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: 10324612
• 负责人: John Friend
• 金额: $ 76.31万
• 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/10324612
• 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; Prognostic Marker; 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/antagonist; intravenous administration; lymph nodes; meetings; neoplastic cell; novel therapeutics; open label; partial response; patient population; primary endpoint; 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 Waldenstrom的大球蛋白血症（WM）是一种无法治愈的恶性肿瘤。 B细胞非霍奇金淋巴瘤（NHL）的慢性形式，其特征在于小B淋巴细胞，浆细胞类动物 淋巴细胞和浆细胞通常涉及骨髓，淋巴结和器官，例如脾脏 和肝脏还具有骨骼的侦探水平 骨髓参与。 取决于预后指标。 高级淋巴瘤或治疗性汇编。 在一线WM患者中。 单克隆抗体）或利妥昔单抗与蛋白酶体抑制剂以及ibrutinib的组合 患者。 治疗。 我们提出了Cl 131的临床开发，用于治疗不在的患者中的复发WM 对ibrutinib（或Ether bruton的酪氨酸激酶抑制剂）反应，或者对其不耐受。 具有磷脂醚（PLE）核的放射治疗，预计将具有分解功效和安全性 剖面并为CL 131实际修改该疾病而提供持久功效，而不论其基础如何 WM的遗传景观。 对恶性肿瘤细胞的辐射，并最大程度地减少放射性暴露。 进入富含肿瘤细胞表面的脂质筏，并将其尽可能如盖特瓦尔进入。 联合非临床数据证实，使用Cl 131的给药会抑制肿瘤生长 并提高了生存率。 标签，多中心，对复发或难治性类型的B细胞恶性肿瘤类型的患者进行CL 131的研究， 总体缓解率为100％，一名患者有组成，四名患者患有部分患者 反应，一名患者对IgM进行​​了最小反应的重新修订45％（50％的修订等于A 部分响应）。 和至少50例失败的患者的静脉注射CLR 131的安全研究 护理标准第一线治疗仪，并且对任何BTK抑制剂失败或次错反应（即 ibrutinib，Zanubrutinib或acalabrutinib）。 检查了患者人群。