Mount Vernon Cancer Centre; Paul Strickland Scanner Centre, Northwood, Middlesex, United Kingdom.
Clin Cancer Res. 2012 Jun 15;18(12):3428-39. doi: 10.1158/1078-0432.CCR-11-3376. Epub 2012 May 29.
The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) induces significant tumor necrosis as a single agent. Preclinical models have shown that the addition of an anti-VEGF antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity.
Patients with advanced solid malignancies received CA4P at 45, 54, or 63 mg/m(2) on day 1, day 8, and then every 14 days. Bevacizumab 10 mg/kg was given on day 8 and at subsequent cycles four hours after CA4P. Functional imaging with dynamic contrast enhanced-MRI (DCE-MRI) was conducted at baseline, after CA4P alone, and after cycle 1 CA4P + bevacizumab.
A total of 63 mg/m(2) CA4P + 10 mg/kg bevacizumab q14 is the recommended phase II dose. A total of 15 patients were enrolled. Dose-limiting toxicities were grade III asymptomatic atrial fibrillation and grade IV liver hemorrhage in a patient with a history of hemorrhage. Most common toxicities were hypertension, headache, lymphopenia, pruritus, and pyrexia. Asymptomatic electrocardiographic changes were seen in five patients. Nine of 14 patients experienced disease stabilization. A patient with ovarian cancer had a CA125 response lasting for more than a year. DCE-MRI showed statistically significant reductions in tumor perfusion/vascular permeability, which reversed after CA4P alone but which were sustained following bevacizumab. Circulating CD34(+) and CD133(+) bone marrow progenitors increased following CA4P as did VEGF and granulocyte colony-stimulating factor levels.
CA4P in combination with bevacizumab appears safe and well tolerated in this dosing schedule. CA4P induced profound vascular changes, which were maintained by the presence of bevacizumab.
血管破坏剂（VDA）combretastatin A4 磷酸盐（CA4P）作为单一药物可诱导显著的肿瘤坏死。临床前模型表明，将抗血管内皮生长因子（VEGF）抗体添加到 VDA 中可减弱存活肿瘤边缘的再血管化，从而显著增加抗肿瘤活性。
患有晚期实体恶性肿瘤的患者接受 CA4P 治疗，剂量分别为 45、54 或 63mg/m2，于第 1 天、第 8 天给予，然后每 14 天给予一次。贝伐单抗 10mg/kg 于第 8 天和随后的每个周期 CA4P 给药后 4 小时给予。在基线、单独给予 CA4P 后和第 1 个 CA4P+贝伐单抗周期后进行动态对比增强 MRI（DCE-MRI）功能成像。
63mg/m2 CA4P+10mg/kg 贝伐单抗 q14 是推荐的 II 期剂量。共纳入 15 例患者。剂量限制性毒性为 3 级无症状性心房颤动和 1 例有出血史的 4 级肝出血。最常见的毒性反应为高血压、头痛、淋巴细胞减少、瘙痒和发热。5 例患者出现无症状性心电图改变。14 例患者中有 9 例病情稳定。1 例卵巢癌患者 CA125 反应持续超过 1 年。DCE-MRI 显示肿瘤灌注/血管通透性呈统计学显著降低，单独给予 CA4P 后逆转，但给予贝伐单抗后持续存在。CA4P 后循环 CD34+和 CD133+骨髓祖细胞增加，同时 VEGF 和粒细胞集落刺激因子水平升高。
在该剂量方案下，CA4P 联合贝伐单抗似乎安全且耐受良好。CA4P 诱导了明显的血管变化，贝伐单抗的存在维持了这些变化。
