Mullamitha Saifee A, Ton Nhuan C, Parker Geoff J M, Jackson Alan, Julyan Peter J, Roberts Caleb, Buonaccorsi Gio A, Watson Yvonne, Davies Karen, Cheung Sue, Hope Lynn, Valle Juan W, Radford John A, Lawrance Jeremy, Saunders Mark P, Munteanu Mihaela C, Nakada Marian T, Nemeth Jeffrey A, Davis Hugh M, Jiao Qun, Prabhakar Uma, Lang Zhihui, Corringham Robert E, Beckman Robert A, Jayson Gordon C
Cancer Research, UK.
Clin Cancer Res. 2007 Apr 1;13(7):2128-35. doi: 10.1158/1078-0432.CCR-06-2779.
A fully human monoclonal antibody to anti-alpha(v) integrins (CNTO 95) has been shown to inhibit angiogenesis and tumor growth in preclinical studies. We assessed the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors.
In this phase I trial, CNTO 95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0, 28, 35, and 42, and clinical assessments, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and [(18)F]-2-fluorodeoxyglucose positron emission tomography (FDG-PET) were done. Patients achieving stable disease or better were eligible for extended dosing every 3 weeks for up to 12 months.
Among the 24 enrolled patients, CNTO 95 was associated with one episode of grade III and four episodes of grade II infusion-related fever (all responded to acetaminophen). Of the six patients who received extended dosing, one patient (10.0 mg/kg), with cutaneous angiosarcoma, had a 9-month partial response. Pre- and post-treatment lesion biopsies confirmed tumor cell alpha(v) integrin expression, as well as CNTO 95 penetration of the tumor and localization to tumor cells in association with reduced bcl-2 expression. A lesion in one patient (10.0 mg/kg) with stable ovarian carcinosarcoma was no longer detectable by FDG-PET by day 49. Exposure to CNTO 95 seemed to increase in a greater-than-dose-proportional manner; dose-dependent mean half-life ranged from 0.26 to 6.7 days.
CNTO 95 was generally well tolerated. Six patients received extended therapy, including one patient with a prolonged response. Biopsy data confirmed tumor localization and pharmacodynamic activity.
在临床前研究中，一种完全人源化的抗α(v)整合素单克隆抗体（CNTO 95）已显示出可抑制血管生成和肿瘤生长。我们评估了CNTO 95在晚期难治性实体瘤患者中的安全性和药代动力学。
在这项I期试验中，于第0、28、35和42天输注CNTO 95（0.1、0.3、1.0、3.0和10.0 mg/kg），并进行临床评估、动态对比增强磁共振成像（DCE-MRI）和[（18）F]-2-氟脱氧葡萄糖正电子发射断层扫描（FDG-PET）。病情稳定或好转的患者有资格每3周延长给药一次，最长可达12个月。
在24名入组患者中，CNTO 95与1次III级和4次II级输液相关发热事件相关（均对乙酰氨基酚有反应）。在6名接受延长给药的患者中，1名患有皮肤血管肉瘤的患者（10.0 mg/kg）有9个月的部分缓解。治疗前后的病变活检证实肿瘤细胞α(v)整合素表达，以及CNTO 95在肿瘤中的渗透和在肿瘤细胞中的定位，同时伴有bcl-2表达降低。到第49天时，1名患有稳定卵巢癌肉瘤的患者（10.0 mg/kg）的一处病变在FDG-PET上不再可检测到。对CNTO 95的暴露似乎以大于剂量比例的方式增加；剂量依赖性平均半衰期范围为0.26至6.7天。
CNTO 95总体耐受性良好。6名患者接受了延长治疗，包括1名有延长反应的患者。活检数据证实了肿瘤定位和药效学活性。
