Abstract
Purpose
To evaluate the efficacy and safety of masitinib combined with gemcitabine in patients with advanced pancreatic cancer.
Patients and methods
Twenty-two non-randomised patients with unresectable, locally advanced (n = 9) or metastatic pancreatic cancer (n = 13) received oral masitinib (9 mg/kg/day) combined with standard gemcitabine. All patients were naıve to systemic chemotherapy or radiotherapy. The primary endpoint was time-to-progression (TTP) with efficacy and safety analyses performed on the intent-to-treat population. Secondary endpoints included overall survival (OS), as well as, subgroup analyses according to baseline disease, and performance status.
Results
Overall median TTP was 6.4 months (95% CI [2.7–11.7]); 8.3 and 2.7 months, respectively, for locally advanced and metastatic patients; 6.4 and 0.8 months, respectively, for patients with KPS [80–100] or KPS [70]. Median OS was 7.1 months (95% CI [4.8–17.0]); 8.4 and 6.8 months for locally advanced or metastatic patients, respectively; 8.0 and 4.4 months in patients with KPS [80–100] or KPS [70], respectively. The 18-month observed survival rate was similar for locally advanced (22%) and metastatic patients (23%) and reached 28% for KPS [80–100] patients. The most common suspected adverse events were nausea, vomiting, rash, diarrhoea, peripheral oedema, anaemia, lymphopenia, thrombocytopenia, pyrexia, neutropenia, asthenia, leucopoenia, and abdominal pain, and most were of grades 1–2 severity.
Conclusions
The efficacy and safety of masitinib combined with gemcitabine are encouraging, with extended survival and median TTP that support initiation of a phase 3 trial.
References
American Cancer Society (2008) Cancer facts and figures 2008. American Cancer Society, Atlanta. http://www.cancer.org:downloads/STT/2008CAFFfinalsecured.pdf
Wisinski KB, Wahl AO, Small W Jr, Benson AB III (2007) Inoperable pancreatic cancer: standard of care. Oncology (Williston Park) 21(13):1558–1564 (discussion 1565, 1570–1572)
Ghaneh P, Costello E, Neoptolemos J (2007) Biology and management of pancreatic cancer. Gut 56(8):1134–1152. doi:10.1136/gut.2006.103333
Saif MW (2008) Is there a standard of care for the management of advanced pancreatic cancer? Highlights from the gastrointestinal cancers symposium. Orlando, FL, USA. Jan 25–27, 2008. JOP 9(2):91–98. doi:v09i02a02[pii]
Xie DR, Liang HL, Wang Y, Guo SS, Yang Q (2006) Meta-analysis on inoperable pancreatic cancer: a comparison between gemcitabine-based combination therapy and gemcitabine alone. World J Gastroenterol 12(43):6973–6981
Saif MW (2006) Pancreatic cancer: highlights from the 42nd annual meeting of the American Society of Clinical Oncology, 2006. JOP 7(4):337–348. doi:v07i04a02[pii]
Burris HA III, 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 (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25(15):1960–1966. doi:JCO.2006.07.9525[pii]10.1200/JCO.2006.07.9525
Hwang RF, Yokoi K, Bucana CD, Tsan R, Killion JJ, Evans DB, Fidler IJ (2003) Inhibition of platelet-derived growth factor receptor phosphorylation by STI571 (Gleevec) reduces growth and metastasis of human pancreatic carcinoma in an orthotopic nude mouse model. Clin Cancer Res 9(17):6534–6544
Kimura W, Ma J, Takeshita A, Yamamoto T, Moriya T, Hirai I, Fuse A (2007) Analysis of c-kit protein expression in pancreatic neoplasms and its implication for prognosis. Hepatogastroenterology 54(80):2203–2208
Ebert M, Yokoyama M, Friess H, Kobrin MS, Buchler MW, Korc M (1995) Induction of platelet-derived growth factor A and B chains and over-expression of their receptors in human pancreatic cancer. Int J Cancer 62(5):529–535
Furuyama K, Doi R, Mori T, Toyoda E, Ito D, Kami K, Koizumi M, Kida A, Kawaguchi Y, Fujimoto K (2006) Clinical significance of focal adhesion kinase in resectable pancreatic cancer. World J Surg 30(2):219–226. doi:10.1007/s00268-005-0165-z
Gabarra-Niecko V, Schaller MD, Dunty JM (2003) FAK regulates biological processes important for the pathogenesis of cancer. Cancer Metastasis Rev 22(4):359–374
Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE (2004) Focal adhesion kinase gene silencing promotes anoikis and suppresses metastasis of human pancreatic adenocarcinoma cells. Surgery 135(5):555–562. doi:10.1016/j.surg.2003.10.017S0039606003006536[pii]
Duxbury MS, Ito H, Benoit E, Zinner MJ, Ashley SW, Whang EE (2003) RNA interference targeting focal adhesion kinase enhances pancreatic adenocarcinoma gemcitabine chemosensitivity. Biochem Biophys Res Commun 311(3):786–792. doi:S0006291X03021478[pii]
