A phase II dose expansion clinical trial testing the efficacy of CD24Fc for the prophylaxis of severe graft vs host disease and leukemia relapse

摘要 异基因造血干细胞移植(HSCT)是治疗广泛性骨质疏松症的唯一有效方法。 成人高危白血病和骨髓发育不良谱系。然而，大约40%的成年患者 HSCT后一年内死亡，主要原因是白血病复发和III-IV级移植物抗宿主 疾病(GVHD)。为了应对这些挑战，我们开发了CD24Fc融合蛋白来选择性地 抑制DAMPS(危险相关分子模式)诱导的炎症，并发现它有效 在临床前模型中，在不影响移植物抗白血病(GVL)效应的情况下预防GVHD。在一个 直接SBIR II期获奖，我们已经完成了IIA期随机双盲单次递增剂量 试验包括8名患者的3个剂量队列(1：3安慰剂：治疗)，共纳入24名受试者。 令人惊讶的是，数据表明，与安慰剂组和当代HSCT对照组相比 接受相同标准护理的患者，CD24Fc不仅降低了严重GVHD的发生率，而且 也降低了白血病复发的发生率，导致严重急性白血病患者的统计显著增加 无GVHD生存期(AGFS)超过180天，无病生存期超过800天。因此，我们举行了一个结束 与FDA的第二阶段会议达成一致，我们能够提交第三阶段的协议 临床试验。除了第二阶段会议结束外，我们还与FDA举行了电话会议， 关于突破性治疗指定(BTD)申请的建议。我们被建议表演一场公开的- LABEL II期剂量扩展试验使用与IIA期试验相同的多次给药方案。在这里我们 建议进行第二阶段剂量扩展临床试验，共涉及20名患者，以测试临床 CD24Fc预防可以显著改善180天AGFS的假设超过匹配的历史 来自国家数据库的控制。我们建议的研究解决了两个最紧迫的医疗需求 用于白血病患者的HSCT，有可能显著提高高危白血病患者的存活率 并因此将对HSCT产生转型影响。此外，我们的研究可能会允许赞助商获得 FDA的突破性治疗指定，从而大大加快了临床的步伐 用于患者护理的CD24Fc的开发。

Summary Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative therapy for a broad spectrum of high risk leukemia and myelodysplasia in adults. However, approximately 40% of adult patients die within one year following HSCT, primarily due to leukemia relapse and grade III-IV graft versus host disease (GVHD). To combat these challenges, we have developed the CD24Fc fusion protein to selectively inhibit DAMPs (danger-associated molecular patterns)-induced inflammation and discovered that it effectively prevents GVHD without affecting the graft vs-leukemia (GVL) effect in preclinical models. With the support of a direct SBIR phase II award, we have completed a phase IIA randomized double blind single ascending dose trial comprised of 3 dosing cohorts of 8 patients (1:3 placebo:treatment), with a total enrollment of 24 subjects. Surprisingly, the data suggest that, in comparison to the placebo group and contemporary controls of HSCT patients receiving the same standard of care, CD24Fc not only reduced the incidence of severe GVHD, but also reduced the incidence of leukemia relapse, resulting in statistically significant increases in severe acute GVHD-free survival (AGFS) over 180 days and disease-free survival over 800 days. As result, we held an end of phase II meeting with the FDA who agreed that we are in a position to submit a protocol for a phase III clinical trial. In addition to the end of phase II meeting, we also had a teleconference with the FDA for their advice on an application for Breakthrough Therapy Designation (BTD). We were advised to perform an open- label phase II dose expansion trial using the same multiple dosing regimen from the phase IIA trial. Here we propose to perform the phase II dose expansion clinical trial involving a total of 20 patients to test the clinical hypothesis that CD24Fc prophylaxis can significantly improve 180 day AGFS over matched historical controls from the national database. Our proposed studies address the two most pressing medical needs for HSCT in leukemia patients with the potential to significantly improve survival of high risk leukemia patients and will thus have a transforming impact to HSCT. In addition, our study may allow the sponsor to receive Breakthrough Therapy Designation from the FDA and thus greatly accelerate the pace of the clinical development of CD24Fc for patient care.