Celecoxib therapy for patients with recurrent respiratory papillomatosis

描述（由申请方提供）：复发性呼吸道乳头状瘤病（RRP）是一种由人乳头状瘤病毒（HPV）引起的可能危及生命的疾病。这种疾病的特征是良性肿瘤的反复生长，主要在喉部，但有时会延伸到气管和肺部。在喉部，乳头状瘤损害声音并导致气道阻塞。在肺部，它们往往是致命的。没有有效、安全的治疗方法。常规治疗是手术切除，但手术并不能防止疾病复发，这被认为是由于潜伏的HPV感染被激活。目前的实验性治疗只能帮助一部分患者，而那些患有肺部疾病的患者通常没有反应。本申请的目的是检验塞来昔布（一种诱导酶环氧合酶-2（考克斯-2）的抑制剂）作为手术辅助治疗时可预防或减少疾病复发的假设。该申请基于我们对乳头状瘤中考克斯-2及其产生的Eschlandin水平升高的初步研究，支持考克斯-2在RRP病理生理学中作用的体外结果，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岁或以上的中度至重度疾病患者将有资格入组。经过6个月的评估期以确定乳头状瘤生长率后，患者随机分配至早期治疗组（塞来昔布治疗12个月，随后安慰剂治疗12个月）或延迟治疗组（安慰剂治疗12个月，随后塞来昔布治疗12个月）。所有患者将参与研究2.5年。目的1，本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持续反应。目标2将反应的可能变化与选择的临床和人口统计学特征相关联。目的3-4将阐述可能的作用机制，确定分子标志物是否与塞来昔布通过考克斯-2依赖性或非依赖性机制起作用一致（目的3），以及塞来昔布治疗是否减少潜伏性HPV DMA的持续性（目的4）。总之，这些目标将确定塞来昔布治疗是否有效治疗呼吸道乳头状瘤，确定哪些患者将作出反应，并增加我们对塞来昔布对这种疾病的影响的理解。

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.