The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2–3 days post-crolibulin (13–24 mg/m²). ADC maps were computed from DW-MRI. Pre-contrast T₁ maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC_90s) and the Extended Tofts Model parameters k^trans, v_e, and v_p were calculated. There was a strong correlation between higher plasma drug \({C}^{max}\) and a linear combination of (1) reduction in tumor fraction with \({AUC}_{90s}>15.8\) mM s, and, (2) increase in tumor fraction with \({v}_{e}<0.3\). A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with \({\text{ADC}} < 1.1 \times 10^{ - 3} \;{\text{mm}}^{2} /{\text{s}}\), and, (2) increase in tumor fraction with \(v_{e}<0.3\). These findings are suggestive of cell swelling and decreased tumor perfusion 2–3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.

血管破坏剂克罗布林与秋水仙碱结合位点结合并产生抗血管和细胞凋亡作用。在克罗布林的多中心 1 期临床研究 (NCT00423410) 中，我们使用动态对比增强 MRI (DCE-MRI) 和弥散加权 MRI (DW-MRI)测量了治疗引起的肿瘤灌注和水扩散率 ( ADC ) 的变化，并计算出克罗布林药代动力学的相关性。11 名患有晚期实体瘤的受试者在基线和使用克罗布林 (13-24 mg/m ² )后 2-3 天通过 MRI 成像。ADC图是根据 DW-MRI 计算的。造影前Ť _1对地图进行了计算，与DCE-MRI系列共同配准的，和下面积的钆浓度曲线-AT-90秒的AUC映射（₉₀) 和扩展 Tofts 模型参数k ^trans、v _e和v _p被计算出来。较高血浆药物\({C}^{max}\)与 (1) 肿瘤分数减少与\({AUC}_{90s}>15.8\)  mM s的线性组合之间存在强相关性，并且, (2) 肿瘤分数增加\({v}_{e}<0.3\)。较高的血浆药物 AUC 与 (1) 肿瘤分数增加的线性组合相关，\({\text{ADC}} < 1.1 \times 10^{ - 3} \;{\text{mm}}^{ 2} /{\text{s}}\)，以及 (2) 肿瘤分数增加\(v_{e}<0.3\). 这些发现表明在用克罗布林治疗 2-3 天后细胞肿胀和肿瘤灌注减少。此处报告的多变量线性回归模型可以为克利布林联合细胞毒性或免疫肿瘤药物的未来临床研究中的克利布林剂量提供信息。