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（由申请人提供）：NF-kB在乳腺癌的进展中发挥重要作用。乳腺癌中 NF-kB 水平升高，而周围组织中 NF-kB 水平正常。 NF-kB 是一种抗凋亡因子。它参与负责血管生成、转移和防止细胞凋亡的基因的激活。 NF-kB 通路的调节通过蛋白质 IkB 进行。它通常存在于与 IkB 结合的细胞质中。激活导致 IkB 泛素化和降解。 NF-kB 通路可以通过蛋白酶体抑制来改变。除了 NF-kB 之外，p21 和 p27 在细胞周期中也发挥着重要作用。两者都促进细胞周期停滞。这些基因的表达可以在癌发生过程中发生改变。与 NF-kB 类似，它们由蛋白酶体控制。蛋白酶体在细胞周期调节中发挥重要作用。它通常会降解泛素化标记的蛋白质。蛋白酶体的抑制会导致泛素化蛋白的积累，包括 p21 和 p27。 NF-kB 活性随着蛋白酶体抑制而降低。 PS-341 是一种蛋白酶体抑制剂。它已被证明在细胞培养和异种移植模型中具有临床活性。 PS-341 已被证明可以降低 NF-kB 活性并下调 NF-k 控制基因。 PS-341 还会导致 p21 和 p27 的积累。 I 期试验表明，该药物无论是单独使用还是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，且不会改变任一药物的毒性。本申请旨在检查 PS-341/阿霉素用于治疗转移性乳腺癌患者的临床疗效。它包括具有临床和生物学终点的 II 期试验。主要临床终点是总体缓解率。生物学终点旨在评估 PS-341 的生物学影响。将评估五个终点：a) 20S 蛋白酶体抑制； b) 泛素化蛋白缀合物的积累； c) p21和p27蛋白水平； d) UPA 水平和 e) VEGF 水平。