Lockhart Albert Craig, Cropp Gillian F, Berlin Jordan D, Donnelly Edwin, Schumaker Robert D, Schaaf Larry J, Hande Kenneth R, Fleischer Arthur C, Hannah Alison L, Rothenberg Mace L
Vanderbilt University Medical Center, Nashville, TN, USA.
Am J Clin Oncol. 2006 Apr;29(2):109-15. doi: 10.1097/01.coc.0000199882.53545.ac.
Determine the toxicity, tolerability, and pharmacokinetics of SU5416, a vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, coadministered with bolus 5-fluorouracil (5-FU), leucovorin, and irinotecan (IFL) in untreated patients with metastatic colorectal cancer.
SU5416 (85 or 145 mg/m2) was administered twice weekly throughout a 6-week period along with standard IFL (4 weeks on/2 weeks off). Plasma samples were assayed for SU5416, irinotecan, and SN-38 by reverse-phase HPLC. Contrast enhanced, color Doppler sonography was performed on patients at the MTD to identify changes in tumor perfusion.
Eleven patients received treatment with SU5416 85 mg/m2 (n = 5) or 145 mg/m2 (n = 6). At 85 mg/m2, no DLTs were observed. At 145 mg/m2, grade 3 diarrhea and vomiting were observed during cycle 1; other grade 3 toxicities included fatigue, nausea, anorexia, anemia, pain, urinary retention, and hypertension. The pharmacokinetics of irinotecan and SN-38 were not altered by coadministration of SU5416. SU5416 pharmacokinetics were not altered by IFL. Contrast-enhanced, color Doppler sonography was performed on 2 patients and demonstrated reduced tumor perfusion after treatment in a patient who responded to treatment and increased perfusion in a patient who developed progressive disease. Three patients (27%) had confirmed partial responses, 2 patients (18%) had unconfirmed partial responses, and 4 patients (36%) had stable disease.
Twice weekly SU5416 can be administered with bolus IFL without unexpected toxicities or altering the pharmacokinetic behavior of the administered drugs. Changes in tumor blood perfusion can be detected by contrast-enhanced, color Doppler sonography. The further development of SU5416 was halted before this study was completed.
确定血管内皮生长因子受体-2（VEGFR-2）酪氨酸激酶抑制剂SU5416与大剂量5-氟尿嘧啶（5-FU）、亚叶酸钙和伊立替康（IFL）联合应用于未经治疗的转移性结直肠癌患者时的毒性、耐受性和药代动力学。
在为期6周的时间内，每周两次给予SU5416（85或145mg/m²），同时给予标准的IFL方案（4周用药/2周停药）。通过反相高效液相色谱法测定血浆样本中的SU5416、伊立替康和SN-38。在最大耐受剂量（MTD）对患者进行对比增强彩色多普勒超声检查，以确定肿瘤灌注的变化。
11例患者接受了SU5416 85mg/m²（n = 5）或145mg/m²（n = 6）的治疗。在85mg/m²剂量时，未观察到剂量限制性毒性（DLT）。在145mg/m²剂量时，第1周期出现3级腹泻和呕吐；其他3级毒性包括疲劳、恶心、厌食、贫血、疼痛、尿潴留和高血压。SU5416的联合应用未改变伊立替康和SN-38的药代动力学。IFL的应用也未改变SU5416的药代动力学。对2例患者进行了对比增强彩色多普勒超声检查，其中1例治疗有反应的患者治疗后肿瘤灌注减少，1例病情进展的患者灌注增加。3例患者（27%）确认部分缓解，2例患者（18%）未确认部分缓解，4例患者（36%）病情稳定。
每周两次给予SU5416与大剂量IFL联合应用时，不会出现意外毒性，也不会改变所用药物的药代动力学行为。对比增强彩色多普勒超声检查可检测到肿瘤血流灌注的变化。在本研究完成之前，SU5416的进一步研发已停止。
