Phase II Trial of PS341/Dox in Metastatic Breast Cancer

PS341/Dox 治疗转移性乳腺癌的 II 期试验

• 批准号: 7027074
• 负责人: ANNE M TRAYNOR
• 金额: $ 16.99万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027074
• 关键词: antineoplastics; breast neoplasms; cell cycle proteins; clinical research; clinical trial phase II; combination chemotherapy; doxorubicin; drug adverse effect; enzyme activity; enzyme inhibitors; female; human subject; human therapy evaluation; lymphocyte; metastasis; neoplasm /cancer chemotherapy; nuclear factor kappa beta; oncoprotein p21; patient oriented research; protease inhibitor; proteasome; protein kinase; ubiquitin; vascular endothelial growth factors

DESCRIPTION (provided by applicant): NF-kB plays an important role in the progression of breast cancer. Elevated levels of NF-kB have been demonstrated in breast cancer, with normal levels in the surrounding tissue. NF-kB is an anti-apoptotic factor. It is involved in the activation of genes responsible for angiogenesis, metastasis and preventing apoptosis. Regulation of the NF-kB pathway occurs through the protein IkB. It is normally found in the cytoplasm bound to IkB. Activation results in the ubiquination and degradation of IkB. The NF-kB pathway can be altered through proteasome inhibition. In addition to NF-kB, p21 and p27 play important roles in the cell cycle. Both promote cell cycle arrest. The expression of these genes can be altered in carcinogenesis. Similar to NF-kB, they are controlled by proteasome. The proteasome serves an important role in cell cycle regulation. It normally degrades proteins marked by ubiquination. Inhibition of proteasome results in the accumulation of ubiquinated proteins, including p21 and p27. NF-kB activity decreases with proteasome inhibition. PS-341 is a proteasome inhibitor. It has been shown to have clinical activity in cell cultures and xenograft models. PS-341 has been shown to decrease NF-kB activity and downregulate NF-k controlled genes. PS-341 also results in the accumulation of p21 and p27. Phase I trials have shown the agent to have antitumor activity, both alone and in combination. The combination of PS-341 and doxorubicin has been demonstrated to have activity in a xenograft model, without altering toxicity of either agent. This application proposes to examine the clinical efficacy of PS-341/doxrubicin when used at treatment for patients with metastatic breast cancer. It consists of a phase II trial with clinical and biologic endpoints. The primary clinical endpoint is overall response rate. The biologic endpoints seek to assess the biologic affect of PS-341. Five endpoints will be assessed: a) 20S proteasome inhibition; b) accumulation of ubiquinated protein conjugates; c) p21 and p27 protein levels; d) UPA levels and e) VEGF levels.

描述(申请人提供)：核因子-kB在乳腺癌的发展中起着重要作用。核因子-kB在乳腺癌中的水平升高，而在周围组织中的水平正常。核因子-kB是一种抗细胞凋亡因子。它参与激活负责血管生成、转移和防止细胞凋亡的基因。核因子-kB途径的调节是通过IKB蛋白实现的。它通常存在于与IKB结合的细胞质中。激活导致IKB的泛化和降解。通过蛋白酶体抑制可以改变核因子-kB途径。除核因子-kB外，p21和p27在细胞周期中发挥重要作用。两者都促进细胞周期停滞。这些基因的表达可以在致癌过程中发生改变。与核因子-kB类似，它们是由蛋白酶体控制的。蛋白酶体在细胞周期调控中起着重要作用。它通常会降解以泛素作用为标志的蛋白质。抑制蛋白酶体会导致泛素蛋白的积累，包括p21和p27。随着蛋白酶体的抑制，核因子-kB活性降低。PS-341是一种蛋白酶体抑制剂。在细胞培养和异种移植模型中，它已被证明具有临床活性。PS-341可降低核因子-kB活性，下调核因子-k调控基因。PS-341还导致p21和p27的积累。I期试验表明，该药物单独和联合使用都具有抗肿瘤活性。PS-341和阿霉素的组合已被证明在异种移植模型中具有活性，而不改变任何一种药物的毒性。本申请旨在检测PS-341/多柔比星在治疗转移性乳腺癌患者时的临床疗效。它由临床和生物学终点的II期试验组成。主要的临床终点是总应答率。生物终点试图评估PS-341的生物影响。将评估五个终点：a)20S蛋白酶体抑制；b)泛素蛋白结合物的积累；c)p21和p27蛋白水平；d)uPA水平和e)VEGF水平。