A PHASE I EVALUATION OF THE SAFETY AND PK OF PRO-1 IN STAGE IV MELANOMA PATIENTS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项研究评估了一种新的DNA递送技术，该技术旨在将基因递送到肿瘤生长部位，从而导致递送基因的肿瘤选择性表达。这项技术被称为SPLP(稳定的质粒-脂质颗粒)，允许静脉注射编码治疗性蛋白质的基因。SPLP是一种特殊的脂质体，它将单个质粒DNA包裹在脂质双层中。SPLP在血液中有很长的循环寿命。SPLP的肿瘤聚集是在长循环时间内被动发生的。事实上，生长中的肿瘤中的血管是漏水的，这使得SPLP能够到达肿瘤细胞。这项研究评估了静脉注射Pro-1给IV期转移性黑色素瘤患者，然后用Valtrex治疗的安全性和药代动力学。Pro-1和Valtrex共同作用杀死肿瘤细胞。主要目的是评估递增剂量Pro-1的安全性，并测量Pro-1从受试者血液中清除的药代动力学。第二个目标是评估在有适当皮肤损害的受试者肿瘤组织中胸苷激酶质粒DNA的存在，以及评估Pro-1治疗和Valtrex治疗后对受试者疾病的临床副作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study evaluates a new DNA delivery technology designed to deliver genes to sites of tumor growth, resulting in tumor-selective expression of the delivered gene. This technology, called SPLP (stable plasmid-lipid particles), allows the intravenous delivery of genes that encode therapeutic proteins. SPLP are specialized liposomes in which a single plasmid DNA is encapsulated inside a lipid bi-layer. SPLP have a long circulation lifetime in the blood. Tumor accumulation of SPLP takes place passively over the long circulation time. The fact that the blood vessels in growing tumors are leaky allows the SPLP to reach the tumor cells. This study evaluates the safety and pharmacokinetics of the intravenous delivery of Pro-1 to Stage IV metastatic melanoma subjects, followed by treatment with Valtrex. Pro-1 and Valtrex work together to kill tumor cells. The primary objectives are to evaluate the safety of escalating doses of Pro-1 and to measure the pharmacokinetics of Pro-1 clearance from the blood of treated subjects. Secondary objectives are to evaluate the presence of thymidine kinase plasmid DNA in tumor tissue in subjects with appropriate skin lesions and to evaluate the clinical side effects of Pro-1 treatment followed by Valtrex administration on treated subjects' disease.