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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 毛细胞白血病（HCL）是一种罕见的淋巴组织增生性恶性肿瘤，约占所有白血病的2%。 标准治疗是单疗程的2-氯脱氧腺苷（2-CdA），完全或部分缓解率为70%。 用2-CdA再治疗后的应答率相似，但不太持久。 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CD 22。 本研究中使用的研究药物CAT-8015是鼠单克隆抗体抗CD 22抗体RFB 4的重组二硫键稳定Fv，与截短形式的假单胞菌外毒素PE 38融合。 CAT-8015与CD 22结合，复合物通过内吞作用内化。 外毒素结构域转移到细胞质中，催化延伸因子2的ADP核糖基化，导致细胞死亡。 CAT-8015以前未在人体中进行过研究，但类似的抗体缀合物CAT-3888在复发性、难治性HCL的临床研究中显示出显著的活性。 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在复发性或难治性HCL患者中的剂量限制性毒性和最大耐受剂量。 将描述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将患有标准化疗失败的晚期疾病，并将有治疗进展性疾病的医学指征。

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.