Uwagawa T, Misawa T, Sakamoto T, Ito R, Gocho T, Shiba H, Wakiyama S, Hirohara S, Sadaoka S, Yanaga K
Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
Ann Oncol. 2009 Feb;20(2):239-43. doi: 10.1093/annonc/mdn640. Epub 2008 Oct 3.
The primary end points of this study were to determine the dose-limiting toxic effects (DLTs), maximum tolerated dose, and a recommended phase II dose of a synthetic serine protease inhibitor, nafamostat mesilate, in combination with full-dose gemcitabine in patients with unresectable locally advanced or metastatic pancreatic cancer. The secondary end point was to assess therapeutic response.
Patients with previously untreated pancreatic cancer received gemcitabine (1 000 mg/m(2) i.v. for 30 min) on days 1, 8, and 15, with nafamostat mesilate (continuous regional arterial infusion for 24 h through a port-catheter system) on days 1, 8, and 15; this regimen was repeated at 28-day intervals. The initial dose of nafamostat mesilate was 2.4 mg/kg and was escalated in increments of 1.2 mg/kg until a dose of 4.8 mg/kg was achieved. A standard '3+3' phase I dose-escalation design was used. Therapeutic response and clinical benefit response were assessed.
Twelve patients were enrolled in this study. None of the patients experienced DLTs, and nafamostat mesilate was well tolerated at doses up to 4.8 mg/kg in combination with full-dose gemcitabine. This combination chemotherapy yielded a reduction of a high serum level of the tumor marker CA19-9. Pain was reduced in three of seven patients without oral morphine sulfate. Overall survival was 7.1 months for all patients.
This phase I study was carried out safely. This combination chemotherapy showed beneficial improvement in health-related quality of life. The recommended phase II dose of nafamostat mesilate in combination with full-dose gemcitabine is 4.8 mg/kg.
本研究的主要终点是确定一种合成丝氨酸蛋白酶抑制剂甲磺酸萘莫司他与全剂量吉西他滨联合应用于不可切除的局部晚期或转移性胰腺癌患者时的剂量限制性毒性作用（DLTs）、最大耐受剂量和推荐的II期剂量。次要终点是评估治疗反应。
既往未接受过治疗的胰腺癌患者在第1、8和15天接受吉西他滨（1000mg/m²静脉输注30分钟），同时在第1、8和15天接受甲磺酸萘莫司他（通过端口导管系统持续区域动脉输注24小时）；该方案每28天重复一次。甲磺酸萘莫司他的初始剂量为2.4mg/kg，并以1.2mg/kg的增量递增，直至达到4.8mg/kg的剂量。采用标准的“3+3”I期剂量递增设计。评估治疗反应和临床获益反应。
12名患者纳入本研究。所有患者均未出现DLTs，甲磺酸萘莫司他与全剂量吉西他滨联合应用时，剂量高达4.8mg/kg时耐受性良好。这种联合化疗使肿瘤标志物CA19-9的高血清水平降低。7名未使用硫酸吗啡口服的患者中有3名疼痛减轻。所有患者的总生存期为7.1个月。
本I期研究安全进行。这种联合化疗在健康相关生活质量方面显示出有益的改善。甲磺酸萘莫司他与全剂量吉西他滨联合应用的推荐II期剂量为4.8mg/kg。
