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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 毛细胞白血病(HCL)是一种罕见的淋巴增生性恶性肿瘤，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%。2-CDA再治疗后的应答率相似，但持久性较差。重复给药有风险，包括免疫抑制、骨髓再生障碍性贫血、长期细胞减少、感染和神经毒性。 HCL细胞高水平表达CD22。本研究中使用的研究试剂CAT-8015是小鼠抗CD22单抗RFB4与截短形式的假单胞菌外毒素PE38融合的二硫键稳定的重组Fv。CAT-8015与CD22结合，该复合体通过内吞作用内化。外毒素结构域被转移到胞浆中，在那里它催化延伸因子2的ADP核糖化，导致细胞死亡。 CAT-8015以前没有在人类身上进行过研究，但一种类似的抗体结合物CAT-3888在复发、难治性HCL的临床研究中显示了显著的活性。CAT-8015与CD-22的结合亲和力高于CAT-3888。 这项研究的主要目的是确定CAT-8015在复发或难治性HCL患者中的剂量限制性毒性和最大耐受量。将介绍CAT-8015的安全性、有效性、药代动力学和免疫原性。虽然HCL是一种缓慢的疾病，但这项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.