Phase I Trial of Combretastatin A4 Phosphate (CA4P) in Combination with Bevacizumab in Patients with Advanced Cancer
Phase I Trial of Combretastatin A4 Phosphate (CA4P) in Combination with Bevacizumab in Patients with Advanced Cancer
复制标题
DOI：
10.1158/1078-0432.ccr-11-3376
复制
发表时间：
2012-06-15
影响因子：
11.5
通讯作者：
Judson, Ian
中科院分区：
文献类型：
--
作者：
Nathan, Paul;Zweifel, Martin;Judson, Ian
目的：血管干扰剂（VDA） combretastatin A4 phosphate （CA4P）可作为单一药物诱导肿瘤坏死。临床前模型表明，在VDA中添加抗vegf抗体可减弱存活肿瘤边缘的血运重建，从而显著增加抗肿瘤活性。实验设计：晚期实体恶性肿瘤患者在第1天、第8天接受45、54或63 mg/m(2)的CA4P治疗，然后每14天一次。贝伐单抗10mg /kg在CA4P后第8天和随后的周期4小时给予。在基线、单独使用CA4P后以及CA4P +贝伐单抗第1周期后，使用动态对比增强mri （DCE-MRI）进行功能成像。结果：总共63 mg/m(2) CA4P + 10 mg/kg贝伐单抗q14是推荐的II期剂量。共有15名患者入组。剂量限制性毒性是III级无症状心房颤动和IV级肝出血，患者有出血史。最常见的毒性是高血压、头痛、淋巴细胞减少、瘙痒和发热。5例患者无症状心电图改变。14例患者中有9例病情稳定。一名卵巢癌患者的CA125反应持续了一年多。DCE-MRI显示肿瘤灌注/血管通透性降低具有统计学意义，单独使用CA4P后逆转，但贝伐单抗后持续。CA4P后，外周血CD34（+）和CD133（+）骨髓祖细胞水平升高，VEGF和粒细胞集落刺激因子水平升高。结论：CA4P联合贝伐单抗在该给药方案中是安全且耐受性良好的。CA4P诱导了深刻的血管变化，这一变化通过贝伐单抗的存在得以维持。临床癌症研究；18日(12);3428 - 39。(c) 2012年aacr。
Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: 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. Clin Cancer Res; 18(12); 3428-39. (C) 2012 AACR.