Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264, USA.
Clin Cancer Res. 2010 Dec 15;16(24):6132-8. doi: 10.1158/1078-0432.CCR-10-2275. Epub 2010 Oct 29.
MORAb-009 is a chimeric monoclonal antibody that targets mesothelin, a tumor differentiation antigen overexpressed in pancreatic cancer, ovarian cancer, mesothelioma, and other malignancies. We conducted a phase I clinical trial of MORAb-009 in patients with advanced mesothelin-expressing cancers to determine its safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD).
Cohorts consisting of 3 to 6 subjects each received MORAb-009 intravenously on days 1, 8, 15, and 22 at progressively increasing doses ranging from 12.5 to 400 mg/m(2). Disease evaluation with computed tomography occurred on day 35. Subjects with responding or stable disease could receive additional cycles of MORAb-009.
A total of 24 subjects were treated including 13 mesothelioma, 7 pancreatic cancer, and 4 ovarian cancer patients. The median number of MORAb-009 infusions was 4 (range 1-24 infusions). At the 400 mg/m(2) dose level, 2 subjects experienced DLT (grade 4 transaminitis and a grade 3 serum sickness). Thus, although there were other contributing causes of these adverse events, 200 mg/m(2) was considered the MTD. Other adverse events at least possibly related to MORAb-009 included 7 drug hypersensitivity events (all grade 1 or 2) and a thromboembolic event (grade 4). Eleven subjects had stable disease. There was a dose-dependent increase in serum MORAb-009 concentration.
MORAb-009 is well tolerated and the MTD when administered weekly is conservatively set at 200 mg/m(2). In this group of previously treated patients, 11 subjects had stable disease. Phase II studies of MORAb-009 in different mesothelin-expressing cancers are ongoing.
MORAb-009 是一种嵌合单克隆抗体，靶向间皮素，这是一种在胰腺癌、卵巢癌、间皮瘤和其他恶性肿瘤中过度表达的肿瘤分化抗原。我们在表达间皮素的晚期癌症患者中进行了 MORAb-009 的 I 期临床试验，以确定其安全性、剂量限制性毒性（DLT）和最大耐受剂量（MTD）。
每个队列由 3 至 6 名受试者组成，他们在第 1、8、15 和 22 天接受递增剂量的 MORAb-009 静脉注射，剂量范围为 12.5 至 400mg/m²。在第 35 天进行计算机断层扫描疾病评估。有反应或稳定疾病的受试者可以接受额外的 MORAb-009 周期。
共有 24 名受试者接受了治疗，包括 13 名间皮瘤患者、7 名胰腺癌患者和 4 名卵巢癌患者。MORAb-009 输注的中位数为 4 次（范围为 1-24 次输注）。在 400mg/m²剂量水平下，2 名受试者出现 DLT（4 级转氨酶升高和 3 级血清病）。因此，尽管这些不良事件还有其他原因，但 200mg/m²被认为是 MTD。至少可能与 MORAb-009 相关的其他不良事件包括 7 起药物过敏事件（均为 1 或 2 级）和 1 起血栓栓塞事件（4 级）。11 名受试者病情稳定。血清 MORAb-009 浓度呈剂量依赖性增加。
MORAb-009 具有良好的耐受性，当每周给药时，MTD 保守地设定为 200mg/m²。在这组先前接受治疗的患者中，11 名受试者病情稳定。MORAb-009 在不同间皮素表达的癌症中的 II 期研究正在进行中。
