A phase II study of liposomal irinotecan with 5-fluorouracil, leucovorin and oxaliplatin in patients with resectable pancreatic cancer: the nITRO trial

Francesca Simionato, Camilla Zecchetto, Valeria Merz, Alessandro Cavaliere, Simona Casalino, Marina Gaule, Mirko D'Onofrio, Giuseppe Malleo, Luca Landoni, Alessandro Esposito, Giovanni Marchegiani, Luca Casetti, Massimiliano Tuveri, Salvatore Paiella, Filippo Scopelliti, Alessandro Giardino, Isabella Frigerio, Paolo Regi, Paola Capelli, Stefano Gobbo, Armando Gabbrielli, Laura Bernardoni, Vita Fedele, Irene Rossi, Cristiana Piazzola, Serena Giacomazzi, Martina Pasquato, Morena Gianfortone, Stefano Milleri, Michele Milella, Giovanni Butturini, Roberto Salvia, Claudio Bassi, Davide Melisi, Francesca Simionato, Camilla Zecchetto, Valeria Merz, Alessandro Cavaliere, Simona Casalino, Marina Gaule, Mirko D'Onofrio, Giuseppe Malleo, Luca Landoni, Alessandro Esposito, Giovanni Marchegiani, Luca Casetti, Massimiliano Tuveri, Salvatore Paiella, Filippo Scopelliti, Alessandro Giardino, Isabella Frigerio, Paolo Regi, Paola Capelli, Stefano Gobbo, Armando Gabbrielli, Laura Bernardoni, Vita Fedele, Irene Rossi, Cristiana Piazzola, Serena Giacomazzi, Martina Pasquato, Morena Gianfortone, Stefano Milleri, Michele Milella, Giovanni Butturini, Roberto Salvia, Claudio Bassi, Davide Melisi

Abstract

Background: Up-front surgery followed by postoperative chemotherapy remains the standard paradigm for the treatment of patients with resectable pancreatic cancer. However, the risk for positive surgical margins, the poor recovery after surgery that often impairs postoperative treatment, and the common metastatic relapse limit the overall clinical outcomes achieved with this strategy. Polychemotherapeutic combinations are valid options for postoperative treatment in patients with good performance status. liposomal irinotecan (Nal-IRI) is a novel nanoliposome formulation of irinotecan that accumulates in tumor-associated macrophages improving the therapeutic index of irinotecan and has been approved for the treatment of patients with metastatic pancreatic cancer after progression under gemcitabine-based therapy. Thus, it remains of the outmost urgency to investigate introduction of the most novel agents, such as nal-IRI, in perioperative approaches aimed at increasing the long-term effectiveness of surgery.

Methods: The nITRO trial is a phase II, single-arm, open-label study to assess the safety and the activity of nal-IRI with fluorouracil/leucovorin (5-FU/LV) and oxaliplatin in the perioperative treatment of patients with resectable pancreatic cancer. The primary tumor must be resectable with no involvement of the major arteries and no involvement or <180° interface between tumor and vessel wall of the major veins. A total of 72 patients will be enrolled to receive a perioperative treatment of three cycles before and three cycles after surgical resection with nal-IRI 50 mg/m2, oxaliplatin 60 mg/m2, leucovorin 200 mg/m2, and 5-fluorouracil 2400 mg/m2, days 1 and 15 of a 28-day cycle. The primary objective is to improve from 40% to 55% the proportion of patients achieving R0 resection after preoperative treatment.

Discussion: The nITRO trial will contribute to strengthen the clinical evidence supporting perioperative strategies in resectable pancreatic cancer patients. Moreover, this study represents a unique opportunity for translational analyses aimed to identify novel immune-related prognostic and predictive factors in this setting.

Trial registration: Clinicaltrial.gov: NCT03528785. Trial registration data: 1 January 2018Protocol number: CRC 2017_01EudraCT Number: 2017-000345-46.

Keywords: R0; nal-irinotecan; peri-operative chemotherapy; resectable pancreatic adenocarcinoma.

Conflict of interest statement

Conflict of interest: DM declares research funding from Shire, Incyte, Evotec, Celgene, iOnctura and consulting role with Eli Lilly, Shire, Evotec, Baxter, Incyte, iOnctura.

© The Author(s), 2020.

Figures

Figure 1.
Figure 1.
Study design diagram.
Appendix 1.
Appendix 1.
Informed consent for screening and enrolling patients in the nITRO trial.
Appendix 2.
Appendix 2.
Informed consent for translational research studies for patients enrolled in the Nitro trial.

