Efficacy of Pomalidomide in HHT-related bleeding

描述（由申请人提供）：遗传性出血性毛细血管扩张症（HHT）是一种罕见的遗传性出血性疾病，由Eng、ALK1或Smad4基因突变引起。HHT的发病机制涉及在包括脑、肺、肝和粘膜在内的多个组织和器官中形成动静脉畸形（AVM）。这些脆弱的动静脉非常容易出血。在HHT的众多临床表现中，复发性鼻出血和胃肠道（小肠）出血最为常见；出血是慢性的，导致对输血和肠外铁的依赖，并严重损害生活质量。对HHT出血表现的治疗是支持性的，因为没有有效的、无毒的治疗方法可以导致avm的持续消退，这已经得到了令人信服的证明。PI对4例因小肠动静脉畸形导致严重胃肠道出血的患者的经验，以及大量的轶事报道表明，沙利度胺可导致HHT患者的动静脉畸形消退并阻止出血。然而，沙利度胺不受专利保护，不由制造商提供临床试验，也不由仿制药制造商生产。因此，我们建议在hht相关出血患者中设计一项泊马度胺III期试验，泊马度胺是第三代沙利度胺类似物，具有更强的抗血管生成活性和更高的安全性。我们期望在一项15例患者的行业资助的试点研究中证明该试验的可行性和泊马度胺对该适应症的活性，所有患者将在该U34开始之前入组。我们已经组建了一个多学科、多机构的方案开发团队，他们将与U24临床试验资源中心合作规划这项研究。该提案的目标是：1)开展一项随机、安慰剂对照的III期研究，以评估波马度胺治疗HHT相关鼻出血和/或胃肠道出血的有效性和安全性；2)计划建立一个从波马度胺治疗前和治疗期间获得的HHT患者血液和血浆成分的存储库，用于定义对波马度胺和其他药物反应的生物标志物。该建议利用创新的计划策略来开发一种新药的临床试验，这可能会导致治疗HHT患者出血的新范例。

DESCRIPTION (provided by applicant): Hereditary Hemorrhagic Telangiectasia (HHT) is a rare, inherited bleeding disorder caused by mutations in Eng, ALK1 or Smad4. The pathogenesis of HHT involves formation of arteriovenous malformations (AVM) in several tissues and organs including the brain, lung, liver and mucosal membranes. These fragile AVMs are highly prone to bleeding. Of the many clinical manifestations of HHT, recurrent epistaxis and gastrointestinal (small bowel) bleeding are most common; bleeding is chronic, leads to dependence on transfusion and parenteral iron, and significantly impairs quality of life. Treatment for the bleeding manifestations of HHT is supportive, since no effective, non-toxic therapy that causes consistent regression of AVMs has been convincingly demonstrated. The PI's experience with four patients with severe gastrointestinal bleeding from small bowel AVMs, as well as numerous anecdotal reports, suggests that thalidomide causes regression of AVMs and arrests bleeding in patients with HHT. However, thalidomide is not patent protected, is not supplied by the manufacturer for clinical trials and is not produced by manufacturers of generics. Therefore, we propose to design a phase III trial of pomalidomide, a third generation thalidomide analogue with greater anti-angiogenic activity and an improved safety profile, in patients with HHT-related bleeding. We expect to demonstrate feasibility for this trial and activit of pomalidomide for this indication in a 15 patient, industry- funded pilot study in which all patients will be enrolled prior to initiation of this U34. We have assembled a multi-disciplinary, multi-institutional protocol development team that will work with the U24 Clinical Trials Resource to plan the study. Goals of this proposal are 1) To develop a randomized, placebo-controlled phase III study to assess the efficacy and safety of pomalidomide in HHT-related epistaxis and/or gastrointestinal bleeding, and 2) To plan a repository of blood and plasma fractions obtained from patients with HHT before and during pomalidomide therapy that will be used for defining biomarkers of response to pomalidomide and other agents. This proposal utilizes innovative planning strategies to develop a clinical trial of a novel agent that may lead to a new paradigm for treatment of bleeding in patients with HHT.