CLINICAL TRIAL: CAT-8015 IN PATIENTS WITH RELAPSED OR REFRACTORY HAIRY CELL LEUK

临床试验：CAT-8015 在复发或难治性毛细胞白血病患者中的应用

• 批准号: 7717934
• 负责人: STEVEN E COUTRE
• 金额: $ 0.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7717934
• 关键词: ADP ribosylation; Accounting; Affinity; Antibodies; Binding; CD22 gene; Cell Death; Cells; Cladribine; Clinical Research; Clinical Trials; Complex; Computer Retrieval of Information on Scientific Projects Database; Cytosol; Disease; Disulfides; Dose-Limiting; Drug Kinetics; Endocytosis; Exotoxins; Felis catus; Funding; Grant; Hairy Cell Leukemia; Hairy cell; Human; Immunosuppression; Indolent; Infection; Institution; Malignant Neoplasms; Marrow; Maximum Tolerated Dose; Medical; Monoclonal Antibodies; Mus; Partial Remission; Patients; Peptide Elongation Factor 2; Progressive Disease; Pseudomonas; Rate; Recombinants; Refractory; Relapse; Research; Research Personnel; Resources; Retreatment; Risk; Safety; Source; Standards of Weights and Measures; Therapeutic immunosuppression; Toxic effect; United States National Institutes of Health; antibody conjugate; chemotherapy; cytopenia; design; immunogenicity; leukemia; neurotoxicity; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hairy cell leukemia (HCL) is a rare lymphoproliferative malignancy accounting for approximately 2% of all leukemias. Standard treatment is a single course of 2-chlorodeoxyadenosine (2-CdA) with complete or partial remission rates of 70%. Response rates after retreatment with 2-CdA are similar but less durable. Repetitive administration carries risks including immunosuppression, marrow aplasia, prolonged cytopenias, infections and neurotoxicity. HCL cells express high levels of CD22. The investigational agent used in this study, CAT-8015, is a recombinant, disulfide-stabilized Fv of the murine monoclonal antibody anti-CD22 antibody, RFB4, fused to a truncated form of pseudomonas exotoxin, PE38. CAT-8015 binds to CD22 and the complex is internalized by endocytosis. The exotoxin domain is translocated to the cytosol where it catalyzes the ADP ribosylation of elongation factor 2, resulting in cell death. CAT-8015 has not been previously studied in humans, but a similar antibody conjugate, CAT-3888 has demonstrated significant activity in clinical studies of relapsed, refractory HCL. CAT-8015 was designed to have greater binding affinity for CD-22 than CAT-3888. The primary objective of this study is to identify the dose-limiting toxicity and maximum tolerated dose of CAT-8015 in patients with relapsed or refractory HCL. Safety, efficacy, pharmacokinetics and immunogenicity of CAT-8015 will be profiled. Although HCL is an indolent disease, all patients in this study will have advanced disease that has failed standard chemotherapy and will have medical indications for treatment of progressive disease.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 毛细胞白血病（HCL）是一种罕见的淋巴增殖性恶性肿瘤，约占所有白血病的2%。 标准治疗是单疗程 2-氯脱氧腺苷 (2-CdA)，完全或部分缓解率为 70%。 Response rates after retreatment with 2-CdA are similar but less durable. 重复给药带来的风险包括免疫抑制、骨髓再生障碍、长期血细胞减少、感染和神经毒性。 HCL 细胞表达高水平的 CD22。 本研究中使用的研究药物 CAT-8015 是鼠单克隆抗体抗 CD22 抗体 RFB4 的重组二硫键稳定 Fv，与截短形式的假单胞菌外毒素 PE38 融合。 CAT-8015 与 CD22 结合，复合物通过内吞作用内化。 外毒素结构域易位至胞质溶胶，催化延伸因子 2 的 ADP 核糖基化，导致细胞死亡。 CAT-8015 之前尚未在人体中进行过研究，但类似的抗体偶联物 CAT-3888 已在复发难治性 HCL 的临床研究中表现出显着的活性。 CAT-8015 被设计为比 CAT-3888 对 CD-22 具有更大的结合亲和力。 本研究的主要目的是确定 CAT-8015 在复发或难治性 HCL 患者中的剂量限制毒性和最大耐受剂量。 将介绍 CAT-8015 的安全性、有效性、药代动力学和免疫原性。 尽管 HCL 是一种惰性疾病，但本研究中的所有患者都患有标准化疗失败的晚期疾病，并且具有治疗进展性疾病的医学指征。