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。 虽然第一种类似物是在50多年前使用的，但在过去五年中，有四种新的同源物被批准用于治疗。 这些临床上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的类似物尚未进入临床。 8-氯-腺苷是一种新型和独特的核苷类似物，是同类产品中首次在临床上进行测试。首先，与其他临床上使用的类似物相比，该药剂具有核糖。第二，8-Cl-Ado被腺苷激酶磷酸化，腺苷激酶在癌细胞中以高比活性存在，而脱氧胞苷激酶激活目前使用的类似物。第三，8-氯-腺苷三磷酸（8-Cl-ATP）被掺入RNA中，对DNA合成没有任何影响。 第四，8-Cl-ATP也掺入到转录物的poly（A）尾，导致多聚腺苷酸化和mRNA合成的抑制。 作为对mRNA合成的作用的结果，存在短寿命转录物的消耗。 第五，生物化学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合酶的底物，8-Cl-ATP是线粒体ATP合酶的抑制剂，线粒体ATP合酶是氧化磷酸化途径的顶端酶，导致细胞生物能量的消耗。总的来说，这些功能使这种类似物成为同类产品中的第一个。 基于这一背景，研究人员假设8-Cl-Ado将对非生长或惰性恶性细胞引起新的药效学反应。 研究人员表示，8-Cl-Ado的独特性得到了该领域同行的认可，因为他们已经获得了美国国家癌症研究所的两个奖项，美国食品和药物管理局的研究药物申请（IND），以及在CLL患者中进行1期临床研究的药物材料。为了实现他们的总体目标并验证他们的假设，研究人员计划追求以下三个目标。 目标1.使用已建立的指南评价8-Cl-Ado的毒性。在CLL受试者中进行I期临床试验，以确定血液学和非血液学毒性特征，并确定MTD和DLT。 目标2.使用已建立的指南评价8-Cl-Ado的疗效。在CLL受试者中进行I期临床试验，以确定药物的临床获益。 确定完全缓解、部分缓解和血液学改善。 目标3：使用明确定义的生物标志物，在CLL患者的I/II期临床试验期间评估8-Cl-Ado的药代动力学和药效学。 研究者指出，这些目标将确立8-Cl-Ado在CLL中的效用，为II期研究提供剂量，并了解该药物单独和联合的最佳使用。

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.