Phase I Trial of Bortezomib and Romidepsin in CLL and Small Cell Lymphoma

硼替佐米和罗米地辛治疗 CLL 和小细胞淋巴瘤的 I 期试验

• 批准号: 7742109
• 负责人: Steven Grant
• 金额: $ 27.47万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-06 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742109
• 关键词: Acetylation; Address; Apoptosis; BIRC4 gene; Bortezomib; Cell Death; Cell Line; Cells; Chronic; Chronic Lymphocytic Leukemia; Depsipeptides; Dose; Down-Regulation; Drug Combinations; Effectiveness; Event; Future; Hematopoietic; Histone Deacetylase Inhibitor; Human; In Vitro; Laboratories; Lymphocyte; Malignant - descriptor; Maximum Tolerated Dose; Mediating; Nuclear; Pathway interactions; Patients; Pharmacodynamics; Phase I Clinical Trials; Positioning Attribute; Prevention; Process; Proteasome Inhibitor; Proteins; Safety; Small-Cell Lymphoma; Techniques; Testing; Toxic effect; X-linked IAP; in vivo; inhibitor/antagonist; leukemia; multicatalytic endopeptidase complex; novel; pre-clinical; pro-apoptotic protein; protein expression; public health relevance; response; synergism

DESCRIPTION (provided by applicant): Previous studies from this and other laboratories have established that histone deacetylase inhibitors (HDACIs) and proteasome inhibitors such as bortezomib interact synergistically to induce apoptosis in malignant human hematopoietic cells. In chronic lymphocytic leukemia (CLL) cells, postulated mechanisms of synergism have focused on bortezomib-mediated blockade of HDACI-induced RelA acetylation and activation of the canonical and alternative NF-:B pathways, resulting in down regulation of NF-:B-dependent survival proteins (e.g., Bcl-xL and XIAP). Very recently, we have observed that when co-administered in vitro at extremely low concentrations (i.e. 3-5 nM each), the Class I HDACI romidepsin (depsipeptide; FK228) interacts with bortezomib to induce very pronounced apoptosis in fresh primary CLL cells as well as .CLL cell lines. Furthermore, these events are associated with prevention of romidepsin-induced activation of the classical and alternative NF-:B pathways, down regulation of the NF-:B dependent proteins Bcl-xL and XIAP, and induction of the pro-apoptotic protein Bim. We now propose to begin testing the in vivo implications of these preclinical findings by conducting a Phase I trial. The specific aims of this proposal are: First, to determine the maximum tolerated dose (MTD) for the combination of bortezomib and romidepsin administered weekly x 3 every 4 weeks in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); to determine the safety and describe the toxicities of the combination; and to document activity of the combination observed in the course of the dose finding study. Second, to demonstrate adequate techniques for the assessment of pharmacodynamic responses of CLL cells to the combination with respect to effects on activation of the canonical and alternative NF-:B pathways (nuclear RelA and p52 as a marker of p100 processing), expression of the NF-:B-dependent proteins XIAP and Bcl-xL, and expression of the pro-apoptotic protein Bim; and to document pharmacodynamic responses observed in the course of the dose finding study. PUBLIC HEALTH RELEVANCE: Studies from our laboratory have shown a potent interaction between the histone deacetylase inhibitor romidepsin and the proteosome inhibitor in inducing cell death in primary chronic lymphocytic leukemia (CLL) cells. The purpose of this study is to determine the maximum tolerated dose (MTD) for the combination administered weekly x 3 every 4 weeks in patients with chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SLL), to determine the safety and describe the toxicities of the combination, and to document activity of the combination observed in the course of the dose finding study. Further, the purpose is to demonstrate adequate techniques for the assessment of pharmacodynamic responses of CLL cells to the combination with respect to effects on activation of the canonical and alternative NF-:B pathways, expression of selected NF-:B-dependent proteins, and expression of pro-apoptotic protein Bim, and to document pharmacodynamic responses observed in the course of the dose finding study. This will position us to perform future trials that will determine the effectiveness of this novel drug combination in patients with CLL or SLL and address the validity of our preclinical pharmacodynamic observations.

描述（由申请人提供）：本实验室和其他实验室的既往研究已经确定，组蛋白脱乙酰酶抑制剂（HDACI）和蛋白酶体抑制剂（如硼替佐米）协同相互作用，诱导恶性人类造血细胞凋亡。在慢性淋巴细胞白血病（CLL）细胞中，协同作用的假定机制集中在硼替佐米介导的HDACI诱导的RelA乙酰化的阻断以及经典和替代NF-：B途径的激活，导致NF-：B依赖性存活蛋白（例如，Bcl-xL和XIAP）。最近，我们已经观察到，当在体外以极低浓度（即各3-5 nM）共同施用时，I类HDACI罗米地辛（缩酚肽; FK 228）与硼替佐米相互作用以在新鲜的原代CLL细胞以及CLL细胞系中诱导非常明显的细胞凋亡。此外，这些事件与预防罗米地辛诱导的经典和替代NF-：B途径的活化、NF-：B依赖性蛋白Bcl-xL和XIAP的下调以及促凋亡蛋白Bim的诱导相关。我们现在建议开始进行I期试验，以测试这些临床前研究结果的体内影响。本提案的具体目的是：首先，确定慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL）患者每周3次每4周一次给予硼替佐米和罗米地辛联合给药的最大耐受剂量（MTD）;确定联合给药的安全性并描述毒性;记录在剂量探索研究过程中观察到的联合给药活性。其次，证明用于评估CLL细胞对联合给药的药效学反应的适当技术，包括对经典和替代NF-：B途径（核RelA和p52作为p100加工的标志物）活化、NF-：B依赖性蛋白XIAP和Bcl-xL表达以及促凋亡蛋白Bim表达的影响;并记录在剂量探索研究过程中观察到的药效学反应。公共卫生相关性：我们实验室的研究表明，组蛋白去乙酰化酶抑制剂romidepsin和蛋白体抑制剂在诱导原发性慢性淋巴细胞白血病（CLL）细胞死亡中存在有效的相互作用。本研究的目的是确定慢性淋巴细胞白血病/小细胞淋巴细胞淋巴瘤（CLL/SLL）患者每周3次每4周一次联合给药的最大耐受剂量（MTD），以确定联合给药的安全性并描述毒性，并记录在剂量探索研究过程中观察到的联合给药活性。此外，目的是证明评估CLL细胞对组合的药效学反应的适当技术，包括对经典和替代NF-：B途径活化、选定NF-：B依赖性蛋白表达和促凋亡蛋白Bim表达的影响，并记录在剂量探索研究过程中观察到的药效学反应。这将使我们能够进行未来的试验，以确定这种新型药物组合在CLL或SLL患者中的有效性，并解决我们临床前药效学观察的有效性。