Borad Mitesh J, Reddy Shantan G, Bahary Nathan, Uronis Hope E, Sigal Darren, Cohn Allen L, Schelman William R, Stephenson Joe, Chiorean E Gabriela, Rosen Peter J, Ulrich Brian, Dragovich Tomislav, Del Prete Salvatore A, Rarick Mark, Eng Clarence, Kroll Stew, Ryan David P
Mitesh J. Borad, Mayo Clinic, Scottsdale; Tomislav Dragovich, Arizona Cancer Center, Tucson, AZ; Shantan G. Reddy, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA; Nathan Bahary, University of Pittsburgh Medical Center, Pittsburgh, PA; Hope E. Uronis, Duke University Medical Center, Durham, NC; Darren Sigal, Scripps Clinic, La Jolla; Peter J. Rosen, Disney Family Cancer Center, Burbank; Clarence Eng and Stew Kroll, Threshold Pharmaceuticals, South San Francisco, CA; Allen L. Cohn, Rocky Mountain Cancer Center, Denver, CO; William R. Schelman, University of Wisconsin Carbone Cancer Center, Madison, WI; Joe Stephenson Jr, Institute for Translational Oncology Research, Greenville, SC; E. Gabriela Chiorean, Indiana University Simon Cancer Center, Indianapolis, IN; Brian Ulrich, Texas Oncology, Wichita Falls, TX; Salvatore A. Del Prete, Hematology Oncology PC, Stamford, CT; Mark Rarick, Kaiser Permanente Northwest Region Oncology Hematology, Portland, OR; and David P. Ryan, Massachusetts General Hospital Cancer Center, Boston, MA.
J Clin Oncol. 2015 May 1;33(13):1475-81. doi: 10.1200/JCO.2014.55.7504. Epub 2014 Dec 15.
TH-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 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.
Two 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.
PFS, 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).
TH-302是一种研究性的低氧激活前体药物，在低氧环境下可释放DNA烷化剂溴异磷酰胺氮芥。这项II期研究（NCT01144455）评估了吉西他滨联合TH-302用于先前未接受过治疗的局部晚期或转移性胰腺癌患者的疗效。
患者按1:1:1随机分配至吉西他滨组（1000mg/m²）、吉西他滨联合240mg/m² TH-302组（G+T240）或吉西他滨联合340mg/m² TH-302组（G+T340）。允许在吉西他滨治疗进展后进行随机交叉治疗。主要终点为无进展生存期（PFS）。次要终点包括总生存期（OS）、肿瘤反应、CA 19-9反应及安全性。
2010年6月至2011年7月共纳入214例患者（77%为转移性疾病）。与单用吉西他滨相比，吉西他滨联合TH-302（联合治疗组）的PFS显著延长（PFS中位数分别为5.6个月和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PFS中位数分别为5.1个月和3.4个月）。G+T240组和G+T340组的PFS中位数分别为5.6个月和6.0个月。吉西他滨组、G+T240组和G+T340组的肿瘤反应率分别为12%、17%和26%（G+T340组与吉西他滨组相比，P = 0.04）。G+T340组CA 19-9的下降幅度大于吉西他滨组（分别为-5398 U/mL和-549 U/mL；P = 0.008）。吉西他滨组、G+T240组和G+T340组的OS中位数分别为6.9个月、8.7个月和9.2个月（P无统计学意义）。最常见的不良事件（AE）为疲劳、恶心和外周水肿（各组发生率相似）。皮肤和黏膜毒性（2%为3级）及骨髓抑制（55%为3级或4级）是最常见的与TH-302相关的AE，但与治疗中断无关。
G+TH-302显著改善了PFS、肿瘤反应及CA 19-9反应。G+T340正在III期MAESTRO研究（NCT01746979）中进一步研究。
