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 中等风险前列腺癌。该适应症是与放射治疗相结合的一线辅助剂。 治疗前列腺癌。预期的结果是提高局部控制率，减少复发和 提高了无病存活率。这笔赠款将使ProstAtak“这一产品的开发和评估成为可能 旨在改善前列腺癌患者预后的随机二期临床研究。前列腺 癌症是美国男性癌症死亡的第二大原因，约有30,000人死亡 预计在2006年。目前的治疗方法为每年230,000名新患者提供了良好的5年生存预后 诊断。然而，每年有60,000-100,000名男性罹患前列腺癌复发，他们 接受手术或药物去势，这是一种延长生命但不能治愈的疗法。消极的去势 影响生活质量。减少前列腺癌复发且不会减少目前的成功的药物 从标准疗法中脱颖而出将具有重要意义。ProstAtak是一种生物药物，由一种 含有疱疹胸苷激酶基因的腺病毒载体(ADV-tk)用于前列腺癌的递送 一种口服抗疱疹前药。当与标准手术或放射治疗相结合时，ProstAtak已被证明 通过一种名为基因介导的细胞毒免疫疗法的技术产生系统性疫苗效应 (GMCI“)。ProstAtak”的主要成分ADV-tk具有良好的安全性，超过300 患者剂量在多个第一阶段试验和一项非随机第二阶段试验中提供。前列腺癌 已经显示出对ProstAtak“单独的，并且在GMCI的背景下”对辐射的敏感性。目的 此应用程序用于支持设计、实施和评估一项随机的第二阶段对照试验 在局部中等风险前列腺癌中，ProstAtak与安慰剂联合放射治疗的比较。 泌尿外科、放射治疗、病理学、免疫学和生物统计学专家工作组 学术机构已被召集起来，合作开发和进行拟议的研究。 该小组已经准备了一份临床方案。中等风险组的选择是基于 非随机研究的阳性结果，在这一患者群体中区分结果的可能性， 因为这一阶段的标准治疗提供了一个机会，可以很容易地合并GMCI，而不需要 给患者增加了极大的不适。拟议中的试验将是第一个进行前瞻性评估的试验 Adv-tk在人类中的疗效，如果成功，可能导致第一种治疗早期前列腺癌的药物 它的主要适应症。第二个目标是对早期阶段的替代终点进行前瞻性评估 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.