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，但在某些人群中，病例数量的增加和恶性肿瘤毒性的增加使其成为一个重大的社会风险。基于发病率和毒性的风险增加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物受者数量的增加，器官移植受者在我们的人口中占越来越大的比例。在大多数系列中，移植后20年，OTR的皮肤癌发病率为50%。长期以来，人们一直观察到皮肤上皮肿瘤形成的启动物和启动物会引起多胺及其限速生物合成酶鸟氨酸脱羧酶（ODC）水平的升高。相反，降低ODC活性的化合物会抑制皮肤肿瘤的形成。二氟甲基鸟氨酸（DFMO）是ODC的特异性抑制剂，已被观察到可显著减少许多不同的启动子和启动子引起的肿瘤形成。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，对靶组织中的ODC活性和多胺水平有显著的抑制作用。由于担心环孢子素等慢性免疫抑制剂会干扰皮肤样本中启动子诱导的ODC活性的充分测量以及DFMO对移植物存活的影响，我们在OTR中进行了0.5和1.0 g/天DFMO的初始I期先导研究。结果显示，28天0.5 g/d的DFMO显著抑制tpa诱导的ODC活性，降低OTR皮肤样品中的多胺（腐胺）水平，且无毒性。在进行DFMO在OTR中的大型III期研究之前，我们建议在皮肤癌高风险的OTR中进行一项2b期随机研究，每天0.5g DFMO与安慰剂对比，为期一年。主要终点是皮肤样本中tpa诱导的ODC活性降低50%以上，持续一年。次要终点是皮肤腐胺减少50%，皮肤病变（光化性角化病和癌）发展减少一年。其他参数包括：毒性评估，包括耳毒性的音频图、移植物状态、依从性、DFMO和免疫抑制剂水平。评估DFMO在OTR人群中的生化和潜在毒性作用的重要性，由于OTR人群中多种恶性肿瘤的发病率增加，以及ODC诱导在许多类型的组织癌变中的重要性，进一步被放大了。

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.