Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas
Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas
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DOI：
10.1158/1078-0432.ccr-04-0157
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发表时间：
2004-09-01
影响因子：
11.5
通讯作者：
Demetri, GD
中科院分区：
文献类型：
--
作者：
Heymach, JV;Desai, J;Demetri, GD
目的：SU5416 （semaxanib）是血管内皮生长因子（VEGF）受体-2和KIT受体酪氨酸激酶的小分子抑制剂。这项H期研究旨在研究SU5416对软组织肉瘤患者的安全性和有效性。实验设计：13例局部晚期或转移性软组织肉瘤患者通过静脉滴注剂量为145 mg/m(2)的SU5416治疗，每周两次。选定病例在治疗前后2个月分别行肿瘤活检。结果：中位无进展生存期为1.8个月。中位总生存期为22.8个月。未观察到客观的肿瘤反应。有证据表明，基线尿VEGF水平高的患者生存期较短（P = 0.04）。未观察到4级毒性。最常见的3级毒性是头痛和血栓形成。其他不太严重的毒性包括疲劳、恶心和腹痛。治疗1个月后，中位收缩压从基线时的118 mmHg上升到133 mmHg （P = 0.01）。治疗后肿瘤活检显示，与基线相比，3例可评估患者的VEGF受体磷酸化水平没有显著降低。一名胃肠道间质瘤患者在SU5416治疗期间进展迅速，随后接受另一种KIT抑制剂甲磺酸伊马替尼治疗，部分缓解持续了36个月。结论：SU5416耐受性相对较好，但对晚期软组织肉瘤没有明显的抗肿瘤活性。相关研究表明，至少在某些情况下，VEGF受体或KIT抑制是不完全的，这可能解释了所观察到的活性缺乏。
Purpose: SU5416 (semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor (VEGF) receptor-2 and KIT receptor tyrosine kinases. This Phase H study was conducted to investigate the safety and efficacy of SU5416 for patients with soft tissue sarcomas.Experimental Design: Thirteen patients with locally advanced or metastatic soft tissue sarcomas were treated with SU5416 via intravenous infusion at a dose of 145 mg/m(2) twice weekly. In selected cases tumor biopsies were taken before and after 2 months of treatment.Results: The median progression-free survival was 1.8 months. Median overall survival was 22.8 months. No objective tumor responses were observed. There was evidence of shorter survival among patients with high baseline urine VEGF levels (P = 0.04). No grade 4 toxicities were observed. The most common grade 3 toxicities were headache and thrombosis. Other less serious toxicities included fatigue, nausea, and abdominal pain. The median systolic blood pressure increased from 118 mmHg at baseline to 133 after 1 month of treatment (P = 0.01). Post-treatment tumor biopsies showed no significant decreases in VEGF receptor phosphorylation compared with baseline in 3 evaluable patients. One patient with gastrointestinal stromal tumor who had rapid progression during SU5416 treatment was subsequently treated with another KIT inhibitor, imatinib mesylate, and had a partial response lasting >36 months.Conclusions: SU5416 was relatively well tolerated but did not demonstrate significant antitumor activity against advanced soft tissue sarcoma. Correlative studies suggest that VEGF receptor or KIT inhibition was incomplete in at least some cases, providing a possible explanation for the observed lack of activity.