References

    1. Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014; 74: 2913–2921.
    1. Vaccaro V, Melisi D, Bria E, et al. Emerging pathways and future targets for the molecular therapy of pancreatic cancer. Expert Opin Ther Targets 2011; 15: 1183–1196.
    1. Tamburrino A, Piro G, Carbone C, et al. Mechanisms of resistance to chemotherapeutic and anti-angiogenic drugs as novel targets for pancreatic cancer therapy. Front Pharmacol 2013; 4: 56.
    1. Vaccaro V, Sperduti I, Vari S, et al. Metastatic pancreatic cancer: is there a light at the end of the tunnel? World J Gastroenterol 2015; 21: 4788–4801.
    1. Melisi D, Calvetti L, Frizziero M, et al. Pancreatic cancer: systemic combination therapies for a heterogeneous disease. Curr Pharm Des 2014; 20: 6660–6669.
    1. Bazzichetto C, Conciatori F, Luchini C, et al. From genetic alterations to tumor microenvironment: the Ariadne’s string in pancreatic cancer. Cells 2020; 9: 309.
    1. Li D, Xie K, Wolff R, et al. Pancreatic cancer. Lancet 2004; 363: 1049–1057.
    1. Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 2010; 304: 1073–1081.
    1. Wolff RA. Adjuvant or neoadjuvant therapy in the treatment in pancreatic malignancies: where are we? Surg Clin North Am 2018; 98: 95–111.
    1. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 2013; 310: 1473–1481.
    1. Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 2017; 389: 1011–1024.
    1. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364: 1817–1825.
    1. Tzeng CWD, Cao HST, Lee JE, et al. Treatment sequencing for resectable pancreatic cancer: influence of early metastases and surgical complications on multimodality therapy completion and survival. J Gastrointest Surg 2014; 18: 16–24; discussion 24–25.
    1. Aloia TA, Lee JE, Vauthey JN, et al. Delayed recovery after pancreaticoduodenectomy: a major factor impairing the delivery of adjuvant therapy? J Am Coll Surg 2007; 204: 347–355.
    1. Mayo SC, Gilson MM, Herman JM, et al. Management of patients with pancreatic adenocarcinoma: national trends in patient selection, operative management, and use of adjuvant therapy. J Am Coll Surg 2012; 214: 33–45.
    1. Haeno H, Gonen M, Davis MB, et al. Computational modeling of pancreatic cancer reveals kinetics of metastasis suggesting optimum treatment strategies. Cell 2012; 148: 362–375.
    1. Rhim AD, Mirek ET, Aiello NM, et al. EMT and dissemination precede pancreatic tumor formation. Cell 2012; 148: 349–361.
    1. Wolff RA, Varadhachary GR, Evans DB. Adjuvant therapy for adenocarcinoma of the pancreas: analysis of reported trials and recommendations for future progress. Ann Surg Oncol 2008; 15: 2773–2786.
    1. Glant JA, Waters JA, House MG, et al. Does the interval from imaging to operation affect the rate of unanticipated metastasis encountered during operation for pancreatic adenocarcinoma? Surgery 2011; 150: 607–616.
    1. Seufferlein T, Ettrich TJ. Treatment of pancreatic cancer-neoadjuvant treatment in resectable pancreatic cancer (PDAC). Transl Gastroenterol Hepatol 2019; 4: 21.
    1. Mokdad AA, Minter RM, Zhu H, et al. Neoadjuvant therapy followed by resection versus upfront resection for resectable pancreatic cancer: a propensity score matched analysis. J Clin Oncol 2017; 35: 515–522.
    1. Gillen S, Schuster T, Büschenfelde CMZ, et al. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med 2010; 7: e1000267.
    1. Versteijne E, Vogel JA, Besselink MG, et al. Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer. Br J Surg 2018; 105: 946–958.
    1. Dhir M, Malhotra GK, Sohal DPS, et al. Neoadjuvant treatment of pancreatic adenocarcinoma: a systematic review and meta-analysis of 5520 patients. World J Surg Oncol 2017; 15: 183.
    1. Versteijne E, Suker M, Groothuis K, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the Dutch randomized phase III PREOPANC trial. J Clin Oncol 2020; 38: 1763–1773.
    1. de W, Marsh R, Talamonti MS, Baker MS, et al. Primary systemic therapy in resectable pancreatic ductal adenocarcinoma using mFOLFIRINOX: a pilot study. J Surg Oncol 2018; 117: 354–362.
    1. Janssen QP, Buettner S, Suker M, et al. Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer: a systematic review and patient-level meta-analysis. J Natl Cancer Inst 2019; 111: 782–794.
    1. Drummond DC, Noble CO, Guo Z, et al. Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy. Cancer Res 2006; 66: 3271–3277.
    1. Kang MH, Wang J, Makena MR, et al. Activity of MM-398, nanoliposomal irinotecan (nal-IRI), in Ewing’s family tumor xenografts is associated with high exposure of tumor to drug and high SLFN11 expression. Clin Cancer Res 2015; 21: 1139–1150.
