Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer
Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer
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DOI：
10.1200/jco.2014.55.7504
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发表时间：
2015-05-01
影响因子：
45.3
通讯作者：
Ryan, David P.
中科院分区：
文献类型：
--
作者：
Borad, Mitesh J.;Reddy, Shantan G.;Ryan, David P.
目的TH-302是一种缺氧激活的前药，在缺氧环境中释放DNA烷基化剂溴异磷酰胺氮芥。此项II期研究（NCT 01144455）评估了吉西他滨加TH-302在先前未经治疗的局部晚期或转移性胰腺癌患者中的应用。1至吉西他滨（1，000 mg/m2）、吉西他滨加TH-302 240 mg/m2（G + T240）或吉西他滨加TH-302 340 mg/m2（G + T340）。允许在吉西他滨治疗进展后进行随机交叉。主要终点是无进展生存期（PFS）。次要终点包括总生存期（OS），肿瘤反应，CA 19-9反应，和safety.Results214例（77%的转移性疾病）在2010年6月和2011年7月之间入组。与吉西他滨单药治疗相比，吉西他滨+TH-302（汇总组合组）的PFS显著更长（中位PFS分别为5.6 vs 3.6个月;风险比为0.61; 95%CI为0.43至0.87; P = 0.005;转移性疾病的中位PFS分别为5.1 vs 3.4个月）。G + T240和G + T340的中位PFS时间分别为5.6和6.0个月。吉西他滨、G + T240和G + T340组的肿瘤缓解率分别为12%、17%和26%（G + T340 vs吉西他滨，P = .04）。与吉西他滨相比，G + T340的CA 19-9降低更大（分别为-5，398 v -549 U/mL; P = .008）。吉西他滨、G + T240和G + T340的中位OS时间分别为6.9、8.7和9.2个月（P =不显著）。最常见的不良事件（AE）为疲乏、恶心和外周水肿（两组之间的频率相似）。皮肤和粘膜毒性（2% 3级）和骨髓抑制（55% 3级或4级）是最常见的TH-302相关的AE，但与治疗contracting.ConclusionPFS，肿瘤反应，CA 19-9反应显着改善与G + TH-302。G + T340正在III期MAESTRO研究（NCT 01746979）中进一步研究。(C)2014年美国临床肿瘤学会
PurposeTH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer.Patients and MethodsPatients were randomly assigned 1: 1: 1 to gemcitabine (1,000 mg/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G + T240), or gemcitabine plus TH-302 340 mg/m(2) (G + T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety.ResultsTwo hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G + T240 and G + T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G + T240, and G + T340 arms, respectively (G + T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G + T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G + T240, and G + T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation.ConclusionPFS, tumor response, and CA 19-9 response were significantly improved with G + TH-302. G + T340 is being investigated further in the phase III MAESTRO study (NCT01746979). (C) 2014 by American Society of Clinical Oncology