The Angeles Clinic and Research Institute, 2001 Santa Monica Boulevard, Suite 560W, Santa Monica, CA 90404, USA.
Invest New Drugs. 2012 Jun;30(3):1074-81. doi: 10.1007/s10637-011-9639-z. Epub 2011 Feb 18.
In this Phase 1, multicenter, open-label study, intetumumab (CNTO 95), a fully human anti-αv integrin monoclonal antibody was evaluated for safety, pharmacokinetics, and pharmacodynamic activity in patients with melanoma or angiosarcoma.
Patients with histologically-confirmed inoperable melanoma or angiosarcoma refractory to standard treatment were allocated to treatment with 10 mg/kg or 20 mg/kg intetumumab, administered once every 3 weeks for up to four cycles unless unacceptable toxicity or disease progression occurred. Extended dosing was available for patients who responded with stable disease or better.
Eight patients received 10 mg/kg and 11 received 20 mg/kg intetumumab. Baseline patient characteristics were comparable between treatment groups; 18 patients had metastatic malignant melanoma and one had angiosarcoma. No dose-limiting toxicities were observed. Headache was the most common adverse event across both dose groups. Vomiting, nausea and chills were more common, and uveitic reactions lasted longer, in patients treated with 20 mg/kg compared with 10 mg/kg intetumumab. No patient developed antibodies to intetumumab. Intetumumab drug exposure as assessed by area under the curve and maximum serum concentration appeared to increase approximately dose-proportionally from 10 to 20 mg/kg, while volume of distribution remained constant for both doses. Stable disease was observed in two patients with metastatic malignant melanoma (one in each dose group) for at least 6 weeks.
In patients with metastatic malignant melanoma and angiosarcoma in this study, intetumumab demonstrated manageable toxicity, was well tolerated, and presented approximately dose-proportional pharmacokinetics for the 10 mg/kg and 20 mg/kg doses.
在这项 1 期、多中心、开放性研究中，评估了全人源抗-αv 整联蛋白单克隆抗体 intetumumab（CNTO 95）在不可切除的黑色素瘤或血管肉瘤患者中的安全性、药代动力学和药效学活性。
组织学证实无法手术的黑色素瘤或对标准治疗耐药的血管肉瘤患者，按 10 mg/kg 或 20 mg/kg intetumumab 分配治疗，每 3 周给药一次，最多给药 4 个周期，除非出现不可接受的毒性或疾病进展。对有稳定疾病或更好反应的患者可延长给药时间。
8 名患者接受了 10 mg/kg 的剂量，11 名患者接受了 20 mg/kg 的剂量。两组患者的基线特征具有可比性；18 名患者患有转移性恶性黑色素瘤，1 名患有血管肉瘤。未观察到剂量限制毒性。两组患者中最常见的不良反应都是头痛。与 10 mg/kg 组相比，20 mg/kg 组患者更常出现呕吐、恶心和寒战，葡萄膜炎反应持续时间更长。没有患者产生抗 intetumumab 抗体。根据曲线下面积和最大血清浓度评估，intetumumab 的药物暴露似乎在 10 至 20 mg/kg 之间呈约剂量比例增加，而两种剂量的分布容积保持不变。两名转移性恶性黑色素瘤患者（每组各 1 名）至少有 6 周观察到稳定疾病。
在这项研究中，转移性恶性黑色素瘤和血管肉瘤患者中，intetumumab 具有可管理的毒性，耐受性良好，10 mg/kg 和 20 mg/kg 剂量的药代动力学呈约剂量比例关系。
