ALT-803 (IL-15/IL-15Rα-Fc) maintenance after allogeneic transplantation for AML

项目摘要/摘要 明尼苏达大学一直高度致力于BMT CTN。我们在替代捐赠者方面的专业知识 移植物抗宿主病是网络研究成功的基础。我们对网络的参与 包括一名过去的指导委员会主席，六项协议的国家绩效指标，网络出版物的领导角色 并投入机构资源开发和成功执行网络试验。我们的建议 降低异基因造血细胞强度后急性髓系白血病(AML)复发的风险 移植(HCT)仍然是治疗失败的主要原因。我们的机构长期利益 关于自然杀伤(NK)细胞生物学作为移植物抗肿瘤/白血病(GVL)效应的关键中介导致 利用ALT-803开发这一平台，ALT-803是一种由人的两个蛋白质亚基组成的可溶性复合体 与人IL-15受体二聚体α(IL-15Rα)寿司结构域/人高亲和力相关的IL-15变异体 IgG1Fc融合蛋白增强NK细胞特异性和半衰期。我们的假设是，刺激先天的 带有ALT-803的免疫系统将降低复发的累积发生率，并提高 降低强度条件反射(RIC)后的无复发生存期(RFS)。在早期临床试验研究中，我们 证明了ALT-803用于晚期癌症患者的安全性和已确定的副作用 恶性血液病，包括异基因血细胞移植后。ALT-803 AS给药的2期研究 急性髓系白血病和骨髓增生异常综合征低强度异基因红细胞移植后的维护已进入最后阶段 并将提供有关移植后安全性和可行性的进一步数据 维修方法。建议的第3阶段随机安慰剂对照试验的主要目标 该提案中的临床试验旨在确定ALT-803是否提高了无病存活的可能性 急性髓系白血病首次完全缓解减强度同种异体血细胞移植后的维持。管理的管理 免疫调节剂，如ALT-803，旨在降低复发风险并改善术后预后 HCT是许多可能改变战略的做法之一，需要在多中心进行确认 随机临床试验，这是BMT CTN任务的一部分。我们机构继续致力于 网络的成功不仅体现在开发新的协议上，而且还体现在不断完善的内部过程中 支持监管、登记和样本采集要求网络临床试验。

Project Summary/Abstract The University of Minnesota has been highly committed to The BMT CTN. Our expertise on alternative donors and graft-vs-host disease served as the basis for successful Network studies. Our participation in the Network includes a past-Steering Committee chair, national PIs on six protocols, leading roles in Network publications and committing institutional resources to develop and successfully execute Network trials. Our proposal addresses the risk of acute myeloid leukemia (AML) relapse after reduced intensity allogeneic hematopoietic cell transplantation (HCT), which remains the main cause of treatment failure. Our institutions long-lasting interest on natural killer (NK) cell biology as a critical mediator of the graft-versus-tumor/leukemia (GVL) effect led to the development of this platform using ALT-803, a soluble complex consisting of two protein subunits of a human IL-15 variant associated with high affinity to a dimeric human IL-15 receptor α (IL-15Rα) sushi domain/human IgG1 Fc fusion protein enhancing NK cell specificity and half-life. Our hypothesis is that stimulating the innate immune system with ALT-803 will reduce the cumulative incidence of relapse and improved probability of relapse-free survival (RFS), after reduced intensity conditioning (RIC) HCT. In early clinical trial studies we demonstrated the safety and established side effect profile of ALT-803 when given to patients with advanced hematological malignancies, including post-allogeneic HCT. A phase 2 study on ALT-803 administration as maintenance after reduced intensity allogeneic HCT for AML and myelodysplastic syndrome is in the last steps of regulatory approval and will provide further data on the safety and feasibility of the post-transplantation maintenance approach. The primary objective of the proposed the phase 3 randomized placebo-controlled clinical trial in this proposal is to determine if ALT-803 improves the probability of disease-free survival as maintenance after reduced intensity allogeneic HCT for AML in first complete remission. The administration of immune modulatory agents such as ALT-803 aiming reducing the risk of relapse and improve outcomes after HCT is one of many potentially practice changing strategies that require confirmation on a multicenter randomized clinical trial, which is part of the BMT CTN mission. Our institution's continued commitment to the Network's success is not only reflected in developing new protocols, but alos continued internal process to better support regulatory, enrollment and sample collection requirements Network clinical trials.