Swords Ronan T, Greenberg Peter L, Wei Andrew H, Durrant Simon, Advani Anjali S, Hertzberg Mark S, Jonas Brian A, Lewis Ian D, Rivera Gabriel, Gratzinger Dita, Fan Alice C, Felsher Dean W, Cortes Jorge E, Watts Justin M, Yarranton Geoff T, Walling Jackie M, Lancet Jeffrey E
Leukemia Program, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL, United States.
Stanford Cancer Institute, Stanford, CA, United States.
Leuk Res. 2016 Nov;50:123-131. doi: 10.1016/j.leukres.2016.09.012. Epub 2016 Sep 28.
EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion.
EphA3是一种在大多数血液系统恶性肿瘤中过度表达的Ephrin受体酪氨酸激酶。我们开展了一项针对难治性血液系统恶性肿瘤的抗EphA3单克隆抗体KB004的首次人体多中心I期研究，以确定其安全性和耐受性，同时进行药代动力学（PK）和药效学（PD）评估的次要目标以及疗效的初步评估。患者最初进入剂量递增阶段（DEP），随后进入队列扩展阶段（CEP）。在每21天周期的第1、8和15天，以递增剂量通过静脉输注给予KB004。共有50名患者（急性髓系白血病39例、骨髓增生异常综合征/骨髓增殖性肿瘤3例、骨髓增生异常综合征4例、弥漫性大B细胞淋巴瘤1例、蕈样肉芽肿3例）在DEP阶段接受了KB004治疗；另外14名患者在CEP阶段接受了治疗（急性髓系白血病8例、骨髓增生异常综合征6例）。最常见的毒性是79%的患者出现短暂的1级和2级输注反应（IRs）。IRs在剂量高于250mg时成为剂量限制性毒性。在剂量高于190mg时，实现了超过预测有效浓度（1μg/mL）并覆盖剂量之间7天间隔的持续暴露。在急性髓系白血病、蕈样肉芽肿、骨髓增生异常综合征/骨髓增殖性肿瘤和骨髓增生异常综合征患者中观察到了反应。在本研究中，KB004每周输注时耐受性良好且具有临床活性。
