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Annals of Oncology Advance Access published online on October 3, 2008
Annals of Oncology, doi:10.1093/annonc/mdn640
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

A phase I study of full-dose gemcitabine and regional arterial infusion of nafamostat mesilate for advanced pancreatic cancer

T. Uwagawa1,*, T. Misawa1, T. Sakamoto1, R. Ito1, T. Gocho1, H. Shiba1, S. Wakiyama1, S. Hirohara1, S. Sadaoka2 and K. Yanaga1

1 Department of Surgery
2 Department of Radiology, The Jikei University School of Medicine, Tokyo, Japan

* Correspondence to: Dr T. Uwagawa, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. Tel: +81-3-3433-1111 ext. 3401; Fax: +81-3-5472-4140; E-mail: uwatadashi{at}msn.com


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 References
 
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/m2 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.

chemoresistance, gemcitabine, nafamostat mesilate, NF-{kappa}B, pancreatic cancer


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 References
 
Constitutive activation of nuclear factor-{kappa}B (NF-{kappa}B) is a frequent molecular alteration in pancreatic cancer [1–3] and plays an important role in resistance to chemotherapy [4, 5]. Gemcitabine, the standard chemotherapeutic agent for pancreatic cancer, also induces NF-{kappa}B activation and reduces the sensitivity of chemotherapy [6]. Theoretically, gemcitabine chemotherapy combined with an NF-{kappa}B inhibitor could be a novel treatment strategy for pancreatic cancer.

We previously reported that nafamostat mesilate (Figure 1), a synthetic serine protease inhibitor, inhibits I{kappa}B{alpha} phosphorylation and NF-{kappa}B activation; furthermore, it induces tumor necrosis factor receptor-mediated apoptosis of pancreatic cancer cells [7]. Nafamostat mesilate is commercially approved as an effective therapeutic agent for disseminated intravascular coagulation, systemic response syndrome, or pancreatitis in Japan [8, 9]. Our previous data showed that a dose of 1 x 10–6 M of nafamostat mesilate is necessary to inhibit NF-{kappa}B activation and to induce apoptosis of pancreatic cancer cells [7]. An acceptable maximum clinical dose of nafamostat mesilate could reach 1.8 x 10–7 M (under the condition of continuous infusion). Thus, this concentration of nafamostat mesilate is insufficient to inhibit NF-{kappa}B activation and to induce apoptosis of pancreatic cancer. Some reports showed that continuous regional arterial infusion increases the concentration of nafamostat mesilate in the pancreas as compared with i.v. infusion [10, 11]. On the basis of these data, we started the study of i.v. gemcitabine combined with regional arterial infusion of nafamostat mesilate using a port-catheter system for the treatment of pancreatic cancer.


Figure 1
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  		Figure 1. Chemical structures of nafamostat mesilate.

 

   patients and methods
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 Abstract
 introduction
 patients and methods
results
 discussion
 References
 
This protocol was approved by the Institutional Review Board (IRB) of the Jikei University School of Medicine (Tokyo, Japan). All patients provided written informed consent before participation in the trial.

eligibility
Patients with unresectable locally advanced or metastatic pancreatic cancer were eligible for this study. Determination of unresectability was evaluated by helical computed tomography scan, abdominal angiography, and endoscopic ultrasound by using the criteria defined in the National Comprehensive Cancer Network guidelines for pancreatic cancer. Additional eligibility criteria included the following: age between 20 and 80 years, Karnofsky performance status ≥70%, and adequate bone marrow function (absolute neutrophil count > 1500/mm3, hemoglobin >9.0 g/dl, platelets >100 000/mm3). Adequate renal (serum creatinine < 1.5 mg/dl) and hepatic function (bilirubin < 2x upper normal limit; aspartate aminotransferase/alanine aminotransferase < 3x upper normal limit) was also required.

study design
A standard ‘3 + 3’ phase I dose-escalation design was used [12]. Dose-limiting toxicity (DLT) was defined as any one of the following conditions in cycle 1 of chemotherapy: grade 4 neutropenia; neutropenic fever/sepsis; ≥grade 3 thrombocytopenia; nausea, vomiting, or diarrhea lasting for ≥42 days despite adequate supportive care; nonhematologic toxicity ≥grade 3 (asymptomatic laboratory abnormalities were regarded as DLTs only if they were grade 4); any delay in the completion of therapy (therapy duration > 14 days); and inability to deliver >85% of the planned treatment.

treatment
Gemcitabine was i.v. administered at a fixed dose of 1000 mg/m2 for 30 min on days 1, 8, and 15 of each 28-day cycle. One hour before the infusion of gemcitabine, nafamostat mesilate was administered via a port-catheter system for 24 h through the common hepatic artery and celiac artery. The catheter was inserted in the common hepatic artery, and the side hole of the catheter was placed in the celiac artery by using the Seldinger technique. A port-catheter system was implanted in the s.c. tissue of the thigh. Before this treatment, appropriate distribution of contrast medium in the pancreas was confirmed by computed tomography during common hepatic or celiac angiography in each patient.

dose escalation and toxicity
The starting dose of nafamostat mesilate was 2.4 mg/kg, and the dose was escalated in the increments of 1.2 mg/kg until 4.8 mg/kg (Table 1). The maximum dose of nafamostat mesilate (4.8 mg/kg) in this study is a clinically permitted i.v. dose for disseminated intravascular coagulation in Japan. There was no intrapatient dose escalation. Maximum tolerated dose was defined as the dose below which two of six patients developed DLTs. If no DLTs were observed under the dose-escalation level, three doses of nafamostat mesilate were regarded as the recommended phase II dose. Intolerable dose was defined as two or more patients experiencing DLTs. The incidence and severity of all adverse events were assessed according to Common Terminology Criteria for Adverse Events v3.0.


