A phase I study of anti-kinase insert domain-containing receptor antibody, IMC-1C11, in patients with liver metastases from colorectal carcinoma.
A phase I study of anti-kinase insert domain-containing receptor antibody, IMC-1C11, in patients with liver metastases from colorectal carcinoma.
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发表时间：
2003-04
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通讯作者：
J. Posey;T. Ng;Baolian Yang;M. Khazaeli;M. Carpenter;F. Fox;M. Needle;H. Waksal;A. Lobuglio
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作者：
J. Posey;T. Ng;Baolian Yang;M. Khazaeli;M. Carpenter;F. Fox;M. Needle;H. Waksal;A. Lobuglio
血管生成在结直肠癌的发生发展中起重要作用。血管内皮生长因子受体（VEGFR）是一种跨膜糖蛋白，其刺激可导致内皮细胞有丝分裂。在该受体家族中，VEGFR 2/含激酶插入结构域的受体（KDR）似乎主要在肿瘤发生期间上调。嵌合抗KDR抗体IMC-1C 11阻断VEGFR-KDR相互作用并抑制VEGFR诱导的内皮细胞增殖。该试验旨在评估靶向肿瘤发生的重要途径的安全性，耐受性和可行性。实验设计在一项剂量递增的IMC-1C 11单药研究中，我们招募了14名患有结直肠癌和肝转移的患者。本试验评价了IMC-1C 11的安全性、药代动力学、免疫原性和磁共振成像评估的血管效应改变。以0.2 mg/kg（n = 3）、0.6 mg/kg（n = 4）、2.0 mg/kg（n = 3）和4.0 mg/kg（n = 4）每周输注IMC-1C 11，持续4周，这构成一个周期。结果未观察到3级或4级IMC-1C 11相关毒性。在4例患者中观察到轻微的1级出血事件[0.2 mg/kg（n = 1）和0.6 mg/kg（n = 3）]。每例均迅速消退，无需干预。选择IMC-1C 11的起始剂量以实现约5 μ g/ml的C（max）。该浓度在体外阻止KDR磷酸化。药代动力学分析表明，血浆t（1/2）和C（max）具有剂量依赖性，在4 mg/kg剂量水平下，血浆t（1/2）为67 +/- 3 h。14例患者中7例检测到人抗嵌合抗体。IMC-1C 11的抗体在两名患者中抑制了药剂的循环。1例患者的疾病长期稳定7个周期（28周）。治疗4周后，11例患者的肿瘤内流体积转移常数k（in）（min（-1））和增强因子的平均变化与治疗前值相比显著降低。结论IMC-1C 11安全、耐受性好。IMC-1C 11的药物水平被可靠地预测。需要对抗VEGFR/KDR药物进行进一步的临床研究。
PURPOSE Angiogenesis plays an important role in colorectal cancer progression. Stimulation of vascular endothelial growth factor receptor (VEGFR), a transmembrane glycoprotein, results in endothelial mitogenesis. Within this family of receptors, VEGFR 2/kinase-insert-domain-containing receptor (KDR) appear to be principally up-regulated during tumorigenesis. A chimeric anti-KDR antibody, IMC-1C11, blocks VEGFR-KDR interaction and inhibits VEGFR-induced endothelial cell proliferation. This trial seeks to assess the safety, tolerability and feasibility of targeting an important pathway in tumorigenesis. EXPERIMENTAL DESIGN In a dose-escalation, single-agent study of IMC-1C11, we enrolled 14 patients with colorectal carcinoma and hepatic metastases. Safety-, pharmacokinetic-, immunogenicity-, and magnetic resonance imaging-assessed alteration of vascular effects of IMC-1C11 were evaluated in this trial. IMC-1C11 was infused weekly at 0.2 mg/kg (n = 3), 0.6 mg/kg (n = 4), 2.0 mg/kg (n = 3), and 4.0 mg/kg (n = 4) for 4 weeks, which constituted a cycle. RESULTS No grade-3 or -4 IMC-1C11-related toxicities were observed. Minor grade-1 bleeding events were observed in four patients [0.2 mg/kg (n = 1) and 0.6 mg/kg (n = 3)]. Each resolved quickly and required no intervention. The starting dose of IMC-1C11 was selected to achieve a C(max) of approximately 5 micro g/ml. This concentration prevented KDR phosphorylation in vitro. Pharmacokinetic analysis demonstrated that the plasma t(1/2) and C(max) were dose dependent with a plasma t(1/2) of 67 +/- 3 h at the 4-mg/kg dose level. Human antichimeric antibodies were detected in 7 of 14 patients. The antibodies to IMC-1C11 inhibited the circulation of the agent in two patients. One patient had prolonged stable disease for seven cycles (28 weeks). The mean changes in tumor-influx volume-transfer constant k(in) (min(-1)) and enhancement factor after 4 weeks of therapy were significantly decreased compared with pretreatment values in 11 patients. CONCLUSION IMC-1C11 was both safe and well tolerated. Drug levels of IMC-1C11 were reliably predicted. Further clinical investigation of anti-VEGFR/KDR agents is warranted.