SQUALAMINE PLUS CARBOPLATIN AND PACLITAXEL IN NSC LUNG C

角鲨胺加卡铂和紫杉醇治疗 NSC 肺 C

• 批准号: 2874250
• 负责人: JOAN H SCHILLER
• 金额: $ 7.2万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-15 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2874250
• 关键词: angiogenesis inhibitors; antineoplastics; carboplatin; clinical research; clinical trial phase I; combination chemotherapy; dosage; drug administration rate /duration; drug adverse effect; drug interactions; human subject; human therapy evaluation; injection /infusion; neoplasm /cancer chemotherapy; neoplasm /cancer classification /staging; neoplasm /cancer pharmacology; nonsmall cell lung cancer; paclitaxel; pharmacokinetics

The goal of this proposal is to access the response rate, side effects and pharmacokinetics of a novel angiogenesis inhibitor, squalamine, when combined with a commonly used chemotherapy regimen carboplatin and paclitaxel (carbo/taxol) for advanced non-small cell lung cancer (NSCLC). Squalamine is a novel, selective inhibitor of new blood vessel formation which we have demonstrated significantly enhances the anti- tumor effects of platin compounds in our human lung cancer xenograft model. Originally identified in a screen for anti-microbial agents, it is an aminosterol that is postulated to inhibit new blood vessel growth by selectively inhibiting the sodium-hydrogen antiporter sodium-proton exchanges and inhibiting hydrogen efflux out of the endothelial cell. We examined the anti-tumor effects of squalamine with or without cytotoxic agents in human lung cancer cell lines in murine xenografts, and found that squalamine enhances the anti-tumor effects of platinum analogues in our preclinical model system by 50% to 100%. Given the significant enhancement of anti-tumor activity we observed with platin analogues in our human tumor xenograft model, and the widespread usage of carbo/taxol in the United States in advanced NSCLC, we are proposing a pilot and safety study of squalamine plus carbo/taxol in patients with Stage IIIB (pleural effusion only) and IV NSCLC. The primary objective of this study is to assess the response rate of squalamine when administered as a five-day continuous infusion in conjunction with carboplatin/taxol every three weeks. The secondary objectives are to evaluate the side effects and pharmacokinetics of squalamine when administered with these two agents. Using a two stage design, we will first establish a safe dose of squalamine that can be administered with carbo/taxol and then demonstrate that the three drug regimen is at least as efficacious as carbo/taxol alone. Once we have documented that squalamine plus carbo/taxol is safe and efficacious, we will be able to test our hypothesis that squalamine enhances time to progression and survival of advanced NSCLC patients compared to carbo/taxol alone. This will require a future randomized Phase III trial comparing carbo/taxol with and without squalamine.

该提案的目的是与新型血管生成抑制剂Squalamine的反应率，副作用和药代动力学，与常用的化学疗法方案甲op蛋白和紫杉醇（碳水化合物/紫杉醇）结合使用，用于晚期的非小细胞肺癌（NSCLC）。 Squalamine是一种新型的新血管形成的选择性抑制剂，我们已经证明，在我们的人类肺癌异种移植模型中，我们已经显着增强了白素化合物的抗肿瘤作用。它最初是在抗微生物剂的筛选中鉴定出来的，它是一种氨基醇，假定可以通过选择性地抑制氢钠抗钠钠 - 普罗替型钠腐蚀并抑制内皮细胞的氢排放来抑制新血管生长。我们检查了鼠类异种移植物中人类肺癌细胞系中有或没有细胞毒性剂的尖具有或不含细胞毒性剂的抗肿瘤作用，并发现尖锐的番他胺在我们的临床前模型系统中铂类类似物的抗肿瘤效应提高了50％至100％。鉴于我们在人类肿瘤异种移植模型中使用铂类似物观察到的抗肿瘤活性的显着增强，在美国高级NSCLC中，在美国，碳/紫杉醇的广泛使用，我们提出了一项针对IIIB阶段IIIB患者的Smocalamine Plus Carbo/carbo/carbo/carbo的安全性研究（仅在IIIB阶段）（仅Plearral ralural enfusion）和IV nsclc。这项研究的主要目的是每三周与卡泊素/紫杉醇一起评估五舍胺的反应率。次要目标是评估与这两种药物一起施用时，鳞胺的副作用和药代动力学。使用两阶段的设计，我们将首先建立可以用碳/紫杉醇施用的安全剂量的番薯胺，然后证明三种药物方案至少与单独的碳水化合物/紫杉醇一样有效。一旦我们记录了Smothamine Plus Carbo/紫杉醇是安全有效的，我们将能够测试我们的假设，即鳞胺会增强与单独碳水化合物/紫杉醇相比，高级NSCLC患者的进展和生存时间。这将需要未来的随机III期试验，以比较有或没有鳞胺的碳/紫杉醇。