Phase II study of the Src kinase inhibitor saracatinib (AZD0530) in metastatic melanoma
Phase II study of the Src kinase inhibitor saracatinib (AZD0530) in metastatic melanoma
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DOI：
10.1007/s10637-012-9897-4
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发表时间：
2013-06-01
影响因子：
3.4
通讯作者：
Gajewski, Thomas F.
中科院分区：
文献类型：
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作者：
Gangadhar, Tara C.;Clark, Joseph I.;Gajewski, Thomas F.
背景Src激酶在黑色素瘤中被激活，抑制Src激酶活性具有临床前抗肿瘤作用。因此，靶向这一途径可能对转移性黑色素瘤患者具有治疗活性。患者和方法我们进行了一项Src激酶抑制剂saracatanib（AZD 0530）治疗转移性黑色素瘤患者的多中心、开放标签研究。23例患者接受了saracatanib，剂量为每日175 mg。主要目的是确定该药物是否对晚期黑色素瘤患者具有临床活性，以及是否增加无进展生存期。还评估了对循环T细胞的功能作用。结果23例患者接受口服saracatanib连续每日给药方案。无客观临床缓解。Saracatanib通常耐受良好，很少有3-4级不良事件。T细胞功能在大多数患者中被抑制，基于治疗后与治疗前样品中超抗原诱导的IL-2产生的减少。结论Saracatanib作为单一药物在晚期黑色素瘤患者中的临床活性最低，本研究缺乏客观反应证明了这一点。在大多数治疗的患者中T细胞细胞因子产生减少表明该药剂具有潜在的免疫抑制活性。
Background Src kinases are activated in melanoma, and inhibition of Src kinase activity has pre-clinical anti-tumor effects. Targeting this pathway could therefore have therapeutic activity in patients with metastatic melanoma. Patients and methods We conducted a multi-center, open-label study of the Src kinase inhibitor saracatanib (AZD0530) in patients with metastatic melanoma. Twenty-three patients received saracatanib at a dose of 175 mg daily. The primary objectives were to determine whether this agent had clinical activity in patients with advanced melanoma and whether it increased progression free survival. Functional effects on circulating T cells were also assessed. Results Twenty-three patients received oral saracatanib on a continuous daily dosing regimen. There were no objective clinical responses. Saracatanib was generally well tolerated with few grade 3-4 adverse events. T cell function was inhibited in most patients, based on decreased superantigen-induced IL-2 production in post- versus pre-treatment samples. Conclusions Saracatanib has minimal clinical activity as a single agent in an unselected population of patients with advanced melanoma, as evidenced by a lack of objective responses in this study. Reduced T cell cytokine production in most treated patients suggests potential immune suppressive activity by this agent.