Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer.
Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer.
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DOI：
10.1016/j.ygyno.2012.04.006
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发表时间：
2012-07
影响因子：
4.7
通讯作者：
Mills GB
中科院分区：
文献类型：
--
作者：
Fu S;Hennessy BT;Ng CS;Ju Z;Coombes KR;Wolf JK;Sood AK;Levenback CF;Coleman RL;Kavanagh JJ;Gershenson DM;Markman M;Dice K;Howard A;Li J;Li Y;Stemke-Hale K;Dyer M;Atkinson E;Jackson E;Kundra V;Kurzrock R;Bast RC Jr;Mills GB
在逆转紫杉烷耐药和AKT抑制的基础上，我们启动了AKT抑制剂perifosine与多西他赛在紫杉烷和铂耐药或难治性上皮性卵巢癌中的I期试验。病理证实的高级别上皮性卵巢癌患者（紫杉烷耐药，n = 10；紫杉烷难治，n = 11）被纳入研究。采集外周血样本和肿瘤活检，并进行18F-FDG-PET和DCE-MRI扫描进行药效学和影像学研究。患者共接受42个治疗周期。未观察到剂量限制性毒性。中位无进展生存期和总生存期分别为1.9个月和4.5个月。一名PTEN突变患者实现了7.5个月的部分缓解（PR），另一名PIK3CA突变患者病情稳定（SD） 4个月。另外2例无明显PI3K通路畸变的患者实现了SD。2例RAS突变患者进展迅速。磷酸化S6降低与18F-FDG-PET反应相关。患者耐受perifosine 150mg PO每日加多西紫杉醇75mg /m2每4周。在PI3K通路突变的卵巢癌患者中，需要进一步的临床评价perifosine联合多西紫杉醇对生物标志物和疗效的影响。
On the basis of reversal of taxane resistance with AKT inhibition, we initiated a phase I trial of the AKT inhibitor perifosine with docetaxel in taxane and platinum-resistant or refractory epithelial ovarian cancer. Patients with pathologically confirmed high-grade epithelial ovarian cancer (taxane resistant, n = 10; taxane refractory, n = 11) were enrolled. Peripheral blood samples and tumor biopsies were obtained and 18F-FDG-PET and DCE-MRI scans were performed for pharmacodynamic and imaging studies. Patients received a total of 42 treatment cycles. No dose-limiting toxicity was observed. The median progression-free survival and overall survival were 1.9 months and 4.5 months, respectively. One patient with a PTEN mutation achieved a partial remission (PR) for 7.5 months, and another patient with PIK3CA mutation had stable disease (SD) for 4 months. Two other patients without apparent PI3K pathway aberrations achieved SD. Two patients with RAS mutations demonstrated rapid progression. Decreased phosphorylated S6 correlated with 18F-FDG-PET responses. Patients tolerated perifosine 150 mg PO daily plus docetaxel at 75 mg/m2 every 4 weeks. Further clinical evaluation of effects of perifosine with docetaxel on biological markers and efficacy in patients with ovarian cancer with defined PI3K pathway mutational status is warranted.
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DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.5
作者：
Hennessy, Bryan T.;Lu, Yiling;Mills, Gordon B.
通讯作者：
Mills, Gordon B.
影响因子：
3.6
作者：
Argiris, Athanassios;Cohen, Ezra;Vokes, Everett
通讯作者：
Vokes, Everett
影响因子：
3.8
作者：
Leighl, Natasha B.;Dent, Susan;Moor, Malcolm J.
通讯作者：
Moor, Malcolm J.
影响因子：
45.3
作者：
Liu, G;Rugo, HS;Herbst, RS
通讯作者：
Herbst, RS