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首页 » BIOON报道 » Clin Cancer Res:达沙替尼与其他药物合用治疗晚期复发性卵巢癌

Clin Cancer Res:达沙替尼与其他药物合用治疗晚期复发性卵巢癌

来源:生物谷 2012-11-28 11:37

2012年11月27日 讯 /生物谷BIOON/ --Moffitt癌症中心和杜克大学医学中心研究人员进行完成的I期临床试验,当口服Src家族酪氨酸激酶抑制剂达沙替尼结合紫杉醇和卡铂治疗晚期或复发性卵巢癌患者时,达沙替尼的最大耐受剂量。他们发现与其他两个药物的组合治疗患者,每天达沙替尼150毫克的量是最佳的。

这项研究发表在10月的Clinical Cancer Research杂志上。达沙替尼有治疗晚期卵巢癌的潜力,因为SRC途径在增加细胞的迁移,增殖,存活,侵袭和血管生成中发挥了重要作用。SRC途径已被发现在固体肿瘤中是经常失调的,SRC的存在会增加化疗难度。

以前的实验室研究表明SRC抑制后能增强紫杉醇​​+顺铂对卵巢癌细胞系的细胞毒性。体内研究发现SRC抑制后导致肿瘤的生长减少。

这是首次有研究确定结合紫杉醇和卡铂的达沙替尼的合适剂量,可向前推动进入II期或III期临床研究。这些试验可以更好地帮助我们了解患者对药物结合治疗的耐受性。

研究发现,达沙替尼与紫杉醇两种药物并不会相互影响各自功效,使用达沙替尼与化疗药物相结合可以更好地产生协同效应。
 
研究人员得出结论:寻找生物标志物来指导使用有针对性的治疗是极为重要的。虽然SRC基因的表达不响应治疗,但研究小组发现了几个差异表达的基因与患者对治疗的反应和病情进展有关。不幸的是,这些生物标志物一直无法被识别证明哪些妇女是最有可能受益于达沙替尼治疗的,所以应进一步研究探索相关的生物标记,确定最有可能受益于达沙替尼的患者人群。(生物谷:Bioon.com)

A Phase I Trial of Dasatinib, an Src-Family Kinase Inhibitor, in Combination with Paclitaxel and Carboplatin in Patients with Advanced or Recurrent Ovarian Cancer.

A. A. Secord, D. K. Teoh, W. T. Barry, M. Yu, G. Broadwater, L. J. Havrilesky, P. S. Lee, A. Berchuck, J. Lancaster, R. M. Wenham.

Purpose: We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in the treatment of advanced and recurrent epithelial ovarian cancer.

Experimental Design: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics, and pharmacodynamics. Using a “3+3” design, cohorts of three to six patients received paclitaxel (175 mg/m2) and carboplatin (AUC 6) every 3 weeks with escalating doses of dasatinib (100, 120, and 150 mg daily), followed by an eight-patient expansion cohort.

Results: Twenty patients were enrolled between June 2007 and December 2009. The median age was 61 years (range: 42–82) with a median of 2 prior regimens (range: 0–6), and 71% had platinum-sensitive disease. There were three to six patients in each cohort, and eight in the expansion cohort. Pharmacokinetics were observed over the first two cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3–4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3–4), and fatigue (10% grade 3). The RR was 40% [three complete responses, (15%); five partial responses, (25%)],10 patients (50%) had stable disease, and two were not evaluable. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively.

Conclusions: Due to the high incidence of myelosuppression with subsequent cycles, the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity

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