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

AML同种异体移植后ALT-803 (IL-15/IL-15Rα-Fc)维持

• 批准号: 10429929
• 负责人: Shernan Grace Holtan
• 金额: $ 18.48万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429929
• 关键词: AML/MDS; Acute Myelocytic Leukemia; Address; Affinity; Allogenic; Biological Sciences; Blood; Bone Marrow Transplantation; Cells; Cellular biology; Chimeric Proteins; Clinical; Clinical Research; Clinical Sciences; Clinical Trials; Clinical Trials Network; Complex; Data; Development; Disease; Disease remission; Disease-Free Survival; Donor Lymphocyte Infusion; Dysmyelopoietic Syndromes; Education; Enrollment; Equilibrium; Goals; Graft-Versus-Tumor Induction; Half-Life; Hematologic Neoplasms; Homologous Transplantation; Human; IgG1; Immune response; Immunoconjugates; Immunologic Tests; Immunomodulators; Incidence; Innate Immune System; Institution; Interleukin-15; Intervention; Investigation; Killer Cells; Lead; Lectin; Lymphocyte; Maintenance; Maintenance Therapy; Malignant Neoplasms; Mediator of activation protein; Minnesota; Mission; Myeloid-derived suppressor cells; NK Cell Activation; Natural Killer Cells; Ohio; Outcome; Patients; Phase; Placebo Control; Placebos; Positioning Attribute; Probability; Process; Protein Subunits; Protocols documentation; Publications; Randomized; Randomized Clinical Trials; Recombinants; Regulatory T-Lymphocyte; Relapse; Research; Resources; Risk; Role; Safety; Serum; Specificity; Subcutaneous Injections; Sushi Domain; T-Lymphocyte; Transplantation; Treatment Efficacy; Treatment Failure; Universities; Variant; base; conditioning; design; design and construction; dimer; early phase clinical trial; experience; fighting; graft vs host disease; hematopoietic cell transplantation; immune activation; improved; improved outcome; in vivo; interest; interleukin-15 receptor; killer immunoglobulin-like receptor; leukemia; leukemia relapse; novel; phase 2 study; post-transplant; pre-clinical; prevent; randomized placebo controlled trial; randomized placebo-controlled clinical trial; receptor; reconstitution; relapse risk; research clinical testing; safety and feasibility; sample collection; side effect; success; transplant centers

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.

项目摘要/摘要 明尼苏达大学一直致力于BMT CTN。我们关于替代捐助者的专业知识 和移植VS宿主疾病是成功网络研究的基础。我们参与网络 包括过去的委员会主席国家PI关于六个协议的国家PI，在网络出版物中发挥了作用 并承诺制度资源来开发和成功执行网络试验。我们的建议 解决降低强度同种异体造血细胞后急性髓性白血病（AML）释放的风险 移植（HCT），这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，作为移植物肿瘤/白血病（GVL）效应的关键介体导致了 使用ALT-803开发该平台，这是一个由人类的两个蛋白质亚基组成的固体复合物 IL-15变体与二聚体人IL-15受体α（IL-15Rα）寿司域/人类相关的高亲和力相关 IgG1 FC融合蛋白增强了NK细胞特异性和半衰期。我们的假设是刺激先天 具有ALT-803的免疫系统将减少缓解的累积事件，并提高 降低强度调节（RIC）HCT后，无复发生存期（RFS）。在早期临床试验研究中我们 当给予晚期患者时，证明了Alt-803的安全性和确定的副作用。 血液学恶性肿瘤，包括后同种性HCT。关于ALT-803给药的2阶段研究 降低AML强度同种异体HCT和骨髓增生综合征的维护是最后一步 法规批准，并将提供有关移植后安全性和可行性的进一步数据 维护方法。提出的第三阶段随机安慰剂对照的主要目标 该提案中的临床试验是确定ALT-803是否提高了无病生存的可能性 在第一次完全缓解时，AML强度同种异体HCT的强度同种异体HCT后进行维护。管理 免疫调节剂（例如ALT-803）瞄准，以降低继电器的风险并改善结果 HCT是需要在多中心确认的众多潜在练习策略之一 随机临床试验，这是BMT CTN任务的一部分。我们机构一直致力于 网络的成功不仅反映在制定新协议中，而且ALO继续内部流程以更好 支持监管，注册和样本收集需求网络临床试验。