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

项目总结/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 和移植物抗宿主病是成功的网络研究的基础。我们参与网络 包括一位前指导委员会主席、六项协议的国家PI、网络出版物的领导角色 并承诺机构资源，以开发和成功地执行网络试验。我们的建议 解决了降低强度的异基因造血细胞移植后急性髓性白血病（AML）复发的风险 造血干细胞移植（HCT），这仍然是治疗失败的主要原因。我们机构的长期利益 自然杀伤（NK）细胞生物学作为移植物抗肿瘤/白血病（GVL）效应的关键介质，导致 使用ALT-803开发该平台，ALT-803是一种由人的两个蛋白亚基组成的可溶性复合物， 与二聚体人IL-15受体α（IL-15 R α）sushi结构域高亲和力相关的IL-15变体/人 增强NK细胞特异性和半衰期的IgG 1 Fc融合蛋白。我们的假设是刺激先天的 ALT-803的免疫系统将减少复发的累积发生率，并提高复发的可能性。 降低强度预处理（RIC）HCT后的无复发生存期（RFS）。在早期的临床试验研究中， 证实了ALT-803的安全性和已确定的副作用特征，当给予晚期乳腺癌患者时， 血液学恶性肿瘤，包括同种异体后HCT。一项关于ALT-803给药作为 AML和骨髓增生异常综合征患者在降低强度的异基因HCT后的维持治疗处于最后阶段 监管机构的批准，并将提供有关移植后的安全性和可行性的进一步数据， 维护方法。拟定的III期随机安慰剂对照研究的主要目的是 这项建议中的临床试验是为了确定ALT-803是否能改善无病生存的可能性， AML首次完全缓解后，降低强度的同种异体HCT维持治疗。管理 免疫调节剂，如ALT-803，旨在降低复发风险并改善治疗后的结果。 HCT是许多潜在的实践改变策略之一，需要在多中心研究中进行确认。 随机临床试验，这是BMT CTN使命的一部分。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内部流程， 支持网络临床试验的监管、入组和样本采集要求。

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.