Skip to main content

Advertisement

Log in

Safety and activity of masitinib in combination with gemcitabine in patients with advanced pancreatic cancer

  • Clinical Trial Report
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  1. American Cancer Society (2008) Cancer facts and figures 2008. American Cancer Society, Atlanta. http://www.cancer.org:downloads/STT/2008CAFFfinalsecured.pdf

  2. 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)

    Google Scholar 

  3. Ghaneh P, Costello E, Neoptolemos J (2007) Biology and management of pancreatic cancer. Gut 56(8):1134–1152. doi:10.1136/gut.2006.103333

    Article  CAS  PubMed  Google Scholar 

  4. 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]

  5. 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

    CAS  PubMed  Google Scholar 

  6. 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]

    PubMed  Google Scholar 

  7. 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

    CAS  PubMed  Google Scholar 

  8. 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

    Article  CAS  PubMed  Google Scholar 

  9. 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

    CAS  PubMed  Google Scholar 

  10. 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

    PubMed  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. 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

    Article  PubMed  Google Scholar 

  13. 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

    Article  CAS  PubMed  Google Scholar 

  14. 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]

    Article  CAS  PubMed  Google Scholar 

  15. 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]

    Article  CAS  PubMed  Google Scholar 

  16. 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

    CAS  PubMed  Google Scholar 

  17. 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

    Article  CAS  PubMed  Google Scholar 

  18. 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

    Article  CAS  PubMed  Google Scholar 

  19. 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

    Article  PubMed  Google Scholar 

  20. Theoharides TC (2008) Mast cells and pancreatic cancer. N Engl J Med 358(17):1860–1861

    Article  CAS  PubMed  Google Scholar 

  21. 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

    Article  CAS  PubMed  Google Scholar 

  22. 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

  23. 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

    Article  CAS  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed  Google Scholar 

  25. 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

    Article  CAS  PubMed  Google Scholar 

  26. 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

    Article  CAS  PubMed  Google Scholar 

  27. 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

    Article  PubMed  Google Scholar 

  28. 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

    Article  PubMed  Google Scholar 

  29. 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

    Article  CAS  PubMed  Google Scholar 

  30. 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

    Article  CAS  PubMed  Google Scholar 

  31. 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

    Article  CAS  PubMed  Google Scholar 

  32. 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

    Article  PubMed  Google Scholar 

  33. 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]

    Article  PubMed  Google Scholar 

  34. 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

    CAS  PubMed  Google Scholar 

  35. 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

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eric Raymond.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-010-1299-8

Keywords

Navigation