A randomized phase II study of weekly nab-paclitaxel plus gemcitabine or simplified LV5FU2 as first-line therapy in patients with metastatic pancreatic cancer: the AFUGEM GERCOR trial

Jean-Baptiste Bachet, Benoist Chibaudel, Franck Bonnetain, Pierre Validire, Pascal Hammel, Thierry André, Christophe Louvet, GERCOR group, Jean-Baptiste Bachet, Benoist Chibaudel, Franck Bonnetain, Pierre Validire, Pascal Hammel, Thierry André, Christophe Louvet, GERCOR group

Abstract

Background: Metastatic pancreatic adenocarcinoma (PAC) prognosis remains dismal and gemcitabine monotherapy has been the standard treatment over the last decade. Currently, two first-line regimens are used in this setting: FOLFIRINOX and nab-paclitaxel plus gemcitabine. Increasing translational data on the predictive value of hENT1 for determining gemcitabine efficacy suggest that a non-gemcitabine-based regimen is favored in about 60 % of patients with PAC due to high resistance of PAC to this cytotoxic drug. This study aims to evaluate the efficacy of weekly nab-paclitaxel combined with gemcitabine or a simplified (s) LV5FU2 regimen in patients with previously untreated metastatic PAC.

Methods/design: AFUGEM is a two-stage, open-label, randomized, multicenter, phase II trial. Patients with PAC who meet the inclusion criteria and provide written informed consent will be randomized in a 1:2 ratio to either nab-paclitaxel (125 mg/m(2)) plus gemcitabine (1000 mg/m(2)) given on days 1, 8, and 15 every 28 days or nab-paclitaxel (125 mg/m(2)) plus sLV5FU2 (leucovorin 400 mg/m(2) followed by bolus 400 mg/m(2) 5-fluorouracil and by 5-fluorouracil 2400 mg/m(2) as an 46-h intravenous infusion) given on days 1 and 15 every 28 days. A total of 114 patients will be randomized to one of the treatment arms. The primary endpoint is progression-free survival at 4 months. Secondary outcomes are rate and duration of response, disease control, overall survival, safety, and quality of life. Potential biomarkers of gemcitabine (hENT1, dCK) and 5-fluorouracil (TS) efficacy will be assessed.

Discussion: The AFUGEM trial is designed to provide valuable information regarding efficacy and tolerability of nab-paclitaxel plus gemcitabine and nab-paclitaxel plus sLV5FU2 regimens. Identification of potential predictive biomarkers of gemcitabine and 5-fluorouracil is likely to drive therapeutic decisions in patients with metastatic PAC.

Trial registration: AFUGEM is registered at Clinicaltrials.gov: NCT01964534 , October 15, 2013.

