Celecoxib therapy for patients with recurrent respiratory papillomatosis

描述(申请人提供)：复发性呼吸道乳头状瘤病(RRP)是一种由人类乳头瘤病毒(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，主要发生在喉部，但有时也会扩散到气管和肺部。在喉部，乳头状瘤损害嗓音并导致呼吸道阻塞。在肺部，它们往往是致命的。没有有效、安全的医疗方法。传统的治疗方法是手术切除，但手术并不能防止疾病的复发，这被认为是由于潜伏的HPV感染激活所致。目前的实验性治疗只帮助了一小部分患者，而那些患有肺部疾病的患者通常没有反应。这项应用的目的是检验这样一种假设，即作为手术的辅助手段，使用环氧合酶-2(COX-2)的抑制剂塞来昔布治疗将预防或减少复发的疾病。这一应用是基于我们对乳头状瘤中COX-2及其产生的前列腺素水平升高的初步研究，体外结果支持COX-2在RRP的病理生理学中的作用，其他研究显示塞来昔布在其他疾病中的抗肿瘤特性，包括HPV诱导的疾病，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、安慰剂对照的多中心临床试验，旨在评估塞来昔布治疗RRP的疗效。18岁或以上患有中重度疾病的患者将有资格参加。在确定乳头状瘤生长速度的6个月评估期后，患者被随机分到早期治疗组和延迟治疗组，前者先接受12个月的塞来昔布治疗，然后再接受12个月的安慰剂治疗，后者先接受12个月的安慰剂治疗，然后再接受12个月的塞来昔布治疗。所有患者将在这项研究中持续两年半。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停用塞来昔布后的反应是否持续。目标2将把可能的反应变异与选定的临床和人口学特征联系起来。AIMS 3-4将阐述可能的作用机制，确定分子标志物与塞来昔布是否通过COX-2依赖或独立机制起作用(AIMS 3)，以及Celecoxib治疗是否减少潜伏性HPV DMA的持久性(AIM 4)。总之，这些目标将决定塞来昔布治疗呼吸道乳头状瘤是否有效，决定哪些患者会有反应，并增加我们对塞来昔布对这种疾病的影响的了解。

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.