Multicenter, Open-Label, Phase I/II Study of Tocilizumab, an Anti–Interleukin-6 Receptor Monoclonal Antibody, Combined with Gemcitabine in Patients with Advanced Pancreatic Cancer Shuichi Mitsunaga 1,2* , Takuji Okusaka 3 , Masafumi Ikeda 1 , Masato Ozaka 4 , Shinichi Ohkawa 5 , Tatsuya Ioka 6 , Tomomi Shimura 7 , Kumi Sato 7 , Kimio Terao 7 , Atsushi Ochiai 2 , and Junji Furuse 8 1 Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan 2 Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Chiba, Japan 3 Department of Hepatobiliary Pancreatic, National Cancer Center Hospital, Tokyo, Japan 4 Gastroenterological Internal Medicine, The Cancer Institute Hospital, Tokyo, Japan 5 Division of Hepato-biliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan 6 Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and CVD, Osaka, Japan 7 Clinical Research Planning Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan 8 Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan * Corresponding author: Shuichi Mitsunaga, Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan, Tel: 81471331111; Fax: +81471330335; E-mail: smitsuna@east.ncc.go.jp Received date: Nov 21, 2016, Accepted date: Jan 24, 2017, Published date: Jan 31, 2017 Copyright: © 2017 Mitsunaga S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Background: To assess the efficacy, safety and pharmacokinetics of tocilizumab + gemcitabine in patients with advanced pancreatic cancer. Methods: Patients with treatment-naive advanced pancreatic cancer and high inflammatory burden (C-reactive protein ≥ 2 mg/dl) without obvious infections received tocilizumab (8 mg/kg) intravenously every 2 weeks with intravenous gemcitabine (1,000 mg/m 2 ) on days 1, 8 and 15 of each 4-week cycle until disease progression or study withdrawal. Interleukin-6 signalling inhibition biomarkers were measured. Efficacy analyses included overall survival, progression-free survival, tumour response and clinical symptoms. Adverse events and laboratory parameters were also assessed. Results: Fifteen patients received tocilizumab+gemcitabine. Tumour response was observed in two patients (13%). Six patients (40%) died within 2 months of treatment start. Median overall survival was 2.5 months (95% confidence interval, 1.4-5.8); median progression-free survival was 1.8 months (95% confidence interval, 0.8-3.6). Overall and progression-free survival tended to be longer in patients with modest than in patients with higher elevations of baseline C-reactive protein. Changes in C-reactive protein and IL-6 occurred. Although tocilizumab +gemcitabine was tolerable, results were inconclusive because of the brevity of the evaluation period resulting from the death or premature withdrawal of patients. Dose interruption attributed to haematologic toxicity was frequently observed. Conclusions: Tocilizumab+gemcitabine failed to show a clear clinical benefit in patients with advanced pancreatic cancer and high inflammatory burden. To evaluate conclusively the benefit of tocilizumab, future study designs should use a comparator treatment that does not interfere with interleukin-6 signalling and that includes better patient selection criteria. Keywords: C-reactive protein; Gemcitabine; Interleukin-6 receptor; Pancreatic cancer; Tocilizumab Introduction Pancreatic cancer was the fourth leading cause of cancer death in Japan in 2014 [1], and the 5-year survival rate remains <10% [2]. Gemcitabine is the mainstay of treatment for advanced cases; however, its benefit, both alone and combined with other therapies, has been modest [3].Cancer-related inflammation contributes to patient morbidity and mortality [4]. Inflammation is linked to the proliferation and survival of malignant cells, angiogenesis and alteration of immune responses to cancer treatments [4]. Interleukin-6 (IL-6) mediates several biological activities [5] and is a key cytokine of inflammatory response [4]. It is involved in constitutional symptoms such as fever, fatigue and weight loss and in increased production of acute-phase reactants [6,7]. In pancreatic cancer, IL-6 induces cancer cell epithelial-to- mesenchymal transition, migration and invasion [8,9]. Elevated IL-6 levels are associated with more advanced tumour stage 1 and larger tumour burden [10,11]. IL-6 also appears to play a key role in cancer- induced cachexia [12-14], a multifactorial condition characterised by anaemia, progressive muscle wasting, weight loss and poor Mitsunaga et al., J Med Diagn Meth 2017, 6:1 DOI: 10.4172/2168-9784.1000234 Research Article Open Access J Med Diagn Meth, an open access journal ISSN:2168-9784 Volume 6 • Issue 1 • 1000234 J o u r n a l o f M e d i c a l D i a g n o s t i c M e t h o d s ISSN: 2168-9784 Journal of Medical Diagnostic Methods