Kornberg L, Earp HS, Parsons JT, Schaller M, Juliano RL (1992) Cell adhesion or integrin clustering increases phosphorylation of a focal adhesion-associated tyrosine kinase. J Biol Chem 267(33):23439–23442
Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH, Schlaepfer DD (2000) FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol 2(5):249–256. doi:10.1038/35010517
Friess H, Guo XZ, Nan BC, Kleeff O, Buchler MW (1999) Growth factors and cytokines in pancreatic carcinogenesis. Ann N Y Acad Sci 880:110–121
van Nimwegen MJ, van de Water B (2007) Focal adhesion kinase: a potential target in cancer therapy. Biochem Pharmacol 73(5):597–609. doi:S0006-2952(06)00505-3[pii]10.1016/j.bcp.2006.08.011
Theoharides TC (2008) Mast cells and pancreatic cancer. N Engl J Med 358(17):1860–1861
Hahn K, Oglivie G, Rusk T, Devauchelle P, Leblanc A, Legendre A, Powers B, Leventhal PS, Kinet JP, Palmerini F, Dubreuil P, Moussy A, Hermine O (2008) Masitinib is safe and effective for the treatment of canine mast cell tumors. J Vet Intern Med 22(6):1301–1309. doi:JVIM190[pii]10.1111/j.1939-1676.2008.0190.x
Bui BN, Blay JY, Duffaud F, Hermine O, Hermine O, Le Cesne A (2007) Preliminary efficacy and safety results of masitinib administered front line in patients with advanced GIST—a phase 2 study. J Clin Oncol ASCO Ann Meet Proc Part I 25 No 18S(Suppl 20):10025
Soria JC, Massard C, Magne N, Bader T, Mansfield CD, Blay JY, Bui BN, Moussy A, Hermine O, Armand JP (2009) Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers. Eur J Cancer 45(13):2333–2341. doi:10.1016/j.ejca.2009.05.010
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216
Storniolo AM, Enas NH, Brown CA, Voi M, Rothenberg ML, Schilsky R (1999) An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma. Cancer 85:1261–1268
Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A (2008) Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol 9(1):39–44. doi:S1470-2045(07)70383-2[pii]10.1016/S1470-2045(07)70383-2
Van Glabbeke M, Verweij J, Casali PG et al (2006) Predicting toxicities for patients with advanced gastrointestinal stromal tumours treated with imatinib: a study of the European Organisation for Research and Treatment of Cancer, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group (EORTC-ISG-AGITG). Eur J Cancer 42:2277–2285
Tebib J, Mariette X, Bourgeois P et al (2009) Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study. Arthritis Res Ther 11:R95
Kullmann F, Hollerbach S, Dollinger MM, Harder J, Fuchs M, Messmann H, Trojan J, Gabele E, Hinke A, Hollerbach C, Endlicher E (2009) Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study. Br J Cancer 100(7):1032–1036. doi:6604983[pii]10.1038/sj.bjc.6604983
Ko AH, Dito E, Schillinger B, Venook AP, Xu Z, Bergsland EK, Wong D, Scott J, Hwang J, Tempero MA (2008) A phase II study evaluating bevacizumab in combination with fixed-dose rate gemcitabine and low-dose cisplatin for metastatic pancreatic cancer: is an anti-VEGF strategy still applicable? Invest New Drugs 26(5):463–471. doi:10.1007/s10637-008-9127-2
Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T, Zaniboni A, Ducreux M, Aitini E, Taieb J, Faroux R, Lepere C, de Gramont A (2005) 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 23(15):3509–3516. doi:23/15/3509[pii]10.1200/JCO.2005.06.023
Ueno H, Okusaka T, Ikeda M, Morizane C, Ogura T, Hagihara A, Tanaka T (2007) Phase II study of combination chemotherapy with gemcitabine and cisplatin for patients with metastatic pancreatic cancer. Jpn J Clin Oncol 37(7):515–520. doi:hym060[pii]10.1093/jjco/hym060
Park JK, Yoon YB, Kim YT, Ryu JK, Yoon WJ, Lee SH (2008) Survival and prognostic factors of unresectable pancreatic cancer. J Clin Gastroenterol 42(1):86–91. doi:10.1097/01.mcg.0000225657.30803.9d00004836-200801000-00017[pii]
Pietras K, Rubin K, Sjoblom T, Buchdunger E, Sjoquist M, Heldin CH, Ostman A (2002) Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res 62(19):5476–5484
Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, Rubin K (2001) Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 61(7):2929–2934
Acknowledgments
The authors thank Dr. Marie-Pierre Furrer, PhD and Colin Mansfield, PhD who provided medical writing services on behalf of AB Science. Financial support for this study was provided by AB science, SA.
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Mitry, E., Hammel, P., Deplanque, G. et al. Safety and activity of masitinib in combination with gemcitabine in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol 66, 395–403 (2010). https://doi.org/10.1007/s00280-010-1299-8
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DOI: https://doi.org/10.1007/s00280-010-1299-8