A phase II, pharmacokinetic, and biologic study of semaxanib and thalidomide in patients with metastatic melanoma.
A phase II, pharmacokinetic, and biologic study of semaxanib and thalidomide in patients with metastatic melanoma.
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Semaxanib 和沙利度胺治疗转移性黑色素瘤患者的 II 期药代动力学和生物学研究。
DOI：
10.1007/s00280-006-0255-0
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发表时间：
2007
影响因子：
3
通讯作者：
Patnaik,A
中科院分区：
文献类型：
--
作者：
Mita,MonicaM;Rowinsky,EricK;Forero,Leonardo;Eckhart,SGail;Izbicka,Elzbieta;Weiss,GeoffreyR;Beeram,Muralidhar;Mita,AlainC;deBono,JohannS;Tolcher,AnthonyW;Hammond,LisaA;Simmons,Paul;Berg,Kristin;Takimoto,Chris;Patnaik,A
目的：本II期研究评价血管内皮生长因子受体2小分子酪氨酸激酶抑制剂赛马昔布和沙利度胺联合治疗转移性黑色素瘤的疗效、耐受性、药代动力学(PK)和药效学(PD)特征。患者和方法：对既往至少一种生物和/或化疗方案失败的转移性黑色素瘤患者，采用递增剂量的沙利度胺联合固定剂量的沙利度胺治疗。结果：12例患者接受沙利度胺145 mg/m2的固定剂量每周2次静脉注射治疗44个疗程从每天200毫克开始，患者内部剂量递增是可以容忍的。在第一个疗程中，赛马西尼在沙利度胺之前1天开始治疗，允许单独评估赛马西尼的PKS(疗程1)和与沙利度胺联合治疗(疗程2)。主要毒副反应包括深静脉血栓形成、头痛和下肢浮肿。10例可评价疗效的患者中，1例完全缓解20个月，1例部分缓解12个月。此外，4名患者病情稳定，持续时间为2至10个月。Semaxanib的pKs的特征是药物暴露参数与单药II期研究中观察到的参数相当，表明没有主要的药物-药物相互作用。赛马昔布的最大血药浓度在第1疗程为1.2~3.8万μg/ml，在第2疗程为1.1~3.9万μg/ml，平均半衰期为1.3h(±0.31)h。生物学研究显示，治疗4个月以上的转移性黑色素瘤患者的血清VEGF值升高。结论：赛马昔布联合沙利度胺治疗转移性黑色素瘤疗效确切。在晚期黑色素瘤和其他恶性肿瘤患者中，可能需要进一步评估针对多条血管生成途径的治疗策略。
Purpose: This phase II study evaluated the combination of semaxanib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2, and thalidomide in patients with metastatic melanoma to assess the efficacy, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the combination.Patients and methods: Patients with metastatic melanoma, who had failed at least one prior biologic and/or chemotherapeutic regimen, were treated with escalating doses of thalidomide combined with a fixed dose of semaxanib.Results: Twelve patients were enrolled and received 44 courses of semaxanib at the fixed dose of 145 mg/m2intravenously twice-weekly in combination with thalidomide, commencing at 200 mg daily with intrapatient dose escalation as tolerated. Treatment with semaxanib was initiated 1 day before thalidomide in the first course, permitting the assessment of the PKs of semaxanib alone (course 1) and in combination with thalidomide (course 2). The principal toxicities included deep venous thrombosis, headache, and lower extremity edema. Of ten patients evaluable for response, one complete response lasting 20 months and one partial response lasting 12 months were observed. Additionally, four patients had stable disease lasting from 2 to 10 months. The PKs of semaxanib were characterized by drug exposure parameters comparable to those observed in single-agent phase II studies, indicating the absence of major drug–drug interactions. Maximum semaximib plasma concentration values were 1.2–3.8 μg/ml in course 1 and 1.1–3.9 μg/ml in course 2. The mean terminal half-life was 1.3 ( ± 0.31) h. Biological studies revealed increasing serum VEGF concentrations following treatment in patients remaining on study for more than 4 months.Conclusion: The combination of semaxanib and thalidomide was feasible and demonstrated anti-tumor activity in patients with metastatic melanoma who had failed prior therapy. Further evaluations of therapeutic strategies that target multiple angiogenesis pathways may be warranted in patients with advanced melanoma and other malignancies.