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

总结 异基因造血干细胞移植（HSCT）是目前唯一建立的广泛的治愈性治疗方法。 成人高危白血病和骨髓增生异常综合征。然而，大约40%的成年患者 HSCT后一年内死亡，主要由于白血病复发和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， 抑制DAMPs（危险相关分子模式）诱导的炎症，并发现它有效 在临床前模型中预防GVHD而不影响移植物抗白血病（GVL）效应。并辅之以有效的 直接SBIR II期奖，我们已经完成了IIA期随机双盲单次剂量递增 试验包括3个给药队列，每组8名患者（安慰剂：治疗比例为1：3），共入组24名受试者。 令人惊讶的是，数据表明，与安慰剂组和同期HSCT对照组相比， 在接受相同标准治疗的患者中，CD24 Fc不仅降低了严重GVHD的发生率， 也降低了白血病复发的发生率，导致严重急性白血病的发生率在统计学上显著增加。 无GVHD生存期（AGFS）超过180天，无病生存期超过800天。结果，我们结束了 与FDA的第二阶段会议，他们同意我们能够提交第三阶段的方案 临床试验除了第二阶段会议的结束，我们还与FDA举行了一次电话会议， 申请突破性疗法认定（BTD）的建议。我们被建议进行开放式- 标签II期剂量扩展试验，使用与IIA期试验相同的多次给药方案。这里我们 拟开展II期剂量扩展临床试验，共纳入20例患者， 假设CD24 Fc预防可以显著改善180天AGFS超过匹配历史 国家数据库的控制。我们提出的研究解决了两个最紧迫的医疗需求 对于白血病患者的HSCT有可能显著改善高危白血病患者的生存率 并因此将对HSCT产生变革性影响。此外，我们的研究可能允许申办者接收 FDA的突破性治疗指定，从而大大加快了临床的步伐 开发用于患者护理的CD24 Fc。

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.