Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
Clin Cancer Res. 2011 Nov 1;17(21):6914-23. doi: 10.1158/1078-0432.CCR-11-0793. Epub 2011 Aug 10.
A phase I dose-escalating study of pazopanib was conducted to determine the maximum tolerated dose (MTD), pharmacokinetic/pharmacodynamic relationships, and clinical activity in patients with advanced hepatocellular carcinoma (HCC).
Asian patients (N = 28) were dose escalated on pazopanib (200-800 mg) once daily (QD) on 21-day cycles, with MTD as the primary endpoint using a modified 3 + 3 design. Changes in tumor vasculature were evaluated by dynamic contrast-enhanced MRI (DCE-MRI).
Two of five patients at the 800-mg dose level experienced dose-limiting toxicities [grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations and grade 3 malaise]. The MTD in patients with HCC (Child-Pugh class A) was 600 mg QD. Diarrhea, skin hypopigmentation, and AST elevation were the most commonly reported adverse events at the MTD. Mean C(max) and area under the concentration-time curve (AUC(0-6)) of pazopanib and its metabolites did not increase dose proportionally across the 200 to 800 mg range. Reductions in IAUGC and K(trans) were shown at all pazopanib doses evaluated, with the greatest reductions at 600 and 800 mg. Although larger DCE-MRI parameter decreases were associated with larger C(24) and C(max) values, there was no constant relationship between tumor perfusion decreases measured by DCE-MRI and plasma pazopanib pharmacokinetic parameters. Overall, 19 patients (73%) had either partial response or stable disease.
Pazopanib has a manageable safety profile in patients with advanced HCC, and 600 mg was chosen for further development of pazopanib in advanced HCCs. Moreover, pazopanib reduced tumor vessel leakage, as shown by DCE-MRI, indicating a direct effect on HCC vasculature that might be associated with its antitumor activity.
一项帕唑帕尼的 I 期剂量递增研究旨在确定晚期肝细胞癌（HCC）患者的最大耐受剂量（MTD）、药代动力学/药效学关系和临床活性。
亚洲患者（N=28）接受帕唑帕尼（200-800mg）每日一次（QD）21 天周期的剂量递增，MTD 为主要终点，采用改良的 3+3 设计。通过动态对比增强 MRI（DCE-MRI）评估肿瘤血管变化。
在 800mg 剂量水平的 5 名患者中有 2 名发生剂量限制毒性[3 级天冬氨酸氨基转移酶（AST）/丙氨酸氨基转移酶（ALT）升高和 3 级不适]。HCC（Child-Pugh 分级 A）患者的 MTD 为 600mg QD。腹泻、皮肤色素减退和 AST 升高是 MTD 时最常见的不良反应。帕唑帕尼及其代谢物的 Cmax 和 AUC0-6 均值并未随 200-800mg 范围呈剂量比例增加。在评估的所有帕唑帕尼剂量下，IAUGC 和 Ktrans 均降低，在 600 和 800mg 时降低最大。尽管较大的 DCE-MRI 参数降低与较大的 C24 和 Cmax 值相关，但 DCE-MRI 测量的肿瘤灌注减少与血浆帕唑帕尼药代动力学参数之间没有恒定关系。总的来说，19 名患者（73%）有部分缓解或疾病稳定。
帕唑帕尼在晚期 HCC 患者中具有可管理的安全性特征，选择 600mg 用于晚期 HCC 中帕唑帕尼的进一步开发。此外，帕唑帕尼通过 DCE-MRI 降低肿瘤血管漏出，表明其对 HCC 血管有直接作用，可能与其抗肿瘤活性有关。
