Sargrastim and Plerixafor vs. Filgrastim for Allogeneic Stem Cell Mobilization

沙格司亭和普乐沙福对比非格司亭用于同种异体干细胞动员

• 批准号: 8495404
• 负责人: PETER WESTERVELT
• 金额: $ 15.73万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-08 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495404
• 关键词: Acute Graft Versus Host Disease; Adrenal Cortex Hormones; Allogenic; Antigen-Presenting Cells; Blood Component Removal; Bone Marrow Transplantation; CD34 gene; CSF3 gene; Cells; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical Trials Design; Clinical Trials Network; Engraftment; Equilibrium; Failure; Filgrastim; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Human; Incidence; Institution; Instruction; Morbidity - disease rate; Mus; Outcome; Patients; Phase; Phase II Clinical Trials; Principal Investigator; Randomized; Recurrent disease; Safety; Siblings; Source; Stem cell transplant; Testing; Time; Toxic effect; Transplant Recipients; Transplantation; United States; Universities; Washington; arm; base; disorder risk; experience; graft vs host disease; in vivo; leukemia; meetings; mortality; phase 2 study; pre-clinical; preclinical study; programs; standard of care; trial comparing

DESCRIPTION (provided by applicant): The Bone Marrow Transplant (BMT)/Leukemia Progrann at Washington University ranks among the largest in the United States, performing nearly 400 transplants annually, including over 150 allogeneic transplants. The program has been affiliated with the BMT Clinical Trials Network since its inception, as part of the Case Western Consortium, and has made significant contributions to CTN through clinical trials accrual and trial design input. As part of this application to become a Core Clinical Center, we propose to leverage extensive institutional experience and expertise in hematopoietic stem cell (HSC) mobilization by leading a randomized phase II clinical trial comparing sargrastim (GM-CSF) plus plerixafor with filgrastim (G-CSF) alone for allogeneic sibling donor HSC mobilization. The basis for this proposal is prior observation of a significantly lower incidence of acute GVHD in allogeneic recipients transplanted with GM-CSF mobilized HSCs compared with G-CSF mobilized HSCs, as well as pre-clinical data demonstrating synergy between GM-CSF and plerixafor. In preclinical and clinical studies we have shown that GM-CSF (in mice) and plerixafor (in humans) mobilize unique subsets of both accessory cells and hematopoietic stem cells that when infused into transplant recipients results in both rapid multilineage engraftment and reduced GvHD. The benefit of reduced GvHD is balanced by the fact that both GM- CSF and plerixafor are relatively weak mobilizing agents in humans and result in failure to reach the minimum number of CD34* cells/kg necessary for transplantation (>2 x 10(R)) after a single 20 liter apheresis between 25- 40% of the time. Therefore combining these agents may overcome this apparent reduced mobilization seen with each agent individually while presen/ing the unique effects of reducing GvHD in vivo. In order to test this hypothesis we have initiated a pilot phase 11 study at our institution to assess the feasibility of GM-CSF/plerixafor mobilization. We expect to complete accrual within the next 8-12 months. Assuming minimum criteria for HSC mobilization efficiency and acute GVHD incidence are met, we will propose to proceed with a larger multicenter randomized Phase II study through CTN to compare this approach with the current standard of care (G-CSF), with a primary endpoint of comparing the incidence of acute GVHD between the two arms. Our hypothesis is that the experimental arm will result in a significant reduction (40%) in the incidence of acute GVHD, without compromise in the number of HSCs collected or increased donor toxicity. Completion of this study would require accrual a total of 108 patients over an anticipated period of 1-2 years. If successful, this study would provide a significant step forward in the field, by reducing a major cause of transplant-related morbidity and mortality. RELEVANCE (See instructions): Acute GVHD remains a significant obstacle to successful outcomes in allogeneic stem cell transplantation, and a source of substantial transplant-related morbidity and mortality. Treatment of acute GVHD with corticosteroids is likewise associated with considerable long-term toxicity. Hence, reduction in the incidence of acute GVHD, without compromising the risk of disease relapse, would represent a significant advance.

描述（由申请人提供）：华盛顿大学的骨髓移植 (BMT)/白血病计划是美国最大的骨髓移植中心之一，每年进行近 400 例移植手术，其中包括超过 150 例同种异体移植。该计划自成立以来一直隶属于 BMT 临床试验网络，作为 Case Western 联盟的一部分，并通过临床试验应计和试验设计输入为 CTN 做出了重大贡献。作为核心临床中心申请的一部分，我们建议通过领导一项随机 II 期临床试验，比较沙格司亭 (GM-CSF) 加普乐沙福与非格司亭 (G -CSF）单独用于同种异体供体 HSC 动员。该提议的基础是先前观察到，与 G-CSF 动员的 HSC 相比，移植 GM-CSF 动员的 HSC 的同种异体受体中急性 GVHD 的发生率显着降低，并且临床前数据证明了 GM-CSF 和普乐沙福之间的协同作用。在临床前和临床研究中，我们已经表明，GM-CSF（小鼠）和普乐沙福（人类）动员辅助细胞和造血干细胞的独特亚群，当将其输注到移植受者体内时，会导致快速多谱系植入并降低 GvHD。 GM-CSF 和普乐沙福在人体中都是相对较弱的动员剂，导致无法达到移植所需的最低 CD34* 细胞/kg 数量（>2 x 10(R)），从而平衡了减少 GvHD 的益处）在 25-40% 的时间内进行单次 20 升血浆分离术后。因此，组合这些药物可以克服每种药物单独观察到的明显的动员减少，同时呈现减少体内GvHD的独特效果。为了检验这一假设，我们在我们的机构启动了一项试点第 11 阶段研究，以评估 GM-CSF/plerixafor 动员的可行性。我们预计在未来 8-12 个月内完成应计。假设满足 HSC 动员效率和急性 GVHD 发生率的最低标准，我们将建议通过 CTN 进行更大规模的多中心随机 II 期研究，以将该方法与当前的护理标准 (G-CSF) 进行比较，主要终点为比较两组之间急性 GVHD 的发生率。我们的假设是，实验组将导致急性 GVHD 的发生率显着降低 (40%)，而不会影响收集的 HSC 数量或增加供体毒性。完成这项研究需要在预计的 1-2 年时间内招募总共 108 名患者。如果成功，这项研究将通过减少移植相关发病率和死亡率的主要原因，在该领域向前迈出重要一步。相关性（参见说明）：急性 GVHD 仍然是同种异体干细胞移植成功的一个重大障碍，也是移植相关发病率和死亡率的一个重要来源。用皮质类固醇治疗急性 GVHD 同样与相当大的长期毒性有关。因此，在不影响疾病复发风险的情况下降低急性 GVHD 的发生率将是一个重大进步。