An Open-Label, Multicenter, Phase 2/3 Efficacy and Safety Study of a targeted radiotherapy in Patients with Relapsed or Refractory Waldenstroms Macroglobulinemia

摘要 瓦尔登斯特伦巨球蛋白血症（WM）是一种无法治愈且危及生命的恶性肿瘤。这是一种罕见的， 一种慢性B细胞非霍奇金淋巴瘤（NHL），以小B淋巴细胞、浆细胞样 淋巴细胞和浆细胞，通常涉及骨髓、淋巴结和器官如脾 和肝脏。患者还具有可检测水平的单克隆免疫球蛋白（IG）M丙种球蛋白病， 骨髓受累WM患者从诊断开始的中位生存期约为6年， 取决于预后指标。死亡的主要原因包括疾病进展，转化为 高度恶性淋巴瘤或治疗并发症。虽然使用了许多药物，但没有标准治疗方法 在一线WM患者中。建议包括使用利妥昔单抗（抗CD 20 单克隆抗体）或利妥昔单抗与蛋白酶体抑制剂的组合，以及对于某些情况， 患者因为所有患者的疾病最终都会进展，而伊曲替尼是唯一获批的二线药物 尽管在治疗方面存在一些问题，但在复发性或难治性环境中的患者中仍然存在显著的未满足的医疗需求。 我们建议临床开发的治疗复发WM的患者谁不 对伊鲁替尼（或其他布鲁顿酪氨酸激酶抑制剂）有反应或不耐受。 具有磷脂醚（PLE）核心的放射性药物，预期具有增强的功效和安全性 简介，并提供持久的疗效，由于RES 131实际上改变了疾病，无论潜在的 WM的遗传景观。PLE 131利用PLEs的肿瘤靶向特性提供靶向递送 放射线对恶性肿瘤细胞和最大限度地减少辐射暴露于正常组织。PLEs选择性地插入 转化为脂质筏，脂质筏在肿瘤细胞表面富集，并将其用作细胞进入的门户。 合并的非临床数据证实，给予THA 131可抑制肿瘤生长 提高生存率。更重要的是，来自参加我们II期开放试验的6名WM受试者的初步数据- 在复发性或难治性选定类型的B细胞恶性肿瘤患者中进行的一项TBI 131标签、多中心研究， 总体缓解率为100%，1例患者完全缓解，4例患者部分缓解， 反应，一名患者具有最小反应，显示IgM减少45%（50%减少相当于 部分响应）。在这个项目中。我们将进行一项非随机、开放标签、多中心、II/III期疗效研究， 在至少50例WM失败的患者中进行的静脉给药利多卡因131的安全性研究 标准一线治疗并且对任何BTK抑制剂无效或具有次优反应（即， 伊布替尼、扎努替尼或阿卡拉布替尼）。这项研究将使我们能够获得监管机构对131的批准， 检查患者人群。

ABSTRACT Waldenstrom’s Macroglobulinemia (WM) is an incurable and life-threatening malignant tumor. It is a rare and chronic form of B-cell non-Hodgkin lymphoma (NHL), characterized by small B lymphocytes, plasmacytoid lymphocytes, and plasma cells typically involving the bone marrow, lymph nodes, and organs such as spleen and liver. Patients also have detectable levels of monoclonal immunoglobulin (Ig) M gammopathy with bone marrow involvement. The median survival of WM patients from the time of diagnosis is approximately 6 years, depending on prognostic indicators. The main causes of death include disease progression, transformation to high-grade lymphoma or therapeutic complications. While many drugs are utilized, there is no standard treatment in first-line WM patients. Recommendations include using chemoimmunotherapy with rituximab (anti-CD20 monoclonal antibodies) or the combination of rituximab with proteasome inhibitors as well as ibrutinib for some patients. Because all patients’ disease eventually progresses, and ibrutinib is the only approved second line therapy, there continues to be a significant unmet medical need in patients in the relapsed or refractory setting. We propose the clinical development of CLR 131 for the treatment of relapsed WM in patients who do not respond to ibrutinib (or other Bruton’s tyrosine kinase inhibitors) or are intolerant to it. CLR 131, a tumor targeted radiotherapeutic with a phospholipid ether (PLE) core, is expected to have an enhanced efficacy and safety profile and provide durable efficacy due to CLR 131 actually modifying the disease, regardless of the underlying genetic landscape of WM. CLR 131 exploits the tumor-targeting properties of PLEs to provide a targeted delivery of radiation to malignant tumor cells and minimizes radiation exposure to normal tissues. PLEs selectively insert into lipid rafts, which are enriched on the surface of tumor cells, and use them as a gateway for cellular entry. The combined nonclinical data confirm that administration with CLR 131 results in inhibition of tumour growth and increased survival. More importantly, preliminary data from 6 WM subjects participating in our Phase II open- label, multi-center, study of CLR 131 in patients with relapsed or refractory select types of B-cell malignancies, showed an overall response rate of 100%, with one patient with a complete response, four patients with a partial response, one patient with a minimal response showing a 45% reduction in IgM (50% reduction equates to a partial response). In this project. we will conduct a non-randomized open-label, multi-center, Phase II/III efficacy and safety study of intravenous administration of CLR 131 in at least 50 patients with WM who have failed standard of care first line treatment and either failed or had a suboptimal response to any BTK inhibitors (i.e., ibrutinib, zanubrutinib or acalabrutinib). This study will allow us to receive regulatory approval for CLR 131 in the examined patient population.