Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials
Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials
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DOI：
10.1093/annonc/mdi118
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发表时间：
2005-04-01
影响因子：
50.5
通讯作者：
Marmé, D
中科院分区：
文献类型：
--
作者：
Drevs, J;Zirrgiebel, U;Marmé, D
背景资料：评价血管生成和活化的内皮细胞的血浆和血清生物标志物以评估PTK 787/ZK 222584（PTK/ZK）的生物活性，PTK 787/ZK 222584是一种靶向所有已知的血管内皮生长因子（VEGF）受体酪氨酸激酶的新型口服血管生成抑制剂。结直肠癌（CRC）患者（n=63）入组PTK/ZK的两项I/II期剂量递增试验，每28天为一个周期，直至停药。病情稳定>= 2个月的患者被归类为“非进展者”。在基线和每个周期第1、8、15、22和28天给药前评估血管生成的血浆标志物VEGF-A和碱性成纤维细胞生长因子（bFGF）以及活化内皮细胞的血清标志物sTIE-2和sE-选择素，并在第1天和第15天给药后10小时进行额外评估。从基线的百分比变化随后与AUC和C-max的PTK/ZK在第1天，周期1和clinical outcome.Results：血浆VEGF-A和bFGF的剂量依赖性增加，观察在第一个周期的PTK/ZK治疗。血浆VEGF-A变化与AUC和C-max的相关性通过E-max模型表征，表明VEGF-A从基线的变化>= 150%与非进展性疾病相关。结论：PTK/ZK治疗结直肠癌患者，血浆VEGF-A和bFGF的变化反映了PTK/ZK的生物学活性，可能有助于确定最佳剂量并与预后相关。
Background: Plasma and serum biomarkers of angiogenesis and activated endothelial cells were evaluated to assess biological activity of PTK787/ZK 222584 (PTK/ZK), a novel oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases.Patients and methods: Patients with colorectal cancer (CRC) (n=63) were enrolled into two phase I/II dose escalation trials of PTK/ZK in 28-day cycles until discontinuation. Patients with stable disease for >= 2 months were categorized as 'non-progressors'. Plasma markers of angiogenesis, VEGF-A and basic fibroblast growth factor (bFGF), and the serum markers of activated endothelial cells, sTIE-2 and sE-Selectin, were assessed at baseline, and pre-dose on days 1, 8, 15, 22 and 28 of every cycle, with additional assessments 10 h post-dose on days 1 and 15. The percentage change from baseline was subsequently correlated with AUC and C-max of PTK/ZK on day 1, cycle 1 and clinical outcome.Results: A dose-dependent increase in plasma VEGF-A and bFGF was observed in the first cycle of PTK/ZK treatment. The correlation of change in plasma VEGF-A with AUC and C-max was characterized by an E-max model, suggesting that a change of >= 150% from baseline VEGF-A correlated with non-progressive disease. Change from baseline plasma VEGF A within the first cycle of treatment was significantly correlated with clinical outcome by logistic regression analysis (P = 0.027).Conclusions: In patients with CRC treated with PTK/ZK, changes in plasma VEGF-A and bFGF demonstrate biological activity of PTK/ZK, may help to establish optimal dose and correlate with outcome.