Clinical and Immunologic Evaluation of ProstAtak for Prostate Cancer

描述（由申请人提供）：本项目的主要目的是开发一种新的治疗方法，以改善中度风险前列腺癌患者的结局。适应症是与前列腺癌放射治疗联合使用的一线辅助治疗。期望的结果是提高局部控制率，降低复发率和提高无病生存率。这笔赠款将使ProstAtak（TM）的开发和评估成为可能，该产品旨在改善前列腺癌患者的结果，在随机2期临床研究中。前列腺癌是美国男性癌症死亡的第二大原因，预计2006年约有30，000人死亡。目前的治疗为每年23万例新诊断提供了极好的5年生存预后。然而，每年有60，000 - 100，000名男性发生前列腺癌复发，他们接受手术或药物去势，这是一种延长生命但非治愈性的治疗。阉割对生活质量有负面影响。减少前列腺癌复发且不影响标准治疗目前成功的药物将具有重要意义。ProstAtak（tm）是一种生物药物，由具有疱疹胸苷激酶基因（AdV-tk）的腺病毒载体组成，其被配制用于前列腺递送，随后是口服抗疱疹前药。当与标准手术或放射相结合时，ProstAtak（tm）已被证明通过称为基因介导的细胞毒性免疫疗法（GMCI（tm））的技术产生全身疫苗效应。AdV-tk是ProstAtak（TM）的主要成分，具有极好的安全性，在多项1期研究和一项非随机2期研究中提供了超过300例患者剂量。前列腺癌已经显示出对单独的ProstAtak（tm）以及在GMCI（tm）与辐射的背景下的易感性。本申请的目的是支持设计、实施和评价一项随机化II期对照试验，在局部中危前列腺癌患者中比较ProstAtak（tm）联合放疗与安慰剂联合放疗。来自顶级学术机构的泌尿学、放射治疗、病理学、免疫学和生物统计学专家组成了一个工作组，共同合作开发和开展拟议的研究。已经编写了该组的临床方案。根据非随机化研究的阳性结果选择了中危组，这是因为该患者人群的结局可能存在差异，并且该阶段的标准治疗提供了一个容易纳入GMCI（TM）的机会，而不会增加患者的显著不适。这项拟议的试验将是第一个前瞻性评估AdV-tk在人类中的疗效的试验，如果成功，可能会导致第一种以早期前列腺癌为主要适应症的药物。次要目的是前瞻性评估早期前列腺癌的替代终点。

DESCRIPTION (provided by applicant): The main objective of this project is to develop a new therapeutic to improve the outcome for patients with intermediate-risk prostate cancer. The indication is a first-line adjuvant to be combined with radiation therapy for prostate cancer. The desired outcomes are improved local control rate, decreased recurrence and improved disease-free survival. This grant will enable development and evaluation of ProstAtak(tm), a product aimed at improving the outcome of prostate cancer patients, in a randomized Phase 2 clinical study. Prostate cancer is the second leading cause of cancer death in men in the US with approximately 30,000 deaths expected in 2006. Current therapies provide an excellent 5yr survival prognosis for the 230,000 new annual diagnoses. However, each year 60,000-100,000 men develop prostate cancer recurrence for which they receive surgical or pharmacologic castration, a life extending but non-curative therapy. Castration negatively impacts quality of life. Drugs that decrease recurrence of prostate cancer and do not diminish current success from standard therapies would be of great significance. ProstAtak(tm) is a biologic drug composed of an adenoviral vector with the Herpes thymidine-kinase gene (AdV-tk) formulated for prostate delivery followed by an oral antiherpetic prodrug. When combined with standard surgery or radiation, ProstAtak(tm) has been shown to generate a systemic vaccine effect through a technology termed gene mediated cytotoxic immunotherapy (GMCI(tm)). AdV-tk, the principal component of ProstAtak(tm), has an excellent safety profile with over 300 patient doses delivered in multiple Phase 1 studies, and a non-randomized Phase 2 study. Prostate cancer has shown susceptibility to ProstAtak(tm) alone, and in the context of GMCI(tm) with radiation. The purpose of this application is to support design, implementation and evaluation of a randomized Phase 2 controlled trial of ProstAtak(tm) with radiation compared to placebo with radiation in localized intermediate-risk prostate cancer. A working group of urology, radiation therapy, pathology, immunology and biostatistics experts from top academic institutions has been assembled to collaborate in the development and conduct the proposed studies. A clinical protocol from this group has been prepared. The intermediate-risk group was selected based on positive results from the non-randomized study, the potential to differentiate outcomes in this patient population, and because standard treatment for this stage provides an opportunity to easily incorporate GMCI(tm) without adding significant discomfort to the patients. The proposed trial will be the first to prospectively evaluate efficacy of AdV-tk in humans and, if successful, may lead to the first drug with early stage prostate cancer as its primary indication. A secondary objective is to prospectively evaluate surrogate end-points for early stage prostate cancer.