Clinical and Immunologic Evaluation of ProstAtak for Prostate Cancer

描述（由申请人提供）：该项目的主要目标是开发一种新的治疗方法来改善中危前列腺癌患者的预后。该适应症是与前列腺癌放射治疗联合的一线辅助治疗。期望的结果是提高局部控制率，减少复发率和改善无病生存。这笔拨款将用于开发和评估ProstAtak(tm)，该产品旨在改善前列腺癌患者的预后，在一项随机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3万人死亡。目前的治疗方法为每年23万例新诊断提供了良好的5年生存预后。然而，每年有6万至10万男性前列腺癌复发，他们接受手术或药物阉割，这是一种延长生命但无法治愈的治疗方法。阉割会对生活质量产生负面影响。减少前列腺癌复发并且不影响目前标准治疗成功的药物将具有重要意义。ProstAtak（tm）是一种生物药物，由带有疱疹胸腺嘧啶激酶基因（advk -tk）的腺病毒载体组成，用于前列腺递送，随后是口服抗疱疹前药。当与标准手术或放疗联合使用时，ProstAtak（tm）已被证明通过一种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，具有出色的安全性，在多个1期研究和一项非随机2期研究中，超过300例患者服用了AdV-tk。前列腺癌已显示出对ProstAtak（tm）单用和GMCI（tm）联合放疗的易感性。本申请的目的是支持设计、实施和评估一项随机2期对照试验，将前列腺statak （tm）放射治疗与安慰剂放射治疗局部中危前列腺癌进行比较。来自顶级学术机构的泌尿科、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，共同开发和开展拟议的研究。该小组的临床方案已经准备好。中危组的选择是基于非随机研究的阳性结果、该患者群体中分化结局的潜力，以及该阶段的标准治疗提供了一个容易合并GMCI（tm）的机会，而不会给患者带来明显的不适。拟议的试验将是首个对AdV-tk在人类中的疗效进行前瞻性评估的试验，如果成功，可能会成为首个以早期前列腺癌为主要适应症的药物。第二个目的是前瞻性地评估早期前列腺癌的替代终点。前列腺癌复发是一个日益严重的问题，在美国，由于早期诊断和增加使用延长寿命，非治愈性治疗。美国癌症协会估计，2006年将有23万新病例，6万至10万复发病例，3万人死于前列腺癌。一旦复发，治疗是手术或药物阉割，这是不可治愈的，并伴有显著的发病率。通常到死亡时，男性已经遭受前列腺癌复发和治疗副作用的折磨超过10年。治疗给个人和社会带来的成本、生产力损失和因复发而导致的生活质量下降是一个巨大的问题，需要用更有效、毒性更小的新疗法来解决。这个SBIR项目的主要目标是开发一种新的治疗方法来改善中危前列腺癌患者的预后。这笔拨款将用于在一项随机2期临床研究中评估ProstAtak(tm)，该产品旨在改善前列腺癌患者的预后。此外，第二个目的是前瞻性地评估早期前列腺癌的替代终点。目前还没有批准将早期前列腺癌作为主要适应症的药物；ProstAtak（tm）将是第一个。这在一定程度上是由于该疾病的长期自然历史，这转化为令人望而却步的漫长临床开发时间。有效的短期替代终点的可用性将显著影响该疾病治疗发展的整体方法。

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. Prostate cancer recurrence is a growing problem in the US due to earlier diagnosis and increased use of life-extending, non-curative therapies. The American Cancer Society estimates that in 2006 there will be 230,000 new cases, 60,000-100,000 recurrences, and 30,000 deaths from prostate cancer. Upon recurrence, the treatment is surgical or pharmacologic castration, which is non-curative and associated with significant morbidity. Usually by the time of death, men have been suffering from prostate cancer recurrence and the side effects of treatments for over 10 years. The costs to individuals and society of treatment, lost productivity and compromised quality of life due to recurrence are a huge problem, which needs to be addressed with new more effective and less toxic therapies. The main objective of this SBIR project is to develop a new therapeutic to improve the outcome for patients with intermediate-risk prostate cancer. This grant will enable evaluation of ProstAtak(tm), a product aimed at improving the outcome of prostate cancer patients, in a randomized Phase 2 clinical study. In addition, a secondary objective is to prospectively evaluate surrogate end-points for early stage prostate cancer. There are no approved drugs with early stage prostate cancer as their primary indication; ProstAtak(tm) would be a first. This is in part due to the prolonged natural history of the disease, which translates into prohibitory long clinical development times. The availability of validated shorter-term surrogate end-points would significantly impact the overall approach of therapy development for this disease.