Clinical and Immunologic Evaluation of ProstAtak for Prostate Cancer

ProstAtak 治疗前列腺癌的临床和免疫学评价

• 批准号: 7274580
• 负责人: Estuardo Aguilar-Cordova
• 金额: $ 10.11万
• 依托单位: ADVANTAGENE, INC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-10 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7274580
• 关键词: Acute; Address; Adenovirus Vector; Adjuvant; Adverse effects; Advisory Committees; Affect; American Cancer Society; Androgens; Antigen-Presenting Cells; Appendix; Applications Grants; Biometry; Biopsy; Blood specimen; CD8B1 gene; Cancer Etiology; Cancer Patient; Caring; Castration; Cessation of life; Clinical; Clinical Protocols; Clinical Research; Conduct Clinical Trials; Control Groups; Development; Diagnosis; Discipline; Disease; Disease-Free Survival; Distant; Dose; Early Diagnosis; End Point; Enrollment; Evaluation; Failure; Freedom; Future; Genes; Grant; HSV-Tk Gene; Human; Immune; Immunologics; Immunology; Immunotherapy; Individual; Inflammatory Response; Institution; Lead; Life; Localized; Malignant Neoplasms; Malignant neoplasm of prostate; Measurable; Measures; Mediating; Methods; Modeling; Morbidity - disease rate; Neoplasm Metastasis; Operative Surgical Procedures; Oral; Outcome; Pathologic; Pathology; Patients; Performance; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Placebo Control; Placebos; Population; Predisposition; Prodrugs; Productivity; Property; Prostate; Prostate Cancer therapy; Prostate-Specific Antigen; Protocols documentation; Purpose; Quality of life; Radiation; Radiation Oncology; Radiation therapy; Randomized; Randomized Controlled Clinical Trials; Randomized Controlled Trials; Rate; Reagent; Recombinant DNA; Recurrence; Research Design; Research Ethics Committees; Resistance development; Resources; Risk; Safety; Site; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Societies; Staging; Standards of Weights and Measures; Superantigens; Surrogate Endpoint; T-Lymphocyte; TK Gene; Technology; Testing; Therapeutic; Time; Toxic effect; Translating; Tumor Antigens; United States Food and Drug Administration; United States National Institutes of Health; Urology; Vaccines; Work; Writing; base; cancer recurrence; cancer therapy; cell killing; chemotherapy; clinical research site; cost; cytotoxic; deprivation; design; desire; disease natural history; experience; follow-up; implementation trial; improved; men; neoplastic cell; novel therapeutics; outcome forecast; pre-clinical; prevent; randomized placebo controlled trial; response; success; therapy development; tumor; uptake

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.

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，以改善中危前列腺癌患者的治疗结果。该适应症是与放射治疗联合治疗前列腺癌的一线辅助药物。期望的结果是提高局部控制率、减少复发和提高无病生存率。这笔赠款将用于在一项随机 2 期临床研究中开发和评估 ProstAtak(tm)，这是一种旨在改善前列腺癌患者预后的产品。前列腺癌是美国男性癌症死亡的第二大原因，预计 2006 年将有约 30,000 人死亡。目前的治疗方法为每年 230,000 例新诊断的患者提供了极好的 5 年生存预后。然而，每年有 60,000-100,000 名男性出现前列腺癌复发，为此他们接受手术或药物阉割，这是一种延长生命但非治愈性的疗法。阉割会对生活质量产生负面影响。减少前列腺癌复发且不削弱标准疗法目前取得的成功的药物将具有重要意义。 ProstAtak(tm) 是一种生物药物，由带有疱疹胸苷激酶基因 (AdV-tk) 的腺病毒载体组成，配制用于前列腺递送，然后是口服抗疱疹前药。当与标准手术或放射治疗相结合时，ProstAtak(tm) 已被证明可以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，具有出色的安全性，在多项 1 期研究和一项非随机 2 期研究中为超过 300 名患者提供了剂量。前列腺癌已显示出对单独的 ProstAtak(tm) 以及在 GMCI(tm) 和放射治疗的背景下易感。本申请的目的是支持设计、实施和评估 ProstAtak(tm) 放疗与安慰剂放疗治疗局部中危前列腺癌的随机 2 期对照试验。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的工作组已经组建，以合作开发和开展拟议的研究。该小组的临床方案已准备就绪。选择中等风险组的依据是非随机研究的积极结果、区分该患者群体结果的潜力，并且因为该阶段的标准治疗提供了轻松纳入 GMCI(tm) 的机会，而不会给患者带来明显的不适。病人。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，可能会产生第一种以早期前列腺癌为主要适应症的药物。次要目标是前瞻性评估早期前列腺癌的替代终点。由于早期诊断和延长生命的非治愈性疗法的使用增加，前列腺癌复发在美国是一个日益严重的问题。美国癌症协会估计，2006年将有230,000例新发病例、60,000-100,000例复发病例以及30,000例前列腺癌死亡。复发后，治疗方法是手术或药物去势，这是非治愈性的并且与显着的发病率相关。通常到死亡时，男性已经患有前列腺癌复发和治疗副作用超过 10 年。由于复发而给个人和社会带来的治疗成本、生产力损失和生活质量下降是一个巨大的问题，需要通过新的更有效和毒性更低的疗法来解决。该 SBIR 项目的主要目标是开发一种新的治疗方法，以改善中危前列腺癌患者的治疗结果。这笔赠款将用于在随机 2 期临床研究中对 ProstAtak(tm) 进行评估，ProstAtak(tm) 是一种旨在改善前列腺癌患者预后的产品。此外，第二个目标是前瞻性评估早期前列腺癌的替代终点。目前还没有批准以早期前列腺癌为主要适应症的药物； ProstAtak(tm) 将是第一个。这部分是由于该疾病的自然病程较长，这意味着临床开发时间过长。经验证的短期替代终点的可用性将显着影响该疾病治疗开发的整体方法。