Phase I study of telatinib (BAY 57-9352): analysis of safety, pharmacokinetics, tumor efficacy, and biomarkers in patients with colorectal cancer.
Phase I study of telatinib (BAY 57-9352): analysis of safety, pharmacokinetics, tumor efficacy, and biomarkers in patients with colorectal cancer.
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DOI：
10.1186/2045-824x-3-16
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发表时间：
2011-07-29
期刊：
影响因子：
--
通讯作者：
Christensen O
中科院分区：
文献类型：
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作者：
Mross K;Frost A;Scheulen ME;Krauss J;Strumberg D;Schultheiss B;Fasol U;Büchert M;Krätzschmer J;Delesen H;Rajagopalan P;Christensen O
Telatinib （BAY 57-9352）是一种口服小分子血管内皮生长因子受体2和3 （VEGFR-2/-3）和血小板源性生长因子受体β酪氨酸激酶抑制剂。在这项包括II期扩展部分的多中心I期剂量递增研究中，39例难治性结直肠癌（CRC）患者被纳入14天开/ 7天停的28天重复周期（n = 11）或连续给药组（n = 28），接受≥600mg telatinib每日两次（bid）。高血压（28%）和腹泻（15%）是CTC 3级患者中最常见的药物相关不良事件。在该人群中，在600 ~ 1500 mg剂量范围内，特拉替尼剂量与个体Cmax和AUC之间没有明显的关系。根据RECIST没有达到部分缓解，但41%的患者在治疗期间达到了一定的肿瘤缩小。动态对比增强磁共振成像测量的肿瘤血流量和sVEGFR-2血浆水平随着替拉替尼AUC的增加而下降（0-12）。特拉替尼治疗耐受性良好。在重度预处理的结直肠癌患者中观察到的单药抗肿瘤活性是有限的。药效学结果提示了替拉替尼的生物活性，证明了进一步评估替拉替尼与标准化疗方案联合用于结直肠癌患者的可行性。
Telatinib (BAY 57-9352) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor β tyrosine kinases. In this multicenter phase I dose-escalation study including a phase II like expansion part, 39 patients with refractory colorectal cancer (CRC) were enrolled into 14 days on / 7 days off in repeating cycles of 28 days (n = 11) or continuous dosing groups (n = 28) to receive ≥ 600 mg telatinib twice-daily (bid). Hypertension (28%) and diarrhoea (15%) were the most frequent study drug-related adverse events of CTC grade 3. In this population, no clear relationship between telatinib dose and individual Cmax and AUC was apparent in the 600 mg bid to 1500 mg bid dose range. No partial remission according to RECIST was reached, but 41% of the patients reached some tumour shrinkage during treatment. Tumour blood flow measured by dynamic contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing telatinib AUC(0-12). Telatinib treatment was well tolerated. The observed single agent antitumor activity in heavily pretreated CRC patients was limited. Pharmacodynamic results are suggestive for the biological activity of telatinib justifying a further evaluation of telatinib bid in combination with standard chemotherapy regimens in CRC patients.