Celecoxib therapy for patients with recurrent respiratory papillomatosis

描述（由申请人提供）：复发性呼吸道乳头状瘤病（RRP）是一种由人乳头状瘤病毒（hpv）引起的潜在威胁生命的疾病。这种疾病的特点是良性肿瘤反复生长，主要在喉部，但有时延伸到气管和肺。在喉部，乳头状瘤损害声音并引起气道阻塞。在肺部，它们通常是致命的。目前还没有有效、安全的治疗方法。传统的治疗方法是手术切除，但手术并不能预防疾病的复发，这被认为是由于潜在的HPV感染的激活。目前的实验性治疗只能帮助一小部分患者，而那些患有肺部疾病的患者通常没有反应。本应用的目的是验证塞来昔布（一种诱导酶环氧化酶-2 （COX-2）的抑制剂）作为手术辅助治疗时可以预防或减少疾病复发的假设。该申请是基于我们对COX-2水平升高及其在乳头状瘤中产生的前列腺素的初步研究，支持COX-2在RRP病理生理中的作用的体外结果，其他研究显示塞来昔布在其他疾病（包括hpv诱导的疾病）中的抗肿瘤特性，以及治疗RRP患者的初步临床数据。该研究是一项II期随机双盲安慰剂对照多中心临床试验，旨在评估塞来昔布治疗RRP的疗效。年龄在18岁或以上且患有中度至重度疾病的患者将符合入组资格。经过6个月的评估期以确定乳头状瘤的生长速度，患者被随机分配到早期治疗组，接受12个月的塞来昔布治疗，然后接受12个月的安慰剂治疗，或者接受12个月的安慰剂治疗，然后接受12个月的塞来昔布治疗。所有患者的研究时间为2.5年。目的1，该研究的主要目的是确定塞来昔布治疗的疗效，以及塞来昔布停药后是否能持续缓解。目的2将反应的可能变化与选定的临床和人口统计学特征联系起来。Aims 3-4将探讨可能的作用机制，确定分子标记是否与塞来昔布通过COX-2依赖或独立机制起作用一致（Aim 3），以及塞来昔布治疗是否降低潜伏性HPV DMA的持久性（Aim 4）。总之，这些目标将确定塞来昔布治疗呼吸道乳头状瘤是否有效，确定哪些患者会有反应，并增加我们对塞来昔布治疗这种疾病的作用的理解。

DESCRIPTION (provided by applicant): Recurrent respiratory papillomatosis (RRP) is a potentially life threatening disease caused by human papillomaviruses (HPVs). The disease is characterized by repeated growth of benign tumors, predominantly in the larynx but sometimes extending into the trachea and lungs. In the larynx, the papillomas impair the voice and cause airway obstruction. In the lungs, they are frequently fatal. There is no effective, safe medical treatment. Conventional treatment is surgical removal, but surgery does not prevent recurrence of disease, which is believed to be due to activation of latent HPV infection. Current experimental treatments only help a subset of patients, and those with pulmonary disease usually do not respond. The goal of this application is to test the hypothesis that treatment with celecoxib, an inhibitor of the inducible enzyme cyclooxygenase-2 (COX-2), will prevent or reduce recurrent disease when used as an adjunct to surgery. The application is based on our preliminary studies of elevated levels of COX-2 and the prostaglandins it produces in papillomas, in vitro results supporting a role for COX-2 in the pathophysiology of RRP, studies by other showing anti-tumor properties of celecoxib in other diseases, including HPV-induced disease, and preliminary clinical data treating patients with RRP. The study is a Phase II randomized double blind placebo controlled multi-center clinical trial to assess the efficacy of celecoxib therapy for RRP. Patients ages 18 or older with moderate to severe disease will be eligible for enrollment. After a 6 month evaluation period to define rate of papilloma growth, patients randomized to an early treatment arm with 12 months of celecoxib therapy followed by 12 months on placebo, or a delayed treatment arm receiving placebo for 12 months followed by 12 months on celecoxib. All patients will be in the study for 2.5 years. Aim 1, the primary aim of the study is to determine efficacy of celecoxib treatment and whether response is sustained when celecoxib is stopped. Aim 2 will correlate possible variation in response with select clinical and demographic characteristics. Aims 3-4 will address possible mechanism of action, determining whether molecular markers are consistent with celecoxib is acting through a COX-2 dependent or independent mechanism (Aim 3), and whether celecoxib therapy reduces persistence of latent HPV DMA (Aim 4). Together, these aims will determine whether celecoxib therapy is effective in treating respiratory papillomas, determine which patients will respond, and increase our understanding of the effects of celecoxib on this disease.