A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma.
A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma.
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DOI：
10.1007/s10637-014-0083-8
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发表时间：
2014-08
影响因子：
3.4
通讯作者：
Messersmith, Wells
中科院分区：
文献类型：
--
作者：
De Jesus-Acosta, Ana;Laheru, Daniel;Maitra, Anirban;Arcaroli, John;Rudek, Michelle A.;Dasari, Arvind;Blatchford, Patrick J.;Quackenbush, Kevin;Messersmith, Wells
notch通路在胰腺腺癌中过度表达。RO4929097是一种口服γ-分泌酶抑制剂，已被安全用于晚期实体瘤患者的单药治疗。我们旨在评估RO4929097在胰腺腺癌（PDA）患者中的疗效。一项两期，单臂II期试验在先前治疗的转移性PDA患者中进行。RO4929097在21天周期的第1-3天、第8-10天和第15-17天以每天20 mg的剂量给药。主要终点是6个月的生存期。次要终点包括总生存期（OS）、有效率、毒性、药代动力学和药效学分析。18例患者被招募，17例处于第一阶段，1例处于第二阶段。在RO4929097被赞助商终止后，决定停止进一步的入组，不再是开发候选药物。12例可评估患者中有3例（25%）病情稳定。6个月生存率为27.8% （95% CI 9.7-53.5）。中位OS为4.1个月（95% CI 2.7-5.8个月），中位无进展生存期为1.5个月（95% CI 1.3-1.6个月）。RO4929097在PDA患者（n=5）中的药代动力学性质与之前报道的其他患者人群相似。3例患者在给药后HeyL基因表达有降低的趋势（p = 0.08）。RO4929097在既往治疗过的PDA患者中耐受性良好。RO4929097的开发已停止，但其他用于胰腺癌的缺口靶向药物的开发仍在继续。
The notch pathway is overexpressed in pancreatic adenocarcinoma. RO4929097, an oral inhibitor of the γ-secretase enzyme has been safely given as a single agent in patients with advanced solid tumors. We aimed to evaluate the efficacy of RO4929097 in patients with pancreatic adenocarcinoma (PDA). A two-stage, single-arm Phase II trial was conducted in patients with previously treated metastatic PDA. RO4929097 was administered at a dose of 20 mg daily on days 1-3, 8-10 and 15-17 of 21-day cycles. The primary endpoint was survival at 6 months. Secondary endpoints included overall survival (OS), response rate, toxicities, pharmacokinetic and pharmacodynamic analyses. Eighteen patients were recruited, 17 in the first stage and one in the 2nd stage. It was decided to stop further enrollment after RO4929097 was discontinued by the sponsor and was no longer a development candidate. Three (25%) of 12 evaluable patients achieved stable disease. The six-month survival rate was 27.8% (95 % CI 9.7–53.5). The median OS was 4.1 months (95 % CI 2.7–5.8 months) and median progression-free survival was 1.5 months (95 % CI 1.3–1.6 months). Pharmacokinetic properties of RO4929097 in patients (n=5) with PDA was similar to that previously reported in other patient populations. There was a trend towards a decrease in HeyL (p = 0.08) gene expression in three patients following study drug administration. RO4929097 was well-tolerated in patients with previously treated PDA. Development of RO4929097 has been discontinued, but development of other notch-targeting agents in pancreatic cancer is continuing.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
11.2
作者：
Wang Z;Li Y;Kong D;Banerjee S;Ahmad A;Azmi AS;Ali S;Abbruzzese JL;Gallick GE;Sarkar FH
通讯作者：
Sarkar FH
影响因子：
3.4
作者：
Richter S;Bedard PL;Chen EX;Clarke BA;Tran B;Hotte SJ;Stathis A;Hirte HW;Razak AR;Reedijk M;Chen Z;Cohen B;Zhang WJ;Wang L;Ivy SP;Moore MJ;Oza AM;Siu LL;McWhirter E
通讯作者：
McWhirter E
DOI：
10.1158/1078-0432.ccr-08-2004
发表时间：
2009-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Mullendore ME;Koorstra JB;Li YM;Offerhaus GJ;Fan X;Henderson CM;Matsui W;Eberhart CG;Maitra A;Feldmann G
通讯作者：
Feldmann G
DOI：
10.4161/cc.8.12.8744
发表时间：
2009-06-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
De La O JP;Murtaugh LC
通讯作者：
Murtaugh LC