SQUALAMINE PLUS CARBOPLATIN AND PACLITAXEL IN NSC LUNG C

该提案的目的是获取新型血管生成抑制剂角鲨胺与常用化疗方案卡铂和紫杉醇（carbo/taxol）联合治疗晚期非小细胞肺癌（NSCLC）时的反应率、副作用和药代动力学。角鲨胺是一种新的，选择性的新血管形成抑制剂，我们已经在我们的人类肺癌异种移植模型中证明了铂化合物的抗肿瘤作用。最初在抗菌药物筛选中发现，它是一种氨基甾醇，被认为通过选择性抑制钠-氢反转运体钠-质子交换和抑制内皮细胞外氢的流出来抑制新血管的生长。我们检测了角鲨胺加或不加细胞毒性药物对小鼠异种移植人肺癌细胞系的抗肿瘤作用，发现角鲨胺在我们的临床前模型系统中使铂类似物的抗肿瘤作用提高了50%至100%。鉴于我们在人类肿瘤异种移植模型中观察到铂类似物显著增强抗肿瘤活性，以及碳/紫杉醇在美国晚期非小细胞肺癌中的广泛使用，我们建议在IIIB期（仅胸腔积液）和IV期非小细胞肺癌患者中进行角鲨胺加碳/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与卡铂/紫杉醇每三周连续输注5天的反应率。次要目的是评估角鲨胺与这两种药物一起使用时的副作用和药代动力学。采用两阶段设计，我们将首先确定可与碳/紫杉醇一起使用的角鲨胺的安全剂量，然后证明三种药物方案至少与碳/紫杉醇单独使用一样有效。一旦我们证明角鲨胺加碳/紫杉醇是安全有效的，我们将能够验证我们的假设，即与单独使用碳/紫杉醇相比，角鲨胺可以延长晚期NSCLC患者的进展时间和生存期。这将需要未来的随机III期试验，比较碳/紫杉醇与角鲨胺和不含角鲨胺。

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.