Phase I Study of KW-0761, a Defucosylated Humanized Anti-CCR4 Antibody, in Relapsed Patients With Adult T-Cell Leukemia-Lymphoma and Peripheral T-Cell Lymphoma
Phase I Study of KW-0761, a Defucosylated Humanized Anti-CCR4 Antibody, in Relapsed Patients With Adult T-Cell Leukemia-Lymphoma and Peripheral T-Cell Lymphoma
复制标题
DOI：
10.1200/jco.2009.25.3575
复制
发表时间：
2010-03-20
影响因子：
45.3
通讯作者：
Ueda, Ryuzo
中科院分区：
文献类型：
--
作者：
Yamamoto, Kazuhito;Utsunomiya, Atae;Ueda, Ryuzo
目的KW-0761是一种去岩藻糖基化的人源化抗CC趋化因子受体4（CCR 4）抗体，具有较强的抗体依赖性细胞毒作用。本I期研究评估了KW-0761的安全性，药代动力学，推荐的II期剂量和疗效复发的CCR 4阳性成人T细胞白血病淋巴瘤（ATL）或外周T细胞淋巴瘤（PTCL）患者和MethodsSixteen患者接受KW-0761每周一次，4周静脉输注。剂量逐步增加，从0.01，0.1，0.5，最后1.0 mg/kg的3 + 3 design.ResultsFifteen患者完成了协议治疗。仅1例患者（1.0 mg/kg剂量）发生3级剂量限制性毒性、皮疹和发热性中性粒细胞减少症以及4级中性粒细胞减少症。其他治疗相关的3 - 4级毒性为淋巴细胞减少症（n = 10）、中性粒细胞减少症（n = 3）、白细胞减少症（n = 2）、带状疱疹（n = 1）和急性输注反应/细胞因子释放综合征（n = 1）。毒性的频率和严重程度均未随剂量递增而增加。未达到最大耐受剂量。因此，II期推荐剂量确定为1.0 mg/kg。没有患者具有可检测水平的抗KW-0761抗体。KW-0761的血浆峰、谷值和0 - 7天的曲线下面积呈剂量和频率依赖性增加。5例患者（31%; 95%CI，11%至59%）达到客观反应：两个完全（0.1; 1.0 mg/kg）和三个部分（0.01; 2在1.0 mg/kg）responses.ConclusionKW-0761耐受在所有剂量水平测试，表现出潜在的疗效对复发的CCR 4阳性ATL或PTCL。因此，需要在1.0 mg/kg剂量下进行后续II期研究。
PurposeKW-0761, a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody, exerts a strong antibody-dependent cellular cytotoxic effect. This phase I study assessed the safety, pharmacokinetics, recommended phase II dose and efficacy of KW-0761 in patients with relapsed CCR4-positive adult T-cell leukemia-lymphoma (ATL) or peripheral T-cell lymphoma (PTCL).Patients and MethodsSixteen patients received KW-0761 once a week for 4 weeks by intravenous infusion. Doses were escalated, starting at 0.01, 0.1, 0.5, and finally 1.0 mg/kg by a 3 + 3 design.ResultsFifteen patients completed the protocol treatment. Only one patient, at the 1.0 mg/kg dose, developed grade 3 dose-limiting toxicities, skin rash, and febrile neutropenia, and grade 4 neutropenia. Other treatment-related grade 3 to 4 toxicities were lymphopenia (n = 10), neutropenia (n = 3), leukopenia (n = 2), herpes zoster (n = 1), and acute infusion reaction/cytokine release syndrome (n = 1). Neither the frequency nor severity of toxicities increased with dose escalation. The maximum tolerated dose was not reached. Therefore, the recommended phase II dose was determined to be 1.0 mg/kg. No patients had detectable levels of anti-KW-0761 antibody. The plasma maximum and trough, and the area under the curve of 0 to 7 days of KW-0761, tended to increase dose and frequency dependently. Five patients (31%; 95% CI, 11% to 59%) achieved objective responses: two complete (0.1; 1.0 mg/kg) and three partial (0.01; 2 at 1.0 mg/kg) responses.ConclusionKW-0761 was tolerated at all the dose levels tested, demonstrating potential efficacy against relapsed CCR4-positive ATL or PTCL. Subsequent phase II studies at the 1.0 mg/kg dose are thus warranted.