Flavopiridol / Bortezomib in Myeloma / B-Cell Neoplasms

黄酮吡醇 / 硼替佐米治疗骨髓瘤 / B 细胞肿瘤

• 批准号: 6905679
• 负责人: Steven Grant
• 金额: $ 21.36万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6905679
• 关键词: B cell lymphoma; SDS polyacrylamide gel electrophoresis; clinical research; clinical trial phase I; drug administration rate /duration; drug adverse effect; drug screening /evaluation; flavopiridol; fluorescence microscopy; human subject; human therapy evaluation; kinase inhibitor; multiple myeloma; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonHodgkin' s lymphoma; nuclear factor kappa beta; patient oriented research; pharmacokinetics; phosphorylation; western blottings

DESCRIPTION (provided by applicant): The results of recent studies indicate that neoplastic cells, particularly those of hematopoietic origin, are exquisitely sensitive to apoptosis induced by simultaneous disruption of survival signaling and cell cycle regulatory pathways. Bortezomib, the prototypical clinically relevant proteasome inhibitor, has shown impressive activity against multiple myeloma refractory to conventional therapies, as well as mantle cell lymphoma (MCL) and indolent NHL. Flavopiridol (NSC 649890), the first cyclin-dependent kinase inhibitor to enter clinical trials, induces apoptosis in malignant human hematopoietic cells at pharmacologically achievable concentrations. Recent preclinical studies from our laboratory indicate that co-administration of bortezomib and flavopiridol at low concentrations results in a highly synergistic induction of mitochondrial damage and apoptosis in human leukemia and myeloma cell lines as well as in primary patient-derived specimens. These events are associated with multiple perturbations in signaling and survival pathways, including activation of the stress-related JNK cascade, down-regulation of the anti-apoptotic proteins Mcl-1 and XlAP, and inactivation of the cytoprotective NF-kB pathway. The hypothesis that similar events will occur in myeloma and lymphoma cells exposed to these agents in vivo has prompted the development of a Phase I trial of bortezomib and flavopiridol in patients with multiple myeloma, MCL, and indolent B-cell NHL. The goals of this project are: (1) To conduct a Phase I trial of flavopiridol and bortezomib administered as bolus IV infusions BIW (days 1 and 4, 8 and 11) q 3 wks to determine the maximally tolerated drug doses for this schedule; (2) To define dose-limiting toxicities; (3) To assess preliminary clinical activity of this regimen in patients with myeloma and B-cell neoplasms; (4) To conduct correlative laboratory and PK studies to test the hypothesis that in vivo administration of bortezomib and flavopiridol will result in NF-kB inactivation, JNK activation, and down-regulation of Mcl-1 and XIAP in multiple myeloma cells.

描述（由申请人提供）：最近的研究结果表明，肿瘤细胞，尤其是造血起源的细胞，对同时破坏生存信号传导和细胞周期调节途径的凋亡非常敏感。硼替佐米是一种原型临床相关的蛋白酶体抑制剂，对多发性骨髓瘤难治性表现出了令人印象深刻的活性，对常规疗法以及地幔细胞淋巴瘤（MCL）和惰性NHL表现出了令人印象深刻的活性。黄素蛋白醇（NSC 649890）是第一个进入临床试验的细胞周期蛋白依赖性激酶抑制剂，可在可实现的药理学浓度下诱导恶性人造血细胞的凋亡。我们实验室的最新临床前研究表明，低浓度的硼替佐米和黄酮葡萄醇的共同给药会导致人类白血病和骨髓瘤细胞系中的线粒体损伤和凋亡的高度协同诱导，以及原发性患者的标本。这些事件与信号传导和存活途径中的多种扰动有关，包括激活与应力相关的JNK级联反应，抗凋亡蛋白MCL-1和XLAP的下调以及细胞保护性NF-KB途径的灭活。在体内暴露于这些药物的骨髓瘤和淋巴瘤细胞中会发生类似事件的假设促使对多发性骨髓瘤，MCL和惰性B细胞NHL的患者进行了硼替佐米和黄酮多醇的I期试验。该项目的目标是：（1）进行I阶段试验的黄素醇和硼替佐米作为IV注入BIW（第1和第4、8和11天）Q 3 WKS以确定此时间表的最大耐受药物剂量； （2）定义限制剂量的毒性； （3）评估该方案对骨髓瘤和B细胞肿瘤患者的初步临床活性； （4）进行相关实验室和PK研究以检验以下假设：在多骨髓瘤细胞中，体内给予硼替佐米和黄酮迪酚将导致NF-KB失活，JNK激活以及MCL-1和XIAP的下调。