A phase 2 trial of dasatinib in advanced melanoma.
A phase 2 trial of dasatinib in advanced melanoma.
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DOI：
10.1002/cncr.25766
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发表时间：
2011-05-15
期刊：
影响因子：
6.2
通讯作者：
Sznol, Mario
中科院分区：
文献类型：
--
作者：
Kluger, Harriet M.;Dudek, Arkadiuz Z.;McCann, Carrie;Ritacco, Jean;Southard, Nadine;Jilaveanu, Lucia B.;Molinaro, Annette;Sznol, Mario
抑制Src激酶（非受体酪氨酸激酶信号传导中间体）可减少黑素瘤细胞增殖和侵袭。达沙替尼抑制c-kit、PDGFβR和EPHA 2以及src激酶c-Src、c-Yes、Lck和Fyn。我们进行了一项达沙替尼治疗黑色素瘤的2期试验，以评估缓解率（RR）、无进展生存期（PFS）和毒性。患有III/IV期未经化疗的不可切除黑色素瘤的成人符合条件。达沙替尼最初以100 mg PO BID连续给予17例患者。由于毒性，起始剂量降至70 mg BID。每8周进行一次肿瘤评估。39例患者入组，36例可评价活性和毒性。5例、4例和3例有肢端雀斑样痣、眼或粘膜原发痣。2例证实部分缓解，持续64周和24周; RR-5%。三个有轻微的反应，持续136，64和28周，一个谁是响应停止由于不遵守。中位PFS为8周; 6个月PFS率为-13%。一名携带13号外显子c-kit突变的患者出现部分缓解，而另一名携带11号外显子c-kit突变的患者病情进展。常见毒副反应为乏力、呼吸困难和胸腔积液。每日达沙替尼对黑色素瘤患者（不包括c-kit突变患者）的活性最低。该研究未达到30%缓解率或6个月PFS的预定终点。达沙替尼总体耐受性较差，通常需要减量或中断给药。由于在没有c-kit突变的小子集中观察到活性，因此确定预测性生物标志物对于将来单独或联合试验中开发达沙替尼治疗黑色素瘤非常重要。
Inhibiting Src kinases (non-receptor tyrosine kinase signaling intermediates) reduces melanoma cell proliferation and invasion. Dasatinib inhibits c-kit, PDGFβR and EPHA2 and src kinases c-Src, c-Yes, Lck and Fyn. We conducted a phase 2 trial of dasatinib in melanoma to assess response rate (RR), progression-free survival (PFS) and toxicity. Adults with stage III/IV chemotherapy-naive unresectable melanoma, were eligible. Dasatinib was initially administered at 100mg PO BID continuously to 17 patients. Due to toxicity, the starting dose was decreased to 70mg BID. Tumor assessments occurred every 8 weeks. Thirty nine patients were enrolled, 36 evaluable for activity and toxicity. Five, four and three had acral-lentiginous, ocular or mucosal primaries. Two had confirmed partial responses lasting 64 and 24 weeks; RR-5%. Three had minor responses lasting 136, 64 and 28 weeks, and one who was responding discontinued due to non-compliance. Median PFS was eight weeks; 6-month PFS rate −13 %. One patient with an exon-13 c-kit mutation had a partial response, while disease in another with an exon-11 c-kit mutation progressed. Common toxicities were fatigue, dyspnea and pleural effusions. Daily dasatinib has minimal activity in unselected melanoma patients, excluding those with c-kit mutations. The study did not meet the pre-specified endpoints of 30% response rate or six-month PFS. Dasatinib was overall poorly tolerated, often requiring dose reduction or interruption. Because activity was observed in a small subset without c-kit mutations, identifying predictive biomarkers is important for future development of dasatinib in melanoma alone or in combination trials.
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影响因子：
8.8
作者：
通讯作者：
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影响因子：
6.2
作者：
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通讯作者：
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DOI：
10.1158/1541-7786.mcr-08-0169
发表时间：
2008-11
期刊：
Molecular cancer research : MCR
影响因子：
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作者：
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通讯作者：
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作者：
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影响因子：
7.3
作者：
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