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）：该实验室和其他实验室的先前研究已经确定，组蛋白脱乙酰基酶抑制剂（HDACIS）和蛋白酶体抑制剂，例如硼替佐米（Bortezomib），可以协同诱导恶性人类造血细胞的凋亡。 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).最近，我们观察到，当以极低的浓度（即3-5 nm）进行体外施用时，I类HDaci romidepsin（depsipeptide; FK228）与Bortezomib相互作用，与bortezomib相互作用，以诱导新鲜的原始cll细胞以及孔很好地诱导非常明显的凋亡。此外，这些事件与预防romidepsin诱导的经典和替代NF-：B途径的激活有关，下调NF-：B：B依赖性蛋白BCl-XL和XIAP以及促凋亡蛋白BIM的诱导。现在，我们建议通过进行I期试验来开始测试这些临床前发现的体内含义。该提案的具体目的是：首先，确定bortezomib和romidepsin的最大耐受剂量（MTD）和慢性淋巴细胞性白血病/小淋巴细胞淋巴瘤（CLL/SLL）患者的每周X 3 3每周X 3 3;确定安全性并描述组合的毒性；并记录在剂量发现研究过程中观察到的组合的活动。 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;并记录在剂量发现研究过程中观察到的药效动力反应。公共卫生相关性：我们实验室的研究表明，组蛋白脱乙酰基酶抑制剂romidepsin和蛋白体抑制剂在诱导原发性慢性淋巴细胞性白血病（CLL）细胞中诱导细胞死亡中存在有效的相互作用。这项研究的目的是确定慢性淋巴细胞性白血病/小细胞淋巴细胞淋巴瘤（CLL/SLL）的患者每周X 3每周X 3的最大耐受剂量（MTD），以确定组合的组合和结合的研究，以确定该研究中的组合活动的安全性和描述。此外，目的是证明对CLL细胞对组合的药物动力学反应的适当技术，以影响对典型和替代性NF-途径的激活，表达所选的NF-：B依赖性蛋白的表达，以及对药物动力学反应的表达以及对药物型响应的表达，并在研究过程中进行了研究。这将使我们进行未来的试验，这将确定这种新型药物组合在CLL或SLL患者中的有效性，并解决临床前药效观察的有效性。