Clinical Trial|Articles in Press

Phase II randomised, double-blind study of mFOLFIRINOX plus ramucirumab versus mFOLFIRINOX plus placebo in advanced pancreatic cancer patients (HCRN GI14-198)

Published:March 10, 2023DOI:


      • The prognosis of pancreatic cancer remains poor.
      • 5FU has proangiogenic activity.
      • VEGFR2 might be a more effective antiangiogenic agent when combined with 5FU.
      • This study compared FOLFIRINOX to FOLFIRINOX ramucirumab (RAM).
      • FOLFIRINOX RAM was well tolerated but no survival difference.



      Vascular endothelial growth factor receptor (VEGFR)-mediated signalling promotes angiogenesis and contributes to resistance to therapy in pancreatic ductal adenocarcinoma (PDAC). Ramucirumab (RAM) is a monoclonal antibody against VEGFR. Based on this preclinical data, we conducted a randomised phase II trial to compare progression-free survival (PFS) between modified FOLFIRINOX with or without RAM in first line therapy for patients with metastatic PDAC.


      This phase II randomised, multi-centre, placebo controlled, and double-blinded, trial randomly assigned patients with recurrent/metastatic PDAC to either mFOLFIRINOX/RAM (Arm A) or mFOLFIRINOX/placebo (Arm B). mFOLFIRINOX (oxaliplatin [85 mg/m2], irinotecan [165 mg/m2], fluorouracil [2400 mg/m2]) was received every 2 weeks, with or without RAM (8 mg/kg). The primary endpoint is PFS at 9 months, and the secondary endpoints include overall survival (OS), response rate and toxicity evaluation in both arms.


      A total of 86 subjects were enrolled, 82 were eligible (42 in Arm A versus 40 in Arm B). The mean age was comparable (61.7 versus 63.0, respectively). Majority of the patients were White (N = 69) and males (N = 43). The median PFS was 5.6 compared to 6.7 months, for Arm A and B, respectively. At 9 months, the PFS rates were 25.1% and 35.0% for Arms A and B, respectively (p = 0.322). The median OS in Arm A was 10.3 compared to 9.7 months for Arm B (p = 0.094). The disease response rate for Arm A was 17.7% compared to Arm B of 22.6% and was not statistically significant. On the univariate and multivariate analysis, there was no difference in distribution between the two arms for age, gender, race and ethnicity. FOLFIRINOX/RAM combination was well tolerated. Patients in Arm A reported a slightly higher number of adverse events (AEs) compared to Arm B (589 versus 516). The most reported AE in either arm was diarrhoea (29 versus 28), fatigue (25 versus 25), vomiting (24 versus 14), weight loss (23 versus 17), and abdominal pain (20 versus 15). Arm A has more serious adverse events than Arm B (43 versus 25, respectively), Sepsis was the most commonly reported in both arms (3 in each), vomiting (3 versus 2), diarrhoea (3 versus 1) and duodenal obstruction (3 versus 0).


      The addition of RAM to FOLFIRINOX did not significantly impact PFS or OS. FOLFIRINOX/RAM combination was well tolerated in the treatment of PCA. (Funded by Eli Lilly; number, NCT02581215)