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  		Table 1. Dose escalation schema

 
therapeutic response
Although the assessment of tumor response was not the primary end point of this study, tumor evaluation was carried out by mainly helical computed tomography scan at the end of every two cycles of the treatment, and response was assessed using Response Evaluation Criteria in Solid Tumors [13]. Furthermore, the tumor marker CA19-9 was measured monthly to monitor response to the treatment [14]. Moreover, clinical benefit response was assessed by parameters such as pain alleviation, Karnofsky performance status, and body weight. These parameters were chosen based on a report of Burris et al. [15]. Pain alleviation was evaluated by analgesic consumption and determination of pain intensity by using a visual analog scale. Body weight was measured every 2 weeks.


   results
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 Abstract
 introduction
 patients and methods
 results
discussion
 References
 
patient characteristics
From February 2007 to May 2008, 12 patients from one institution were enrolled in the study. Patient characteristics are summarized in Table 2. The median follow-up period was 7.1 (range 1.5–14.8) months.


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  		Table 2. Patient and tumor characteristics (n = 12)

 
dose escalation and chemotherapy-related toxicity
The incidence of adverse effects possibly related to nafamostat mesilate or gemcitabine are listed in Table 3. Initially, three patients were enrolled at dose level 1 (gemcitabine 1000 mg/m2; nafamostat mesilate 2.4 mg/kg). No DLT was observed at dose level 1. The third patient developed biliary hemorrhage after the replacement of a plastic biliary stent placed for obstructive jaundice with a self-expandable metallic stent after the fourth cycle. This patient underwent interventional management for this incidence. However, the IRB concluded that this incidence was caused not by the administration of the drug combination in the present study but by the self-expandable metallic stent. Next, three patients were enrolled at dose level 2 (gemcitabine 1000 mg/m2; nafamostat mesilate 3.6 mg/kg). No DLT was observed in these three patients at dose level 2. Subsequently, six patients were enrolled at dose level 3 (gemcitabine 1000 mg/m2; nafamostat mesilate 4.8 mg/kg). No DLT was observed at dose level 3. On the basis of these results, dose level 3 was defined as the recommended dose.


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  		Table 3. Treatment-related adverse events

 
assessment of response
Three patients (25%) achieved partial remission, seven patients had stable disease, and two patients had progressive disease. Currently, four patients have died of pancreatic cancer. Although all patients showed a high level of serum CA19-9 before the treatment, 11 of 12 patients (91%) showed a reduction in the serum CA19-9 level after the treatment. Furthermore, >50% reduction in serum CA19-9 level was achieved in five patients (45%). With regard to the effect of the treatment on health-related quality of life, the reduction of morphine anodyne consumption and Karnofsky performance status was observed. Particularly cancer-related pain, three of them could be weaned off oral morphine sulfate. Moreover, five patients (42%) showed an increase in body weight because of the improvement of a poor appetite (Table 4). To date, overall survival is 7.1 months (Figure 2).


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  		Table 4. Efficacy results

 

Figure 2
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  		Figure 2. Survival time.

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
References
 
NF-{kappa}B activation frequently correlates with chemoresistance and progression of various cancers [16]. Weldon et al. [17] demonstrated that inhibition of NF-{kappa}B increases the efficacy of paclitaxel or doxorubicin. Camp et al. [18] reported that 5-fluorouracil and irinotecan induced NF-{kappa}B activation, which subsequently lead to chemoresistance. According to Banerjee, the inhibition of gemcitabine-induced NF-{kappa}B activation increases the antitumor activity of gemcitabine for pancreatic cancer [19]. Subsequently, several NF-{kappa}B inhibitors such as bortezomib or thalidomide have been used in clinical studies for the treatment of malignant diseases [20, 21]. Currently, gemcitabine is being used as a standard chemotherapeutic agent for the treatment of pancreatic cancer because of improvements in survival and clinical benefits such as pain alleviation, performance status, and body weight as compared with the former standard chemotherapeutic agent 5-fluorouracil [15]. However, many chemotherapeutic combination regimens with gemcitabine have been conducted to achieve more acceptable prognosis [22–24]. Most of the agents that are combined with gemcitabine are anticancer agents. The most interesting point of the regimen used in the present study is that gemcitabine is combined with nafamostat mesilate, which is known as a serine protease inhibitor. That might be the reason of which no DLTs are observed in the dose escalation of nafamostat mesilate.

