DFMO Prevention Study (2b) in Organ Transplant Subjects

描述（由申请人提供）：皮肤癌是美国最常见的恶性肿瘤。虽然大多数非黑色素瘤皮肤癌可以成功治疗，但病例数量的增加和某些人群中恶性肿瘤毒力的增加使其成为一个重大的社会风险。基于发病率和毒力的风险增加的人群的一个例子是器官移植受者（OTR），由于移植物存活率和移植受者数量的增加，我们的人群中的一个不断增长的子集。在大多数系列中，移植后20年OTR中皮肤癌的发病率> 50%。皮肤上皮肿瘤形成的引发剂和促进剂长期以来一直被观察到导致多胺及其限速生物合成酶鸟氨酸脱羧酶（ODC）水平升高。相反，降低ODC活性的化合物抑制皮肤肿瘤形成。二氟甲基鸟氨酸（DFMO）是ODC的特异性抑制剂，并且已观察到显著减少继发于许多不同引发剂和促进剂的肿瘤形成。过去和正在进行的DFMO在华盛顿大学和其他机构的化学预防研究表明，在相对无毒的剂量下，ODC活性和靶组织中的多胺水平显着抑制。由于担心慢性免疫抑制剂（如环孢菌素）干扰充分测量皮肤样本中启动子诱导的ODC活性和DFMO对移植物存活的影响，因此进行了OTR中0.5和1.0 g/天DFMO的初始I期初步研究。结果表明，28天的0.5克/天的DFMO显着抑制TPA诱导的ODC活性，并降低多胺（腐胺）水平在OTR皮肤样本中没有toxicity. Before追求一个大型的III期研究DFMO在OTR，我们建议进行2b期随机研究0.5克/天的DFMO与安慰剂在OTR皮肤癌的高风险，为期一年。主要终点将是一年内皮肤样本中TPA诱导的ODC活性降低50%以上。次要终点将是皮肤腐胺减少50%和皮肤病变（光化性角化病和癌）发展减少1年。其他参数包括：毒性评估，包括耳毒性、移植物状态、依从性和DFMO和免疫抑制剂水平的音频图。评估DFMO在OTR（具有相当大的皮肤癌风险的人群）中的生物化学和潜在毒性作用的重要性通过OTR中多种恶性肿瘤的发病率增加和ODC诱导在许多类型的组织致癌作用中的重要性而进一步放大。

DESCRIPTION (provided by applicant): Skin cancer is the most common malignancy encountered in the US. While most occurrences of non-melanoma skin cancer can be successfully treated, the growing number of cases and the increased virulence of the malignancy in certain populations make it a significant societal risk. An example of a population at increased risk based on incidence and virulence is organ transplant recipients (OTR), a growing subset of our population due to increased graft survival and numbers of graft recipients. In most series, the incidence of skin cancers in OTR has been > 50% by 20 years post-graft. Initiators and promoters of skin epithelial tumor formation have long been observed to cause increased levels of polyamines and their rate-limiting biosynthetic enzyme ornithine decarboxylase (ODC). Conversely, compounds that decrease ODC activity inhibit skin tumor formation. Difluoromethylornithine (DFMO) is a specific inhibitor of ODC and has been observed to significantly reduce tumor formation secondary to many different initiators and promoters. Past and ongoing chemoprevention studies of DFMO at the UW and other institutions have revealed significant inhibition in ODC activity and polyamine levels in target tissues at relatively nontoxic doses. Due to concerns about chronic immunosuppressants, like cyclosporine, interfering with the ability to adequately measure promoter-induced ODC activity in skin samples and DFMO effects upon graft survival, an initial phase I pilot study of 0.5 and 1.0 g/day of DFMO in OTR was performed. It revealed that 28 days of 0.5 g/day of DFMO significantly inhibited TPA-induced ODC activity and decreased polyamine (putrescine) levels in skin samples of OTR without toxicity.Prior to pursuing a large phase III study of DFMO in OTR, we propose to perform a phase 2b randomized study of 0.5g/day of DFMO versus placebo for one year in OTR at high risk for skin cancer. The primary endpoint would be a greater than 50% reduction in TPA-induced ODC activity in skin samples for one year. Secondary endpoints will be a 50% decrease in skin putrescine and decreased development of skin lesions (actinic keratoses and carcinomas) for one year. Additional parameters include: toxicity assessment including audio grams for ototoxicity, graft status, compliance, and DFMO and immunosuppressant levels.The importance of assessing the biochemical and potential toxic effects of DFMO in OTR, a population at considerable risk of skin cancer, is magnified further by the increased incidence of multiple malignancies in OTR and the importance of ODC induction in many types of tissue carcinogenesis.