    1. Kalra AV, Kim J, Klinz SG, et al. Preclinical activity of nanoliposomal irinotecan is governed by tumor deposition and intratumor prodrug conversion. Cancer Res 2014; 74: 7003–7013.
    1. Tsai CS, Park JW, Chen LT. Nanovector-based therapies in advanced pancreatic cancer. J Gastrointest Oncol 2011; 2: 185–194.
    1. Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 2016; 387: 545–557.
    1. Pelzer U, Blanc JF, Melisi D, et al. Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis. Br J Cancer 2017; 116: 1247–1253.
    1. Hubner RA, Cubillo A, Blanc JF, et al. Quality of life in metastatic pancreatic cancer patients receiving liposomal irinotecan plus 5-fluorouracil and leucovorin. Eur J Cancer 2019; 106: 24–33.
    1. Taieb J, Prager GW, Melisi D, et al. First-line and second-line treatment of patients with metastatic pancreatic adenocarcinoma in routine clinical practice across Europe: a retrospective, observational chart review study. ESMO Open 2020; 5: e000587.
    1. Aprile G, Negri FV, Giuliani F, et al. Second-line chemotherapy for advanced pancreatic cancer: which is the best option? Crit Rev Oncol Hematol 2017; 115: 1–12.
    1. Wainberg ZA, Boland PM, Lieu CH, et al. A phase 1/2, open-label, dose-expansion study of liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) and oxaliplatin (OX) in patients with previously untreated metastatic pancreatic cancer (mPAC). World GI Annual Meeting, Barcelona, Spain, 2019.
    1. Ciaravino V, Cardobi N, DE Robertis R, et al. CT texture analysis of ductal adenocarcinoma downstaged after chemotherapy. Anticancer Res 2018; 38: 4889–4895.
    1. Li D, O’Reilly EM. Adjuvant and neoadjuvant therapy for pancreatic cancer. Surg Oncol Clin N Am 2016; 25: 311–326.
    1. Neuzillet C, Gaujoux S, Williet N, et al. Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC). Dig Liver Dis 2018; 50: 1257–1271.
    1. Jamieson NB, Foulis AK, Oien KA, et al. Positive mobilization margins alone do not influence survival following pancreatico-duodenectomy for pancreatic ductal adenocarcinoma. Ann Surg 2010; 251: 1003–1010.
    1. Neoptolemos JP, Stocken DD, Dunn JA, et al. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg 2001; 234: 758–768.
    1. Richter A, Niedergethmann M, Sturm JW, et al. Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience. World J Surg 2003; 27: 324–329.
    1. Wagner M, Redaelli C, Lietz M, et al. Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg 2004; 91: 586–594.
    1. Raut CP, Tseng JF, Sun CC, et al. Impact of resection status on pattern of failure and survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Ann Surg 2007; 246: 52–60.
    1. Willett CG, Lewandrowski K, Warshaw AL, et al. Resection margins in carcinoma of the head of the pancreas. Implications for radiation therapy. Ann Surg 1993; 217: 144–148.
    1. Esposito I, Kleeff J, Bergmann F, et al. Most pancreatic cancer resections are R1 resections. Ann Surg Oncol 2008; 15: 1651–1660.
    1. Verbeke CS, Leitch D, Menon KV, et al. Redefining the R1 resection in pancreatic cancer. Br J Surg 2006; 93: 1232–1237.
    1. Campbell F, Smith RA, Whelan P, et al. Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin. Histopathology 2009; 55: 277–283.
    1. Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg 1997; 226: 248–257; discussion 257–260.
    1. Cameron JL, Riall TS, Coleman J, et al. One thousand consecutive pancreaticoduodenectomies. Ann Surg 2006; 244: 10–15.
    1. Gaedcke J, Gunawan B, Grade M, et al. The mesopancreas is the primary site for R1 resection in pancreatic head cancer: relevance for clinical trials. Langenbecks Arch Surg 2010; 395: 451–458.
    1. Mantovani A, Marchesi F, Malesci A, et al. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 2017; 14: 399–416.
    1. Piro G, Simionato F, Carbone C, et al. A circulating TH2 cytokines profile predicts survival in patients with resectable pancreatic adenocarcinoma. Oncoimmunology 2017; 6: e1322242.
    1. Melisi D, Garcia-Carbonero R, Macarulla T, et al. TGFβ receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer. Cancer Chemother Pharmacol 2019; 83: 975–991.
    1. Melisi D, Garcia-Carbonero R, Macarulla T, et al. Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer. Br J Cancer 2018; 119: 1208–1214.
    1. Nagai M, Sho M, Akahori T, et al. Application of liquid biopsy for surgical management of pancreatic cancer. Ann Gastroenterol Surg 2020; 4: 216–223.
    1. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 2014; 20: 548–554.
    1. Popper K. Conjectures and refutations: the growth of scientific knowledge. London: Routledge, 1963.
    1. Reni M, Balzano G, Zanon S, et al. Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2-3 trial. Lancet Gastroenterol Hepatol 2018; 3: 413–423.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться