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

复发性或难治性华氏巨球蛋白血症患者靶向放疗的开放标签、多中心、2/3 期疗效和安全性研究

• 批准号: 10477049
• 负责人: Jarrod Longcor
• 金额: $ 75.56万
• 依托单位: CELLECTAR BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477049
• 关键词: Agammaglobulinaemia tyrosine kinase; Award; B lymphoid malignancy; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Bone Marrow Involvement; Bone marrow biopsy; Cause of Death; Cell Proliferation; Cell Survival; Chronic; Clinical; Clinical Trials; Clinical trial protocol document; Data; Diagnosis; Disease; Disease Progression; Dose; Drug Utilization; Exposure to; FDA approved; Genetic; Half-Life; I131 isotope; Immuno-Chemotherapy; Immunoglobulin M; In complete remission; Life; Liver; Longterm Follow-up; Lymphoma; Lymphoplasmacytoid Cell; Malignant Neoplasms; Measures; Medical; Membrane Microdomains; Modification; Monoclonal Antibody CD20; Multicenter Studies; Normal Cell; Normal tissue morphology; Organ; Outcome Measure; Patient Outcomes Assessments; Patients; Pharmaceutical Preparations; Phase; Phospholipid Ethers; Plasma Cells; Prevention; Progression-Free Survivals; Property; Proteasome Inhibitor; Radiation exposure; Radio; Radioactive; Radiolabeled; Reaction Time; Recommendation; Refractory; Relapse; Research Design; Rodent Model; Safety; Series; Serum; Signal Pathway; Small Business Innovation Research Grant; Spleen; Surface; Symptoms; Targeted Radiotherapy; Therapeutic; Time; Treatment-related toxicity; Tumor Burden; Tumor Volume; Tyrosine Kinase Inhibitor; Visit; Waldenstrom Macroglobulinemia; analog; anti-CD20; base; cancer cell; cancer type; clinical development; cohort; efficacy evaluation; efficacy study; gammopathy; improved; inhibitor; intravenous administration; lymph nodes; meetings; neoplastic cell; novel therapeutics; open label; partial response; patient population; primary endpoint; prognostic indicator; radiation delivery; response; rituximab; safety study; screening; secondary endpoint; single photon emission computed tomography; standard care; standard of care; symptom treatment; targeted agent; targeted delivery; targeted radiotherapeutic; treatment duration; tumor; tumor growth; uptake

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.

抽象的 华氏巨球蛋白血症（WM）是一种无法治愈且危及生命的恶性肿瘤。 慢性 B 细胞非霍奇金淋巴瘤 (NHL)，特征为小 B 淋巴细胞、浆细胞样 淋巴细胞和浆细胞，通常涉及骨髓、淋巴结和脾脏等器官 患者的骨和肝脏中也可检测到单克隆免疫球蛋白 (Ig) M 丙种球蛋白病。 从诊断之日起，WM 患者的中位生存期约为 6 年， 取决于预后指标。死亡的主要原因包括疾病进展、转化为疾病。 高度淋巴瘤或治疗并发症虽然使用了许多药物，但没有标准的治疗方法。 对于一线 WM 患者，建议使用利妥昔单抗（抗 CD20）化学免疫疗法。 单克隆抗体）或利妥昔单抗与蛋白酶体抑制剂的组合以及依鲁替尼（ibrutinib）对于某些 因为所有患者的疾病最终都会进展，而依鲁替尼是唯一被批准的二线药物。 治疗方面，复发或难治性患者的医疗需求仍然存在重大未得到满足的情况。 我们建议临床开发 CLR 131，用于治疗患有复发性 WM 的患者。 对依鲁替尼（或其他布鲁顿酪氨酸激酶抑制剂）有反应或​​对其靶向肿瘤 CLR 131 不耐受。 以磷脂醚 (PLE) 为核心的放射治疗有望提高疗效和安全性 由于 CLR 131 实际上改变了疾病，无论潜在的情况如何，都可以分析并提供持久的疗效 WM 的遗传景观利用 PLE 的肿瘤靶向特性来提供靶向递送。 选择性插入恶性肿瘤细胞并最大限度地减少对正常组织的辐射暴露。 进入富集在肿瘤细胞表面的筏脂质中，并将其用作细胞进入的门户。 综合非临床数据证实，施用 CLR 131 可抑制肿瘤生长 更重要的是，来自参与我们的 II 期开放研究的 6 名 WM 受试者的初步数据。 针对复发或难治性选定类型 B 细胞恶性肿瘤患者的 CLR 131 标签、多中心研究， 总体缓解率为 100%，其中 1 名患者完全缓解，4 名患者部分缓解 反应，一名反应最小的患者显示 IgM 减少了 45%（减少 50% 相当于 在这个项目中，我们将进行非随机、开放标签、多中心、II/III 期疗效。 对至少 50 名失败的 WM 患者静脉注射 CLR 131 的安全性研究 标准护理一线治疗，并且对任何 BTK 抑制剂（即， ibrutinib、zanubrutinib 或 acalabrutinib）。这项研究将使我们能够获得 CLR 131 的监管批准。 检查患者群体。