SQUALAMINE PLUS CARBOPLATIN AND PACLITAXEL IN NSC LUNG C

这项建议的目的是了解一种新的血管生成抑制剂角鲨胺与常用的化疗方案卡铂和紫杉醇(卡铂/紫杉醇)联合治疗晚期非小细胞肺癌(NSCLC)的有效率、副作用和药代动力学。角鲨胺是一种新型的、选择性的新血管形成抑制剂，我们已经证明，在我们的人肺癌异种移植模型中，它显著增强了铂化合物的抗肿瘤作用。它最初是在抗微生物药物的筛查中发现的，是一种氨基甾醇，被认为通过选择性地抑制钠-氢逆向转运体钠-质子交换和抑制氢从内皮细胞流出来抑制新的血管生长。我们检测了角鲨胺加或不加细胞毒剂对人肺癌细胞系小鼠移植瘤的抗肿瘤作用，发现在我们的临床前模型系统中，角鲨胺使铂类似物的抗肿瘤作用增强了50%到100%。鉴于我们在人类肿瘤异种移植模型中观察到的铂类似物的抗肿瘤活性显著增强，以及美国在晚期非小细胞肺癌中广泛使用卡波/紫杉醇，我们提议对IIIB期(仅限胸腔积液)和IV期非小细胞肺癌患者进行角鲨胺加卡波/紫杉醇的试点和安全性研究。本研究的主要目的是评估角鲨胺每三周与卡铂/紫杉醇联合连续输注五天的有效率。次要目标是评估角鲨胺与这两种药物联合使用时的副作用和药代动力学。使用两阶段设计，我们将首先建立一个安全剂量的角鲨胺，可以与卡波/紫杉醇一起使用，然后证明这三种药物方案至少与卡波/紫杉醇单独使用一样有效。一旦我们证明角鲨胺联合卡波/紫杉醇是安全有效的，我们将能够检验我们的假设，即与单独使用卡波/紫杉醇相比，角鲨胺可以延长晚期非小细胞肺癌患者的进展时间和存活率。这将需要一项未来的随机第三阶段试验，比较使用和不使用角鲨胺的卡波/紫杉醇。

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.