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

8-Cl-腺苷治疗 CLL 的 I 期研究（IND 68,229）

• 批准号: 7578072
• 负责人: VARSHA GANDHI
• 金额: $ 20万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-11-17 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7578072
• 关键词: Phase; study; Cl; adenosine; CLL

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.

描述（由申请人提供）： 核苷类似物在血液恶性肿瘤的治疗中发挥着关键作用。 虽然第一个类似物已在 50 多年前使用，但在过去五年中，有四种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点是它们都是DNA导向的；专门影响 RNA 的类似物尚未进入临床。 8-氯-腺苷是一种新颖且独特的核苷类似物，是同类产品中第一个在临床中进行测试的。首先，与临床上使用的其他类似物相比，该药物含有核糖。其次，8-Cl-Ado 被腺苷激酶磷酸化，腺苷激酶在癌细胞中具有高比活性，而脱氧胞苷激酶则激活目前使用的类似物。第三，8-氯-三磷酸腺苷 (8-Cl-ATP) 掺入 RNA 中，对 DNA 合成没有任何影响。 第四，8-Cl-ATP 也掺入转录物的聚腺苷酸尾中，从而抑制聚腺苷酸化和 mRNA 合成。 由于对 mRNA 合成的影响，短寿命转录本会被耗尽。 第五，生化研究和分子模型数据表明，8-氯-腺苷二磷酸（8-Cl-ADP）是线粒体 ATP 合酶（氧化磷酸化途径的顶端酶）的底物，8-Cl-ATP 是抑制剂。导致细胞生物能量耗尽。总的来说，这些功能使这款模拟产品成为同类产品中的首创。 基于这一背景，研究人员假设 8-Cl-Ado 将引发针对非生长或惰性恶性细胞的新药效学反应。 研究人员表示，8-Cl-Ado的独特性得到了该领域同行的认可，他们获得了美国国家癌症研究所的两项奖项、美国食品和药物管理局的研究药物申请（IND）以及开展药物材料研究。他们对 CLL 患者进行了 1 期临床研究。为了实现他们的总体目标并检验他们的假设，研究人员计划实现以下三个目标。 目标 1. 使用既定指南评估 8-Cl-Ado 的毒性。在 CLL 受试者中进行 1 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. 使用既定指南评估 8-Cl-Ado 的功效。在 CLL 受试者中进行 1 期临床试验，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。 目标 3. 使用明确的生物标志物，在 CLL 患者的 1/2 期临床试验中评估 8-Cl-Ado 的药代动力学和药效学。 研究人员表示，这些目标将确立 8-Cl-Ado 在 CLL 中的效用，为第 2 期研究提供剂量，以及单独和联合使用该药物的最佳使用知识。