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        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics, 2020.
        CA Cancer J Clin. 2020; 70: 7-30
        • Conroy T.
        • et al.
        FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
        N Engl J Med. 2011; 364: 1817-1825
        • Von Hoff D.D.
        • et al.
        Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
        N Engl J Med. 2013; 369: 1691-1703
        • Niethammer A.G.
        • et al.
        Double-blind, placebo-controlled first in human study to investigate an oral vaccine aimed to elicit an immune reaction against the VEGF-Receptor 2 in patients with stage IV and locally advanced pancreatic cancer.
        BMC Cancer. 2012; 12: 361
        • Martin L.K.
        • et al.
        VEGF remains an interesting target in advanced pancreas cancer (APCA): results of a multi-institutional phase II study of bevacizumab, gemcitabine, and infusional 5-fluorouracil in patients with APCA.
        Ann Oncol. 2012; 23: 2812-2820
        • Ellis L.M.
        • et al.
        Vessel counts and vascular endothelial growth factor expression in pancreatic adenocarcinoma.
        Eur J Cancer. 1998; 34: 337-340
        • Higgins K.J.
        • et al.
        Regulation of vascular endothelial growth factor receptor-2 expression in pancreatic cancer cells by Sp proteins.
        Biochem Biophys Res Commun. 2006; 345: 292-301
        • Doi Y.
        • et al.
        VEGF-A/VEGFR-2 signaling plays an important role for the motility of pancreas cancer cells.
        Ann Surg Oncol. 2012; 19: 2733-2743
        • Doi Y.
        • et al.
        Significance of phospho-vascular endothelial growth factor receptor-2 expression in pancreatic cancer.
        Cancer Sci. 2010; 101: 1529-1535
        • Van Cutsem E.
        • et al.
        Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.
        J Clin Oncol. 2009; 27: 2231-2237
        • Kindler H.L.
        • et al.
        Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303).
        J Clin Oncol. 2010; 28: 3617-3622
        • Kindler H.L.
        • et al.
        Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study.
        Lancet Oncol. 2011; 12: 256-262
        • Javle M.
        • et al.
        Bevacizumab combined with gemcitabine and capecitabine for advanced pancreatic cancer: a phase II study.
        Br J Cancer. 2009; 100: 1842-1845
        • Shaked Y.
        • et al.
        Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents.
        Cancer Cell. 2008; 14: 263-273
        • Starlinger P.
        • et al.
        Myelosuppression of thrombocytes and monocytes is associated with a lack of synergy between chemotherapy and anti-VEGF treatment.
        Neoplasia. 2011; 13: 419-427
        • Tabernero J.
        • et al.
        Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study.
        Lancet Oncol. 2015; 16: 499-508
        • Eisenhauer E.A.
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009; 45: 228-247
        • Lakatos E.
        Sample sizes based on the log-rank statistic in complex clinical trials.
        Biometrics. 1988; 44: 229-241
        • Lakatos E.
        Designing complex group sequential survival trials.
        Stat Med. 2002; 21: 1969-1989
      1. SAS Institute Inc. 2013. SAS® 9.4 Statements: Reference. Cary, N.S.I.I.

        • Fukumura D.
        • Jain R.K.
        Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization.
        Microvasc Res. 2007; 74: 72-84
        • Carbone C.
        • et al.
        Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype.
        Clin Cancer Res. 2011; 17: 5822-5832
        • Luo J.
        • et al.
        Pancreatic cancer cell-derived vascular endothelial growth factor is biologically active in vitro and enhances tumorigenicity in vivo.
        Int J Cancer. 2001; 92: 361-369
        • de Jesus V.H.F.
        • et al.
        Retrospective comparison of the efficacy and the toxicity of standard and modified FOLFIRINOX regimens in patients with metastatic pancreatic adenocarcinoma.
        J Gastrointest Oncol. 2018; 9: 694-707
        • Chllamma M.K.
        • et al.
        FOLFIRINOX for advanced pancreatic cancer: the Princess Margaret Cancer Centre experience.
        Br J Cancer. 2016; 115: 649-654
        • Stein S.M.
        • et al.
        Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer.
        Br J Cancer. 2016; 114: 737-743
        • Mahaseth H.
        • et al.
        Modified FOLFIRINOX regimen with improved safety and maintained efficacy in pancreatic adenocarcinoma.
        Pancreas. 2013; 42: 1311-1315
        • Roberts HJ W.J.
        • Yeap B.Y.
        The use of elevated circulating he-patocyte growth factor (HGF) level as a potential prognostic biomarker in locally advanced pancreatic cancer.
        J Clin Oncol. 2021; 39: 429
        • Kelly D B.A.
        • Perera S.
        • et al.
        Familial pancreatic cancer (FPC) status as a clinical biomarker in patients receiving platinum-based systemic therapy: a case-control analysis.
        J Clin Oncol. 2021; 39: 430
        • Goldfarb SD M.K.
        • McAneny B.L.
        • et al.
        Biomarker testing patterns and identification of barriers to testing for homologous re-combination deficiencies across four advanced-stage solid tumors in a multicommunity practice setting.
        J Clin Oncol. 2021; 39: 16
      2. NIH. Anlotinib, toripalimab and Nab-paclitaxel in locally Advanced/Metastatic Pancreatic Cancer (ATNPA). (NCT05218629). 〈〉.