CHEMOPREVENTION OF SKIN CANCER--DFMO PHASE 3 TRIAL

描述：（申请人描述）约800，000新皮肤 癌症每年在美国发生，这对美国来说是一个主要的经济负担。 我们的医疗系统 皮肤癌已被证明与紫外线有关 曝光 在发生的关键生化变化中， 生物合成始终与肿瘤促进相关。 干扰 通过抑制鸟氨酸脱羧酶（ODC）与多胺生物合成 酶与二氟甲基鸟氨酸（DFMO）减少皮肤癌的形成。 DFMO已被证明可以抑制佛波酯诱导的ODC 人类皮肤 该提案被设计为DFMO的第3阶段研究。 第一步是 在334例受试者中进行的为期4周的安慰剂导入研究，以评估依从性， 消除不遵守者（估计为15%）。 第二步为 284例DFMO患者的安慰剂对照、双盲随机化研究（估计） 有基底或鳞状细胞皮肤癌病史的受试者。 受试者将随机分配至安慰剂组或DFMO组，平均4年 （3-5年）。 在治疗期间，约40%的受试者将 会发展出新的皮肤癌 抑制50%的新生皮肤 癌症是预料之中的。 听力将在临床上监测， 听力图 将测量皮肤多胺水平和TPA诱导的ODC 所有随机化受试者研究开始时，60例随机样本 第2、3和4年时每组的受试者，以及 患上皮肤癌。 这项研究将是一项关键性的试验， DFMO和相关的中间生物标志物，ODC和多胺 级别，

DESCRIPTION: (Applicant's Description) Approximately 800,000 new skin cancers occur in the U.S. annually that represent a major economic burden to our health care system. Skin cancers have been shown to be related to UV light exposure. Of the key biochemical changes that occur, polyamine biosynthesis is consistently associated with tumor promotion. Interference with polyamine biosynthesis by inhibiting ornithine decarboxylase (ODC) enzyme with difluoromethylornithine (DFMO) reduces skin cancer formation. DFMO has been shown to inhibit ODC induced by phorbol esters applied to human skin. The proposal is designed as a phase 3 study of DFMO. The first step will be a 4 week placebo run-in study in 334 subjects to assess compliance and eliminate noncompliers (estimated at 15%). The second step is a placebo-controlled, double-blinded randomized study of DFMO in 284 (est.) subjects with a history of basal or squamous cell skin cancer. Subjects will be randomized to placebo or DFMO for an average of 4 years (range 3-5 years). Over the treatment period, about 40% of subjects will be expected to develop new skin cancers. Inhibition of 50% of all new skin cancers is anticipated. Hearing will be monitored clinically and by audiogram. Skin polyamine levels and ODC induction by TPA will be measured at start of study in all randomized subjects, in random samples of 60 subjects on each arm at 2, 3 and 4 years, and in normal skin of subjects who develop skin cancers. This study will be a pivotal trial of the efficacy of DFMO and the associated intermediary biologic markers, ODC and polyamine levels,