Phase 2 Study of Abatacept with Calcineurin Inhibition and Methotrexate for GVHD

描述：(申请人提供) 对于被诊断为侵袭性白血病和其他血液系统恶性肿瘤的患者，造血干细胞移植(HSCT)通常是唯一的治愈机会。然而，HSCT是一种充满并发症的治疗方法。这些并发症导致了与移植相关的高死亡率，大约30%的无血缘关系供体移植的受者死于与移植相关的并发症。其中最突出的两个并发症是严重感染和急性移植物抗宿主病(AGVHD)。移植后感染是机会性生物体的一部分，其中病毒性疾病的发病率和死亡率最高。AGVHD的发生是由于供者和受者之间的组织相容性差异引起的移植供者T细胞的激活和增殖。这些被激活的T细胞可以对宿主组织造成毁灭性的损害，最严重的临床表现发生在皮肤、肝脏和胃肠道。重要的是，aGVHD和感染的风险是相互的：虽然有效的免疫抑制可以降低aGVHD的风险，但由于免疫抑制产生的保护性免疫缺陷，它会导致感染风险增加。也许是由于aGVHD和移植后免疫功能低下的相互风险，尽管每年发生的aGVHD死亡率高得令人无法接受，但多年来没有广泛成功的标准aGVHD预防方案。因此，有一种尚未得到满足的临床需求，即开发更有效地预防aGVHD的策略，同时保留移植受者的保护性免疫反应。越来越多的临床前模型证据表明，一类针对CD28：CD80/86 T细胞共刺激通路的新型免疫调节剂具有显著的抑制aGVHD的活性。其中一种药物abatacept是FDA批准用于治疗类风湿性关节炎的。在这项申请中，研究人员提出了一项“首发疾病”第二阶段试验，以确定在标准的aGVHD预防策略中添加abatacept是否可以通过降低aGVHD的发生率来提高HSCT后的存活率，同时保持抗病毒保护性免疫。这将通过实施以下两个具体目标来实现：(1)进行一项多中心第二阶段随机、双盲、安慰剂对照试验，以评估Abatacept对非血缘关系供者HSCT后aGVHD发生率的影响；(2)评估abatacept对移植后T细胞针对病毒的保护性免疫重建的影响。

DESCRIPTION: (provided by the applicant) Hematopoietic stem cell transplantation (HSCT) often represents the only chance for cure for patients diagnosed with aggressive leukemias and other hematologic malignancies. However, HSCT is a treatment that is plagued with complications. These complications result in a high rate of transplant-related mortality, with approximately 30% of recipients of unrelated donor transplants dying of transplant-related complications. The two most prominent of these complications are severe infection and acute graft-versus host disease (aGVHD). Post-transplant infections comprise the gamut of opportunistic organisms, with the greatest morbidity and mortality arising from viral disease. aGVHD arises due to the activation and proliferation of engrafting donor T cells, triggered by histocompatibility disparities between donor and recipient. These activated T cells can cause devastating damage to host tissues, with the most severe clinical manifestations occurring in the skin, the liver and the gastrointestinal tract. Importantl, the risks of aGVHD and infection are reciprocal: while potent immunosuppression can decrease the risk of aGVHD, it results in an increased risk of infection due to the attendant defects in protective immunity that immunosuppression creates. It is perhaps because of the reciprocal risks of aGVHD and of post-transplant immune incompetence that there have been no broadly successful additions to standard aGVHD prophylaxis regimens in many years, despite the unacceptably high rate of death due to aGVHD that occurs each year. Thus, there is an unmet clinical need to develop strategies that more effectively prevent aGVHD while preserving the transplant recipient's protective immune response. There is growing evidence from preclinical models that a new class of immunomodulatory agents, targeting the CD28:CD80/86 T cell costimulation pathway, has significant activity in inhibiting aGVHD. One of these agents, abatacept, is FDA approved for use in rheumatoid arthritis. In this application, the investigators propose a 'first-in-disease' Phase 2 trial to determine whether the addition of abatacept to a standard aGVHD prophylaxis strategy could increase survival after HSCT by reducing rates of aGVHD, while preserving anti-viral protective immunity. This will be done through the conduct of the following two Specific Aims: (1) To conduct a multicenter Phase 2, randomized, double-blind, placebo controlled trial to assess the impact of abatacept on the incidence of aGVHD after unrelated donor HSCT; (2) To assess the impact of abatacept on post-transplant reconstitution of T cell protective immunity against viruses.