material to conduct their Phase 1 clinical investigation in patients with CLL. To achieve their overall goal and to test their hypothesis, the investigators plan to pursue the following three aims. Aim 1. Using established guidelines evaluate toxicity of 8-Cl-Ado. Conduct the Phase 1 clinical trial in subjects with CLL to determine the hematological and nonhematological toxicity profile and identify the MTD and DLT. Aim 2. Using established guidelines evaluate efficacy of 8-Cl-Ado. Conduct the Phase 1 clinical trial in subjects with CLL to determine the clinical benefits of the drug. Determine complete remission, partial remissions, and hematological improvements. Aim 3. Using well-defined biomarkers, evaluate pharmacokinetics and pharmacodynamics of 8-Cl-Ado during Phase 1/2 clinical trial in patients with CLL. The investigators state that these Aims will establish utility of 8-Cl-Ado in CLL, provide a dose for Phase 2 study, and knowledge for optimal use of this agent alone and in combination.