Eskens Ferry A L M, Steeghs Neeltje, Verweij Jaap, Bloem Johan L, Christensen Olaf, van Doorn Leni, Ouwerkerk Jan, de Jonge Maja J A, Nortier Johan W R, Kraetzschmar Joern, Rajagopalan Prabhu, Gelderblom Hans
Department of Medical Oncology, Erasmus University Medical Center, PO Box 2040, Rotterdam, 3000 CA, the Netherlands.
J Clin Oncol. 2009 Sep 1;27(25):4169-76. doi: 10.1200/JCO.2008.18.8193. Epub 2009 Jul 27.
Telatinib (BAY 57-9352) is an orally available tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -2, VEGFR-3, platelet-derived growth factor receptor-beta, and c-Kit. This phase I dose escalation study was conducted to evaluate the safety and tolerability of telatinib, with additional pharmacokinetic, pharmacodynamic, and efficacy assessments.
Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Doses of continuously administered telatinib were escalated from 20 mg once daily to 1,500 mg twice daily.
Fifty-three patients were enrolled. Most frequently observed drug-related adverse events were nausea (26.4%; grade >or= 3, 0%) and hypertension (20.8%; grade 3, 11.3%; grade 4, 0%). Two dose-limiting toxicities were observed: one poorly controlled hypertension (600 mg twice daily), and one grade 2 weight loss, anorexia, and fatigue (1,500 mg twice daily). A formal maximum-tolerated dose was not reached. Telatinib was rapidly absorbed, with median time to peak concentration (t(max)) lower than 3 hours after dose. A nearly dose-proportional increase in exposure was observed with substantial variability. Telatinib half-life averaged 5.5 hours. Biomarker analyses showed dose-dependent increase in VEGF levels and decrease in plasma soluble VEGFR-2 levels, with a plateau at 900 mg twice daily. A decrease in tumor blood flow (K(trans) and IAUC(60)) was observed with dynamic contrast-enhanced magnetic resonance imaging. Best tumor response was stable disease, observed in 50.9% of patients.
Telatinib was safe and well tolerated up to 1,500 mg twice daily. Based on pharmacodynamic and pharmacokinetic end points, telatinib 900 mg twice daily is the recommended dose for subsequent phase II studies.
特拉替尼（BAY 57-9352）是一种口服有效的酪氨酸激酶抑制剂，可抑制血管内皮生长因子受体（VEGFR）-2、VEGFR-3、血小板衍生生长因子受体-β和c-Kit。本I期剂量递增研究旨在评估特拉替尼的安全性和耐受性，并进行额外的药代动力学、药效学和疗效评估。
纳入对标准治疗难治或无标准治疗可用的实体瘤患者。持续给药的特拉替尼剂量从每日一次20mg递增至每日两次1500mg。
共纳入53例患者。最常观察到的药物相关不良事件为恶心（26.4%；3级及以上，0%）和高血压（20.8%；3级，11.3%；4级，0%）。观察到2例剂量限制性毒性反应：1例高血压控制不佳（每日两次600mg），1例2级体重减轻、厌食和疲劳（每日两次1500mg）。未达到正式的最大耐受剂量。特拉替尼吸收迅速，给药后中位达峰时间（t(max)）低于3小时。观察到暴露量随剂量几乎呈比例增加，但存在较大变异性。特拉替尼半衰期平均为5.5小时。生物标志物分析显示，VEGF水平呈剂量依赖性升高，血浆可溶性VEGFR-2水平降低，每日两次900mg时达到平台期。动态对比增强磁共振成像观察到肿瘤血流（K(trans)和IAUC(60)）降低。最佳肿瘤反应为疾病稳定，见于50.9%的患者。
特拉替尼每日两次1500mg时安全且耐受性良好。基于药效学和药代动力学终点，推荐每日两次900mg的特拉替尼用于后续II期研究。