Figures

Fig. 1
Fig. 1
Design of study protocol
Fig. 2
Fig. 2
Design of study regimens

References

    1. Bouvier AM, Remontet L, Jougla E, Launoy G, Grosclaude P, Buémi A, Tretarre B, Velten M, Dancourt V, Menegoz F, Guizard AV, Macé Lesec’h J, Peng J, Bercelli P, Arveux P, Estève J, Faivre J. Incidence of Gastrointestinal Cancers in France. Gastroenterol Clin Biol. 2004;28(10 Pt 1):877–81. doi: 10.1016/S0399-8320(04)95152-4.
    1. Coleman MP, Gatta G, Verdecchia A, Estève J, Sant M, Storm H, Allemani C, Ciccolallo L, Santaquilani M, Berrino F, EUROCARE Working Group: EUROCARE Working Group EUROCARE-3 Summary: Cancer Survival in Europe at the End of the 20th Century. Ann Oncol. 2003;14(suppl 5):v128–49. doi: 10.1093/annonc/mdg756.
    1. Carpelan-Holmström M, Nordling S, Pukkala E, Sankila R, Lüttges J, Klöppel G, Haglund C. Does Anyone Survive Pancreatic Ductal Adenocarcinoma? A Nationwide Study re-Evaluating the Data of the Finnish Cancer Registry. Gut. 2005;54(3):385–7. doi: 10.1136/gut.2004.047191.
    1. Burris HA, 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. 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(6):2403–13.
    1. Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C. Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer. 2008;8:82. doi: 10.1186/1471-2407-8-82.
    1. Banu E, Banu A, Fodor A, Landi B, Rougier P, Chatellier G, Andrieu JM, Oudard S. Meta-Analysis of Randomised Trials Comparing Gemcitabine-Based Doublets versus Gemcitabine alone in Patients with Advanced and Metastatic Pancreatic Cancer. Drugs Aging. 2007;24(10):865–79. doi: 10.2165/00002512-200724100-00006.
    1. Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III Randomized Comparison of Gemcitabine versus Gemcitabine plus Capecitabine in Patients with Advanced Pancreatic Cancer. J Clin Oncol. 2009;27(33):5513–8. doi: 10.1200/JCO.2009.24.2446.
    1. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M, Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25. doi: 10.1056/NEJMoa1011923.
    1. Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, Tao C, De T, Beals B, Dykes D, Noker P, Yao R, Labao E, Hawkins M, Soon-Shiong P. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006;12(4):1317–24. doi: 10.1158/1078-0432.CCR-05-1634.
    1. Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regime, in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29(34):4548–54. doi: 10.1200/JCO.2011.36.5742.
    1. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703. doi: 10.1056/NEJMoa1304369.
    1. Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF, Abrams R, Benson AB, Macdonald J, Cass CE, Dicker AP, Mackey JR. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology. 2009;136(1):187–95. doi: 10.1053/j.gastro.2008.09.067.
    1. Maréchal R, Bachet JB, Mackey JR, Dalban C, Demetter P, Graham K, Couvelard A, Svrcek M, Bardier-Dupas A, Hammel P, Sauvanet A, Louvet C, Paye F, Rougier P, Penna C, André T, Dumontet C, Cass CE, Jordheim LP, Matera EL, Closset J, Salmon I, Devière J, Emile JF, Van Laethem JL. Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma. Gastroenterology. 2012;143(3):664–74. doi: 10.1053/j.gastro.2012.06.006.
    1. Greenhalf W, Ghaneh P, Neoptolemos JP, Palmer DH, Cox TF, Lamb RF, Garner E, Campbell F, Mackey JR, Costello E, Moore MJ, Valle JW, McDonald AC, Carter R, Tebbutt NC, Goldstein D, Shannon J, Dervenis C, Glimelius B, Deakin M, Charnley RM, Lacaine F, Scarfe AG, Middleton MR, Anthoney A, Halloran CM, Mayerle J, Oláh A, Jackson R, Rawcliffe CL, Scarpa A, Bassi C, Büchler MW, European Study Group for Pancreatic Cancer Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial. J Natl Cancer Inst. 2014;106(1):djt347. doi: 10.1093/jnci/djt347.
    1. Wei CH, Gorgan TR, Elashoff DA, Hines OJ, Farrell JJ, Donahue TR. A meta-analysis of gemcitabine biomarkers in patients with pancreaticobiliary cancers. Pancreas. 2013;42(8):1303–10. doi: 10.1097/MPA.0b013e3182a23ae4.
