DFMO Prevention Study (2b) in Organ Transplant Subjects

描述(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是可以成功治疗的，但在某些人群中，病例数量的增加和这种恶性肿瘤的毒力增加使其成为一个重大的社会风险。根据发病率和毒力，风险增加的人群的一个例子是器官移植接受者(OTR)，由于移植物存活率和移植接受者数量的增加，这是我们人口中一个不断增长的子集。在大多数系列中，到移植后20年，牙齿移植中皮肤癌的发生率一直是50%。长期以来，人们观察到皮肤上皮肿瘤形成的启动子和促进剂会导致多胺及其生物合成限速酶鸟氨酸脱羧酶(ODC)水平的增加。相反，降低ODC活性的化合物可以抑制皮肤肿瘤的形成。二氟甲基鸟氨酸(DFMO)是一种ODC的特异性抑制剂，已被观察到在许多不同的启动剂和促进剂的作用下可显著减少肿瘤的形成。华盛顿大学和其他机构过去和正在进行的DFMO化学预防研究表明，在相对无毒的剂量下，目标组织中的ODC活性和多胺水平受到显著抑制。由于担心慢性免疫抑制剂，如环孢素，干扰了充分测量皮肤样本中启动子诱导的ODC活性的能力，以及DFMO对移植物存活的影响，在OTR中进行了0.5和1.0g/天的DFMO的初始I期试点研究。结果显示，28天每天服用0.5g的DFMO显著抑制了TPA诱导的ODC活性，并降低了无毒OTR皮肤样本中多胺(腐胺)的水平。在进行DFMO在OTR中的大型III期研究之前，我们建议进行一项2b期随机研究，在患皮肤癌的高危OTR中，每天服用0.5g DFMO与服用安慰剂为期一年。主要终点将是TPA在皮肤样本中诱导的ODC活性在一年内减少50%以上。次要终点将是一年内皮肤腐烂减少50%，皮肤损害(光化性角化病和癌症)的发展减少。其他参数包括：毒性评估，包括耳毒性、移植物状态、依从性、DFMO和免疫抑制水平的音频图。评估DFMO对OTR的生化和潜在毒性影响的重要性因OTR中多种恶性肿瘤的发生率增加以及ODC诱导在许多类型的组织癌变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.