A phase I study of full-dose gemcitabine and regional arterial infusion of nafamostat mesilate for advanced pancreatic cancer
A phase I study of full-dose gemcitabine and regional arterial infusion of nafamostat mesilate for advanced pancreatic cancer
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DOI：
10.1093/annonc/mdn640
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发表时间：
2009-02-01
影响因子：
50.5
通讯作者：
Yanaga, K.
中科院分区：
文献类型：
--
作者：
Uwagawa, T.;Misawa, T.;Yanaga, K.
背景：这项研究的主要终点是确定不能切除的局部晚期或转移性胰腺癌患者使用合成丝氨酸蛋白酶抑制剂甲磺酸那法莫司他汀联合全量吉西他滨治疗的剂量限制毒性效应(DLTS)、最大耐受量和推荐的II期剂量。第二个终点是评估治疗反应。患者和方法：既往未经治疗的胰腺癌患者接受吉西他滨(1000 mg/m(2)静脉注射)。第1、8和15天)，第1、8和15天使用甲磺酸那法莫斯特(通过导管系统持续区域动脉输注24小时)，第1、8和15天；该方案每隔28天重复一次。甲磺酸那法莫斯特的初始剂量为2.4毫克/公斤，递增1.2毫克/公斤，直到达到4.8毫克/公斤的剂量。采用标准的“3+3”I期剂量递增设计。结果：12例患者进入本研究。所有患者均未发生DLTS，甲磺酸那法莫斯特与全量吉西他滨联合应用的剂量高达4.8 mg/kg时耐受性良好。这种联合化疗降低了血清肿瘤标记物CA19-9的水平。7名患者中有3名在没有口服硫酸吗啡的情况下疼痛减轻。所有患者的总生存期为7.1个月。结论：这项I期研究是安全进行的。这种联合化疗在与健康相关的生活质量方面显示出有益的改善。推荐的甲磺酸那法莫斯特与全量吉西他滨联合使用的第二阶段剂量为4.8毫克/公斤。
Background: 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 and methods: 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.Results: 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.Conclusion: 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.