Cancer-related pain is one of the most important issues in pancreatic cancer patients and is mostly caused either by direct invasion of tumor into the celiac plexus or the superior mesenteric artery or by inflammation. Some studies have reported that the activation of proteinase-activated receptor-2 (PAR-2), a G-protein-coupled receptor expressed on nociceptive primary afferent neurons, induces a prolonged hyperalgesia and neurogenic inflammation [25, 26]. Furthermore, PAR-2 directly causes pain in inflammatory conditions such as pancreatitis [27]. Although the mechanism by which nafamostat mesilate reduces pancreatic cancer-related pain in some patients remains unclear, it is thought that nafamostat mesilate suppresses PAR-2 activation by inhibiting upstream mediators of the PAR-2 activation pathway [28]. Nafamostat mesilate might reduce pain in pancreatic cancer patients through this mechanism.

Many basic research studies have shown the efficacy of targeting anticancer drug-induced NF-{kappa}B activation to overcome chemoresistance. However, to date, no clinical data have been reported for the combination chemotherapy of gemcitabine with an NF-{kappa}B inhibitor.

Previously, treatment of acute necrotizing pancreatitis with nafamostat mesilate by continuous regional arterial infusion has been carried out safely [29]. In this study, we determined the recommended dose of regional arterial infusion of nafamostat mesilate in combination with full-dose i.v. gemcitabine and demonstrated that this regimen is safe to target gemcitabine-induced NF-{kappa}B activation.

A limitation of this study is that it does not demonstrate the efficacy of the abovementioned regimen for pancreatic cancer because of a small number of patients. However, the clinical data, including overall survival with clinical benefit response, obtained in this study suggest that the initial clinical outcome of this trial has been encouraging.

Received for publication August 3, 2008. Accepted for publication August 25, 2008.


   References
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 Abstract
 introduction
 patients and methods
 results
 discussion
 References
 
1. Sebens S, Arlt A, Schäfer H. NF-kappaB as a molecular target in the therapy of pancreatic carcinoma. Recent Results Cancer Res (2008) 177:151–164.[CrossRef][Medline]

2. Fujioka S, Sclabas GM, Schmidt C, et al. Inhibition of constitutive NF-kappa B activity by I kappa B alpha M suppresses tumorigenesis. Oncogene (2003) 22:1365–1370.[CrossRef][Web of Science][Medline]

3. Sclabas GM, Fujioka S, Schmidt C, et al. NF-kappaB in pancreatic cancer. Int J Gastrointest Cancer (2003) 33:15–26.[CrossRef][Medline]

4. Bharti AC, Aggarwal BB. Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol (2002) 64:883–888.[CrossRef][Web of Science][Medline]

5. Arlt A, Schäfer H. NFkappaB-dependent chemoresistance in solid tumors. Int J Clin Pharmacol Ther (2002) 40:336–347.[Web of Science][Medline]

6. Hering J, Garrean S, Dekoj TR, et al. Inhibition of proliferation by omega-3 fatty acids in chemoresistant pancreatic cancer cells. Ann Surg Oncol (2007) 14:3620–3628.[CrossRef][Web of Science][Medline]

7. Uwagawa T, Li Z, Chang Z, et al. Mechanisms of synthetic serine protease inhibitor (FUT-175)-mediated cell death. Cancer (2007) 109:2142–2153.[Medline]

8. Tsukagoshi S. Molecular specificity of nafamostat mesilate (FUT), a drug used for the treatments of DIC and acute pancreatitis and as an anticoagulant: the pharmacodynamics and pharmacological action. Gan To Kagaku Ryoho (2001) 28:1237–1243. (in Japanese).[Medline]

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15. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol (1997) 15:2403–2413.[Abstract/Free Full Text]

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18. Camp ER, Li J, Minnich DJ, et al. Inducible nuclear factor-kappaB activation contributes to chemotherapy resistance in gastric cancer. J Am Coll Surg (2004) 199:249–258.[CrossRef][Web of Science][Medline]

19. Banerjee S, Zhang Y, Ali S, et al. Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer. Cancer Res (2005) 65:9064–9072.[Abstract/Free Full Text]

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21. Bernardeschi P, Dentico P, Rossi S, et al. Chemoresistant myeloma: phase II clinical study with low-dose thalidomide plus high-dose dexamethasone. J Chemother (2004) 5:90–93.

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23. Reni M, Cereda S, Galli L. PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) for patients with advanced pancreatic cancer: the ghost regimen. Cancer Lett (2007) 256:25–28.[CrossRef][Web of Science][Medline]

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28. Maeda K, Hirota M, Kimura Y, et al. Proinflammatory role of trypsin and protease-activated receptor-2 in a rat model of acute pancreatitis. Pancreas (2005) 31:54–62.[CrossRef][Medline]

29. Takeda K, Matsuno S, Ogawa M, et al. Continuous regional arterial infusion (CRAI) therapy reduces the mortality rate of acute necrotizing pancreatitis: results of a cooperative survey in Japan. J Hepatobiliary Pancreat Surg (2001) 8:216–220.[CrossRef][Medline]


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This Article
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