A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma
A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma
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DOI：
10.1111/j.1365-2141.2012.09251.x
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发表时间：
2012-10-01
影响因子：
6.5
通讯作者：
Stadtmauer, Edward A.
中科院分区：
文献类型：
--
作者：
Bensinger, William;Maziarz, Richard T.;Stadtmauer, Edward A.
在这项开放标签、多中心、1期研究中，在复发性/难治性多发性骨髓瘤（MM）患者中评估了一种全人源抗CD 40拮抗剂单克隆抗体lucatumumab。主要目的是根据剂量限制性毒性（DLT）确定最大耐受剂量（MTD）。次要目的包括安全性、药代动力学、药效学和抗骨髓瘤活性。采用标准3+3剂量递增入组的28例患者接受了1个或2个（n=3）周期的lucatumumab 1.0、3.0、4.5或6.0 mg/kg每周一次，持续4周。常见的lucatumumab相关不良事件为可逆的轻度至中度输注反应。严重不良事件为贫血、寒战、高钙血症和发热（各7%）。DLT包括4级血小板减少、3级丙氨酸氨基转移酶升高和4级脂肪酶升高（各n=1）。MTD为4.5mg/kg。在剂量= 3.0 mg/kg时，在每周输注直至末次输注后5周期间观察到持续的受体占用率（=87%），估计半衰期为419天。12例患者（43%）病情稳定，1例患者（4%）维持部分缓解≥ 8个月。这些结果表明，高达4.5 mg/kg的单药lucatumumab耐受性良好，在复发性/难治性MM中具有中度临床活性，因此需要进一步研究作为联合治疗。
In this open-label, multicentre, phase 1 study a fully human anti-CD40 antagonist monoclonal antibody, lucatumumab, was evaluated in patients with relapsed/refractory multiple myeloma (MM). The primary objective was to determine the maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs). Secondary objectives included safety, pharmacokinetics, pharmacodynamics and antimyeloma activity. Twenty-eight patients, enrolled using a standard 3+3 dose escalation, received one or two (n=3) cycles of lucatumumab 1.0, 3.0, 4.5 or 6.0mg/kg once weekly for 4weeks. Common lucatumumab-related adverse events were reversible, mild-to-moderate infusion reactions. Severe adverse events were anaemia, chills, hypercalcaemia and pyrexia (7% each). DLTs included grade 4 thrombocytopenia, grade 3 increased alanine aminotransferase and grade 4 increased lipase (n=1 each). The MTD was 4.5mg/kg. At doses =3.0mg/kg, sustained receptor occupancy (=87%), observed throughout weekly infusions up to 5weeks after the last infusion, correlated with an estimated half-life of 419d. Twelve patients (43%) had stable disease, and one patient (4%) maintained a partial response for =8months. These findings indicate that single-agent lucatumumab was well tolerated up to 4.5mg/kg with modest clinical activity in relapsed/refractory MM, warranting further study as a combination therapy.