Clinical and Immunologic Evaluation of ProstAtak for Prostate Cancer

摘要 该项目的主要目标是开发一种新的治疗方法，以改善患者的预后， 中危前列腺癌适应症是与放射治疗联合的一线辅助治疗 治疗前列腺癌期望的结果是提高局部控制率，降低复发率， 提高无病生存率。这笔赠款将使开发和评估的ProstAtak "，一种产品 旨在改善前列腺癌患者的预后，在一项随机的2期临床研究中。前列 癌症是美国男性癌症死亡的第二大原因，大约有30，000人死亡 预计在2006年。目前的治疗方法为230，000例新的年度患者提供了极好的5年生存预后。 诊断。然而，每年有60，000 - 100，000名男性发生前列腺癌复发， 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。去势阴性 影响生活质量。减少前列腺癌复发且不影响当前成功的药物 从标准疗法中获得的益处将是非常重要的。ProstAtak "是一种生物药物， 具有疱疹胸苷激酶基因（AdV-tk）的腺病毒载体配制用于前列腺递送， 一种口服抗疱疹前药。当与标准手术或放射治疗相结合时， 通过基因介导的细胞毒性免疫疗法产生全身性疫苗效应 (GMCI"). AdV-tk是ProstAtak的主要成分，具有极好的安全性， 在多项I期研究和一项非随机II期研究中给予的患者剂量。前列腺癌 已经显示出对ProstAtak的敏感性"单独，以及在GMCI的背景下"与辐射。的目的 本申请旨在支持以下随机2期对照试验的设计、实施和评价： 在局部中危前列腺癌中，与安慰剂联合放疗相比，ProstAtak联合放疗。一 泌尿学、放射治疗、病理学、免疫学和生物统计学专家工作组 学术机构已集合在一起，合作制定和进行拟议的研究。 已经编写了该组的临床方案。中危组的选择基于 非随机研究的阳性结果，在该患者人群中区分结局的可能性， 因为这个阶段的标准治疗提供了一个机会，可以很容易地将GMCI "， 给患者增加了明显的不适。这项拟议中的试验将是第一个前瞻性评估 AdV-tk在人类中的有效性，如果成功，可能会导致第一种用于早期前列腺癌的药物， 其主要指示。次要目的是前瞻性评估早期阶段的替代终点 前列腺癌

ABSTRACT 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", 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" 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" has been shown to generate a systemic vaccine effect through a technology termed gene mediated cytotoxic immunotherapy (GMCI"). AdV-tk, the principal component of ProstAtak", 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" alone, and in the context of GMCI" with radiation. The purpose of this application is to support design, implementation and evaluation of a randomized Phase 2 controlled trial of ProstAtak" 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" 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.