    1. Barnes K, Dobrzynski H, Foppolo S, Beal PR, Ismat F, Scullion ER, Sun L, Tellez J, Ritzel MW, Claycomb WC, Cass CE, Young JD, Billeter-Clark R, Boyett MR, Baldwin SA. Distribution and functional characterization of equilibrative nucleoside transporter-4, a novel cardiac adenosine transporter activated at acidic pH. Circ Res. 2006;99(5):510–9. doi: 10.1161/01.RES.0000238359.18495.42.
    1. Mackey JR, Mani RS, Selner M, Mowles D, Young JD, Belt JA, Crawford CR, Cass CE. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res. 1998;58(19):4349–57.
    1. Poplin E, Wasan H, Rolfe L, Raponi M, Ikdahl T, Bondarenko I, Davidenko I, Bondar V, Garin A, Boeck S, Ormanns S, Heinemann V, Bassi C, Evans TR, Andersson R, Hahn H, Picozzi V, Dicker A, Mann E, Voong C, Kaur P, Isaacson J, Allen A. Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. J Clin Oncol. 2013;31(35):4453–61. doi: 10.1200/JCO.2013.51.0826.
    1. Ormanns S, Heinemann V, Raponi M, Isaacson J, Laubender RP, Haas M, Kruger S, Kleespies A, Mann E, Bartosiewicz M, Kirchner T, Boeck S. Human equilibrative nucleoside transporter 1 is not predictive for gemcitabine efficacy in advanced pancreatic cancer: translational results from the AIO-PK0104 phase III study with the clone SP120 rabbit antibody. Eur J Cancer. 2014;50(11):1891–9. doi: 10.1016/j.ejca.2014.04.023.
    1. Sinn M, Sinn BV, Stieler J, Pelzer U, Striefler JK, Oettle H, Bahra M, Dörken B, Denkert C, Blaeker H, Riess H, Lohneis P. Hent1 expression in patients with pancreatic cancer treated with gemcitabine after curative intended resection: Results from the CONKO-001 trial. J Clin Oncol. 2014;32(15_suppl):4124.
    1. Svrcek M, Cros J, Maréchal R, Bachet JB, Fléjou JF, Demetter P: hENT1 testing in pancreatic ductal adenocarcinoma: a comparison between the murine and the rabbit antibodies. Histopathology 2014, in press.
    1. Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW, European Study Group for Pancreatic Cancer Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304(10):1073–81. doi: 10.1001/jama.2010.1275.
    1. Taïeb J, Lecomte T, Aparicio T, Asnacios A, Mansourbakht T, Artru P, Fallik D, Spano JP, Landi B, Lledo G, Desrame J. FOLFIRI.3, a new regimen combining 5-fluorouracil, folinic acid and irinotecan, for advanced pancreatic cancer: results of an Association des Gastro-Enterologues Oncologues (Gastroenterologist Oncologist Association) multicenter phase II study. Ann Oncol. 2007;18(3):498–503. doi: 10.1093/annonc/mdl427.
    1. Dahan L, Bonnetain F, Ychou M, Mitry E, Gasmi M, Raoul JL, Cattan S, Phelip JM, Hammel P, Chauffert B, Michel P, Legoux JL, Rougier P, Bedenne L, Seitz JF, Fédération Francophone de Cancérologie Digestive Combination 5-fluorouracil, folinic acid and cisplatin (LV5FU2-CDDP) followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: final results of a randomised strategic phase III trial (FFCD 0301) Gut. 2010;59(11):1527–34. doi: 10.1136/gut.2010.216135.
    1. Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U: Second-Line Oxaliplatin, Folinic Acid, and Fluorouracil Versus Folinic Acid and Fluorouracil Alone for Gemcitabine-Refractory Pancreatic Cancer: Outcomes From the CONKO-003 Trial. J Clin Oncol 2014, in press.
    1. Von Hoff D, LI CP, Wang-Gillam A, Bodoky G, Dean A, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner R, Chiu CF, Schwartsmann G, Siveke J, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Chen LT, NAPOLI-1 Randomized phase 3 study of MM-398 (NAL-IRI), with or without 5-Fluorouracil and leucovorin, versus 5-Fluorouracil and leucovorin, in metastatic pancreatic cancer progressed on or following gemcitabine-based therapy. Ann Oncol. 2014;25(Suppl 2):ii105. doi: 10.1093/annonc/mdu193.3.
    1. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P, Xeloda Colorectal Cancer Study Group Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001;19(21):4097–106.
    1. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001;19(8):2282–92.
    1. de Gramont A, Bosset JF, Milan C, Rougier P, Bouché O, Etienne PL, Morvan F, Louvet C, Guillot T, François E, Bedenne L. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol. 1997;15(2):808–15.
