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.

摘要 Waldenstrom巨球蛋白血症(WM)是一种无法治愈、危及生命的恶性肿瘤。这是一种罕见的 慢性B细胞非霍奇金淋巴瘤(NHL)，以小B淋巴细胞、浆细胞样变为特征 淋巴细胞和浆细胞，通常累及骨髓、淋巴结和器官，如脾 还有肝脏。患者也有可检测到的骨部单抗免疫球蛋白(Ig)M水平的伽马病 骨髓受累。西医患者从确诊之日起的中位生存期约为6年。 取决于预后指标。死亡的主要原因包括疾病的进展，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，但没有标准的治疗方法 在一线西医患者中。建议包括使用利妥昔单抗(抗CD20)进行化学免疫治疗 单抗)或利妥昔单抗与蛋白酶体抑制剂以及伊布鲁替尼的组合，对某些 病人。因为所有患者的疾病最终都会进展，而伊布鲁替尼是唯一被批准的二线药物 在治疗方面，复发或难治性环境中的患者仍有大量未得到满足的医疗需求。 我们建议将CLR 131用于治疗无复发的西医患者的复发西医。 对伊布鲁替尼(或其他Bruton的酪氨酸激酶抑制剂)有效或不耐受。靶向肿瘤--CLR 131 以磷脂醚(PLE)为核心的放射治疗有望具有更高的疗效和安全性 由于CLR 131实际修改了疾病，无论潜在的疾病如何，都可提供持久的疗效 西医的遗传景观。CLR 131利用PLE的肿瘤靶向特性来提供靶向递送 减少对恶性肿瘤细胞的辐射，最大限度地减少对正常组织的辐射暴露。PLE选择性地插入 进入富含在肿瘤细胞表面的脂筏，并将其用作细胞进入的门户。 综合的非临床数据证实，使用CLR 131可以抑制肿瘤生长 以及更高的存活率。更重要的是，参加我们第二阶段公开赛的6名WM受试者的初步数据- CLR 131在复发性或难治性选定类型B细胞恶性肿瘤患者中的多中心标记研究， 总有效率为100%，其中1例完全缓解，4例部分缓解 反应，一名反应轻微的患者显示IgM下降45%(50%相当于 部分响应)。在这个项目中。我们将进行非随机开放标签、多中心、II/III期疗效试验 至少50例西医失败患者静脉应用CLR 131的安全性研究 标准护理一线治疗并且对任何BTK抑制剂失败或具有次优反应(即， 伊布鲁替尼、扎努布替尼或阿卡拉布替尼)。这项研究将使我们能够获得监管部门对CLR 131的批准 检查了患者群体。