A phase IIA trial for the safety and tolerability of CD24Fc in prophylaxis of graft vs host disease.

项目摘要/摘要 急性移植物抗宿主病(AGVHD)是造成移植相关死亡的主要因素。 (TRM)，大约60%-80%的接受无关供者造血干细胞的受者会发生这种疾病 移植(HSCT)，尽管有标准的免疫抑制预防。因此，新的GVHD预防方法 迫切需要成功地减轻aGVHD和感染等相关并发症的治疗 需要的。此外，异基因造血干细胞移植的一个重要功能是利用供体T细胞消除异基因 白血病细胞，这被称为移植物抗白血病(GVL)。然而，目前的预防和治疗方法 GVHD是建立在全身免疫抑制的基础上的，这种免疫抑制会导致高感染风险和显著的 死亡率，同时通过降低GVL而导致白血病复发。这项研究项目的最终目标是 为进一步开发预防aGVHD的新药候选药物 接受异基因清髓造血干细胞移植的白血病患者。在小鼠模型的临床前试验中，该药物 候选药物CD24Fc已被证明可显著降低移植物抗宿主病的严重程度并提高存活率 保存GVL，是预防白血病患者GVHD的理想药物。关联的活动 温室气体减少和GVL的保存得到了体外数据的有力支持，这些数据描述了 CD24Fc药物制品的作用机制。CD24Fc已被证明在健康人群中是安全的 第一阶段临床试验的人体受试者和目前的项目，即第二阶段临床试验，旨在提供 CD24Fc的首次人体毒性/安全性、药代动力学、药效学和生物活性数据 造血干细胞移植患者。这些数据表明，我们已经不止达到了里程碑 通常设置为第一阶段SBIR赠款，因此我们有资格申请第二阶段直接SBIR应用。建议数 IIa期试验是一项随机、双盲、单次递增剂量试验，由3个剂量队列组成，每个队列8 患者(3：1治疗：安慰剂)，总计划登记24名受试者。临床试验将有两个 分阶段解决的具体目标：具体目标我将确定CD24Fc的安全性和耐受性 在单次递增剂量-递增研究中，定义推荐的第二阶段剂量(或最大剂量 在一项大型IIb期扩大试验中用于预防移植物抗宿主病(GVHD)的耐受量)；以及特定目标II将评估 CD24Fc在白血病和髓系异型增生综合征患者体内的药代动力学和体内活性 正在接收HSCT。CD24Fc将在标准护理预防的背景下应用于患者 由钙调神经磷酸酶抑制剂和甲氨蝶呤组成，以最大限度地提高患者的安全性。建议进行的研究 代表着一个重要的里程碑，不仅对于开发用于治疗的新型免疫调节药物是必要的 一个GVHD，也是为了公司的商业化努力。

Project Summary/Abstract Acute graft-versus-host disease (aGVHD) is a principal contributor to transplant related mortality (TRM), and develops in approximately 60-80% of recipients receiving unrelated donor hematopoietic stem cell transplantation (HSCT) despite standard immunosuppressive prophylaxis. Thus, novel GVHD prophylaxis treatments which successfully attenuate aGVHD and related complications such as infection are urgently needed. In addition, an important function of allogeneic HSCT is to use donor T cells to eliminate allogeneic leukemia cells, this is called the graft-versus-leukemia (GVL). However, current prophylaxis and treatment of GVHD is based on general immunosuppression, which causes high risk of infection and cause significant mortality, while contributing to leukemia relapse by reducing GVL. The ultimate goal of this research project is to further the clinical development of a novel drug candidate for the prophylactic treatment of aGVHD in leukemia patients undergoing allogeneic myeloablative HSCT. In preclinical testing in murine models, the drug candidate, CD24Fc, has been shown to significantly reduce GVHD severity and improve in survival while preserving GVL, making it an ideal drug for prophylaxis of GVHD in leukemia patients. The activity associated with GHVD reduction and GVL preservation is strongly supported by in vitro data that describes the mechanism of action of the CD24Fc drug product. CD24Fc has been demonstrated to be safe in healthy human subjects in a Phase I clinical trial and the current project, a Phase IIa clinical trial, aims to provide the first toxicity/safety, pharmacokinetics, pharmacodynamics and biological activity data for CD24Fc in human HSCT transplantation patients. These data demonstrate that we have more than reached the milestones typically set for phase I SBIR grant, and thus qualify us for phase II direct SBIR application. The proposed Phase IIa trial is a randomized double blind single ascending dose trial comprised of 3 dosing cohorts of 8 patients (3:1 treatment:placebo), for a total planned enrollment of 24 subjects. The clinical trial will have two specific aims addressed by different phases: specific aim I will determine the safety and tolerability of CD24Fc in a single ascending dose-escalation study, and define the recommended Phase II dose (or Maximum Tolerated Dose) for prophylaxis of GVHD in a large Phase IIb expansion trial; and specific aim II will assess the pharmacokinetics and in-human activity of CD24Fc in leukemia and myeloid dysplasia syndrome patients receiving HSCT. CD24Fc will be administered to patients on a background of standard of care prophylaxis comprising a calcineurin inhibitor and methotrexate to maximize patient safety. The proposed study represents a major milestone necessary not only for the development of the novel immunomodulating drug for a GVHD, but also for commercialization effort of the company.