    1. Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008;26(12):2006–12. doi: 10.1200/JCO.2007.14.9898.
    1. Ducreux M, Bennouna J, Hebbar M, Ychou M, Lledo G, Conroy T, Adenis A, Faroux R, Rebischung C, Bergougnoux L, Kockler L, Douillard JY, GI Group of the French Anti-Cancer Centers Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer. 2011;128(3):682–90. doi: 10.1002/ijc.25369.
    1. Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008;19(10):1720–6. doi: 10.1093/annonc/mdn370.
    1. Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, Lyman GH, Pettengell R, Tjan-Heijnen VC, Walewski J, Weber DC, Zielinski C, European Organisation for Research and Treatment of Cancer 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011;47(1):8–32. doi: 10.1016/j.ejca.2010.10.013.
    1. Jamieson NB, Carter CR, McKay CJ, Oien KA. Tissue biomarkers for prognosis in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis. Clin Cancer Res. 2011;17(10):3316–31. doi: 10.1158/1078-0432.CCR-10-3284.
    1. Smith RA, Tang J, Tudur-Smith C, Neoptolemos JP, Ghaneh P. Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer. Br J Cancer. 2011;104(9):1440–51. doi: 10.1038/bjc.2011.110.
    1. Berger SH, Jenh CH, Johnson LF, Berger FG. Thymidylate synthase overproduction and gene amplification in fluorodeoxyuridine-resistant human cells. Mol Pharmacol. 1985;28(5):461–7.
    1. Popat S, Matakidou A, Houlston RS. Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol. 2004;22(3):529–36. doi: 10.1200/JCO.2004.05.064.
    1. Infante JR, Matsubayashi H, Sato N, Tonascia J, Klein AP, Riall TA, Yeo C, Iacobuzio-Donahue C, Goggins M. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol. 2007;25(3):319–25. doi: 10.1200/JCO.2006.07.8824.
    1. Sinn M, Sinn BV, Striefler JK, Lindner JL, Stieler JM, Lohneis P, Bischoff S, Bläker H, Pelzer U, Bahra M, Dietel M, Dörken B, Oettle H, Riess H, Denkert C. SPARC expression in resected pancreatic cancer patients treated with gemcitabine: results from the CONKO-001 study. Ann Oncol. 2014;25(5):1025–32. doi: 10.1093/annonc/mdu084.
    1. Hidalgo M, Plaza C, Illei P, Brachmann C, Heise C, Pierce D, Romano A, Wei X, Lopez-Rios F, Von Hoff D. SPARC analysis in the phase III MPACT trial of nab-paclitaxel (NAB-P) plus gemcitabine (GEM) vs GEM alone for patients with metastatic pancreatic cancer (PC) Ann Oncol. 2014;25(Suppl 2):ii106. doi: 10.1093/annonc/mdu193.4.
    1. Bonnetain F, Bonsing B, Conroy T, Dousseau A, Glimelius B, Haustermans K, Lacaine F, Van Laethem JL, Aparicio T, Aust D, Bassi C, Berger V, Chamorey E, Chibaudel B, Dahan L, De Gramont A, Delpero JR, Dervenis C, Ducreux M, Gal J, Gerber E, Ghaneh P, Hammel P, Hendlisz A, Jooste V, Labianca R, Latouche A, Lutz M, Macarulla T, Malka D, Mauer M, Mitry E, Neoptolemos J, Pessaux P, Sauvanet A, Tabernero J, Taieb J, van Tienhoven G, Gourgou-Bourgade S, Bellera C, Mathoulin-Pélissier S, Collette L. Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials) Eur J Cancer. 2014;50(17):2983–93. doi: 10.1016/j.ejca.2014.07.011.
    1. Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A, GERCOR; GISCAD Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005;23(15):3509–16. doi: 10.1200/JCO.2005.06.023.
    1. Safran H, Perez K, Charpentier K, Clark Austin T, Mantripragada KC, Bishop KD, Lombardo A, Houlihan L, Mitchell K, Rosati K, Martel D, Shaw L. Nab-paclitaxel (nab-P) combined with FOLFOX for advanced pancreatic cancer: A phase I study. J Clin Oncol. 2014;32(15_suppl):4123.
    1. Trouilloud I, Dupont-Gossard AC, Artru P, Lecomte T, Gauthier M, Aparicio T, Thirot-Bidault A, Malka D, Lobry C, Asnacios A, Lacombe S, Fein F, Fanica D, Dubreuil O, Marthey L, Zaanan A, Bonnetain F, Taïeb J. FOLFIRI.3 (CPT-11 plus folinic acid plus 5-FU) alternating with gemcitabine or gemcitabine (G) alone in patients (pts) with previously untreated metastatic pancreatic adenocarcinoma (MPA): Results of the randomized multicenter AGEO phase II trial FIRGEM. J Clin Oncol. 2012;30(15_suppl):4018.

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