A Gynecologic Oncology Group phase II trial of the protein kinase C-beta inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies.
A Gynecologic Oncology Group phase II trial of the protein kinase C-beta inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies.
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妇科肿瘤学组对蛋白激酶 C-β 抑制剂 enzastaurin 进行的 II 期试验，以及对持续性或复发性上皮性卵巢和原发性腹膜恶性肿瘤具有潜在预测和预后价值的标志物的评估。
DOI：
10.1016/j.ygyno.2011.02.013
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发表时间：
2011-06-01
影响因子：
4.7
通讯作者：
Godwin AK
中科院分区：
文献类型：
--
作者：
Usha L;Sill MW;Darcy KM;Benbrook DM;Hurteau JA;Michelin DP;Mannel RS;Hanjani P;De Geest K;Godwin AK
蛋白激酶C （PKC）的激活有助于卵巢上皮性癌或原发性腹膜癌（EOC/PPC）的增殖和血管生成。一项多机构II期试验旨在评估PKCβ抑制剂enzastaurin治疗持续性或复发性EOC/PPC的有效性和安全性，并探索潜在的预后和预测性生物标志物。具有可测量的铂敏感和耐药EOC/PPC的符合条件的妇女持续口服enzastaurin治疗，直到疾病进展或不可接受的毒性。采用两阶段序贯设计来评估≥6个月的无进展生存期（PFS）、肿瘤反应和毒性。转化研究包括TP53、PTEN、PIK3CA和pkc - β ii基因的体细胞突变测序，AKT2和PTEN拷贝数改变的定量PCR检测，以及循环VEGF-A血浆水平的测量。在27名符合条件和可评估的患者中，观察到3名PFS≥6个月的女性（11%）和2名部分缓解的女性（7%）。其中一种获得了持久的反应，并仍在研究中。未观察到4级不良事件。最常见的3级不良事件是体质(4)和胃肠道(3)。TP53基因突变和PTEN基因拷贝数异常是常见的（分别占56%和48%）。Enzastaurin是可以忍受的，但没有足够的活性进行第二阶段的积累。然而，1例患者无进展达44个月。生物标志物和对enzastaurin的反应之间没有关联。探索性分析表明，生存与PTEN拷贝数损失之间存在关联。
Protein kinase C (PKC) activation contributes to proliferation and angiogenesis in epithelial ovarian or primary peritoneal carcinoma (EOC/PPC). A multi-institutional phase II trial was conducted to evaluate the efficacy and safety of PKCβ inhibitor enzastaurin in persistent or recurrent EOC/PPC and to explore potential prognostic and predictive biomarkers. Eligible women with measurable platinum-sensitive and resistant EOC/PPC were treated with continuous administration of oral enzastaurin until disease progression or unacceptable toxicity. A two-stage sequential design was used to evaluate progression-free survival (PFS) ≥ 6-months, tumor response, and toxicity. Translational studies included sequencing of the TP53, PTEN, PIK3CA and PKCβII genes for somatic mutations, quantitative PCR assays for AKT2 and PTEN copy number alterations, and measurement of circulating VEGF-A plasma levels. Among 27 eligible and evaluable patients, 3 women with PFS ≥ 6-months (11%) and 2 women with partial responses (7%) were observed. One of them achieved a durable response and remains on the study. No grade 4 adverse events were observed. Most common grade 3 adverse events were constitutional (4) and gastrointestinal (3). Mutations in the TP53 gene and abnormal copy number in the PTEN gene were common (56% and 48% of cases, respectively). Enzastaurin was tolerable but had insufficient activity to proceed with the second stage of accrual. However, 1 patient has been progression-free for 44 months. No association between a biomarker and response to enzastaurin has been found. Exploratory analysis suggested an association between survival and PTEN copy number losses.
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影响因子：
4.7
作者：
Hoffman, MA;Blessing, JA;Morgan, M
通讯作者：
Morgan, M
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
11.2
作者：
Graff, JR;McNulty, AM;Thornton, D
通讯作者：
Thornton, D
影响因子：
4.7
作者：
Hoffman, MA;Blessing, JA;Nuñez, ER
通讯作者：
Nuñez, ER
影响因子：
45.3
作者：
Fracasso, PM;Blessing, JA;Hoffman, JS
通讯作者：
Hoffman, JS