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

描述：（申请人提供） 造血干细胞移植（HSCT）通常是诊断患有侵袭性白血病和其他血液恶性肿瘤的患者的唯一治愈机会。 然而，HSCT是一种受并发症困扰的治疗方法。 这些并发症导致移植相关死亡率很高，大约30%的非亲属供体移植受者死于移植相关并发症。 这些并发症中最突出的两种是严重感染和急性移植物抗宿主病（aGVHD）。移植后感染包括各种机会性微生物，其中病毒性疾病引起的发病率和死亡率最高。aGVHD是由于移植供体T细胞的活化和增殖而产生的，其由供体和受体之间的组织相容性差异触发。这些活化的T细胞可对宿主组织造成毁灭性损害，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的伴随缺陷，它导致感染风险增加。也许是因为aGVHD和移植后免疫功能不全的相互风险，尽管每年发生的aGVHD导致的死亡率高得令人无法接受，但多年来标准aGVHD预防方案一直没有广泛成功的添加。因此，存在未满足的临床需要，以开发更有效地预防aGVHD同时保持移植受体的保护性免疫应答的策略。 越来越多的来自临床前模型的证据表明，靶向CD 28：CD 80/86 T细胞共刺激通路的一类新的免疫调节剂在抑制aGVHD中具有显著活性。这些药物之一阿巴西普（abatacept）被FDA批准用于类风湿性关节炎。在这项申请中，研究人员提出了一项“首次发病”的2期试验，以确定在标准aGVHD预防策略中加入阿巴西普是否可以通过降低aGVHD的发生率来增加HSCT后的生存率，同时保持抗病毒保护性免疫。这将通过进行以下两个具体目的来完成：（1）进行多中心II期、随机、双盲、安慰剂对照试验，以评估阿巴西普对无关供体HSCT后aGVHD发生率的影响;（2）评估阿巴西普对针对病毒的T细胞保护性免疫的移植后重建的影响。

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.