Investigational New Drugs

, Volume 26, Issue 6, pp 561–565 | Cite as

O-Mel-Inib: A Cancéro-pôle Nord-Ouest multicenter phase II trial of high-dose Imatinib mesylate in metastatic uveal melanoma

  • Nicolas PenelEmail author
  • Corinne Delcambre
  • Xavier Durando
  • Stéphanie Clisant
  • Mohamed Hebbar
  • Sylvie Negrier
  • Charles Fournier
  • Nicolas Isambert
  • Frédéric Mascarelli
  • Frédéric Mouriaux


Background: Nowadays, there is no consensual and effective treatment in metastatic uveal melanoma (MUM). Numerous preclinical data (for example, 75% of MUM express c-kit) suggest that imatinib mesylate (IM) may be a potential treatment of UMM. Methods: The primary objective of this phase II trial was to determine the non-progression rate at 3 months for patients receiving IM at dose of 400 mg twice per day orally. The study was based on a Simon’s optimal design, which allows entry a total of 29 patients, if at least two non-progressions among ten first patients were observed. Result: Thirteen patients including ten assessable patients were enrolled in 12 months. No objective response and only one stable disease with duration of 5 months were noted. Five and one out of 13 enrolled patients experienced grade 3 and grade 4 toxicities, respectively. The most common severe adverse events were abdominal pain. The overall survival was 10.8 months. Conclusions: Despite promising preclinical data, IM is an inactive single agent in MUM. This phase II clinical trial has been stopped at the first step.


Uveal melanoma Imatinib mesylate Metastasis Phase II Targeted therapy 



The authors would like to thank Yvette Vendel, Muriel Chapoutier and Elodie Desrennes. This study was supported by Clinical Research grant RC-071-2005 from Institut National du Cancer (Cancéro-pôle Nord-Ouest) and grant from Novartis Pharmaceutical (to NP).


  1. 1.
    Woll E, Bedikian A, Legha SS (1999) Uveal melanoma: natural history and treatment options for metastatic disease. Melanoma Res 9:575–581PubMedCrossRefGoogle Scholar
  2. 2.
    Bedikian AY, Legha SS, Mavliit G et al (1995) Treatment of uveal melanoma metastatic to the liver. A review of the M.D. Anderson Cancer Center Experience and prognostic factor. Cancer 76:1665–1670PubMedCrossRefGoogle Scholar
  3. 3.
    Grosjean J, Penel N, Gauthier H et al (2004) Dissémination métastatique ultra-tardive de melanoma oculaire: à propos de deux cas. Rev Med Interne 25:147–149PubMedCrossRefGoogle Scholar
  4. 4.
    Shmittel A, Shmidt-Hieber M, Martus P et al (2006) A randomized phase II trial of gemcitabine plus treosulfab versus treosulfan alone in patients with metastaitc uveal melanoma. Ann Oncol 17:1826–1829CrossRefGoogle Scholar
  5. 5.
    Peters S, Voelter V, Zografos L et al (2006) Intra-arterial hepatic fotemustine for the treatment of liver metastases from uveal melanoma: experience in 101 patients. Ann Oncol 17:578–583PubMedCrossRefGoogle Scholar
  6. 6.
    Kodjikian L, Grange JD, Baldo S et al (2005) Prognostic factors of liver metastases from uveal melanoma. Graefes Arch Clin Exp Ophthalmol 243:985–993PubMedCrossRefGoogle Scholar
  7. 7.
    Heinrich MC, Corless CL, Demetri GD et al (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349PubMedCrossRefGoogle Scholar
  8. 8.
    Lynch TJ, Bell DW, Sordella R et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139PubMedCrossRefGoogle Scholar
  9. 9.
    Demetri GD, von Mehren M, Blanke CD et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumours. N Engl J Med 347:472–480PubMedCrossRefGoogle Scholar
  10. 10.
    Penel N, Le Cesne A, Bui BN, et al. (2002) Imatinib for the treatment of aggressive fibromatosis (desmoid tumors) failing local treatment. A Phase II trial of the French Sarcoma Group. J Clin Oncol (Meeting Abstracts) 24(suppl 18): Abstract 9516Google Scholar
  11. 11.
    Maki RG, Awan RA, Dixon RH et al (2002) Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma protuberans. Int J Cancer 100:623–626PubMedCrossRefGoogle Scholar
  12. 12.
    Penel N, Saleron J, Lansiaux A et al (2008) Methodological approaches of clinical studies with targeted therapies. Bull Cancer 95:185–190PubMedGoogle Scholar
  13. 13.
    Mouriaux F, Chahud F, Maurage CA et al (2001) Implication of stem cell factor in the proliferation of choroidal melanocytes. Exp Eye Res 73:151–157PubMedCrossRefGoogle Scholar
  14. 14.
    Mouriaux F, Kherrouche Z, Maurage CA et al (2003) Expression of c-kit receptor in choroidal melanomas. Melanoma Res 13:161–166PubMedCrossRefGoogle Scholar
  15. 15.
    Pereira PR, Odashiro AN, Marshall JC et al (2005) The role of c-kit and imatinib mesylate in uveal melanoma. J Carcinog 19:4–19Google Scholar
  16. 16.
    Lefebvre G, Glotin AL, Calipel A et al (2004) Roles of stem/cell Factors/c-kit and effects of Glivec/STI571 in Human Uveal Melanoma Cell tumoregenesis. J Biol Chem 279:31769–31779CrossRefGoogle Scholar
  17. 17.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumours. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  18. 18.
    Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10PubMedCrossRefGoogle Scholar
  19. 19.
    Wyman K, Atkins MB, Prieto V et al (2006) Multicenter phase II trial of high-dose imatinib mesylate in metastatic melanoma. Significant toxicity with no clinical efficacy. Cancer 106:2005–2011PubMedCrossRefGoogle Scholar
  20. 20.
    Katarjian HM, Talpaz M, O’Brien S et al (2003) Dose escalation of imatinib mesylate can recover resistance to standard-dose therapy inpatients with chronic myelogenous leukaemia. Blood 101:473–475CrossRefGoogle Scholar
  21. 21.
    Verweij J, Casali PG, Zalcberg J et al (2004) Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364:1127–1134PubMedCrossRefGoogle Scholar
  22. 22.
    Fiorentini G, Rossi S, Lanzonova G et al (2003) Potential use of imatinib mesylate in ocular melanoma and liposarcoma expressing immunohistochemical c-kit (CD117). Ann Oncol 14:805PubMedCrossRefGoogle Scholar
  23. 23.
    All-Ericsson C, Girnita L, Muller-Brunotte A et al (2004) c-Kit-dependent growth of uveal melanoma cells: a potential therapeutic target? Invest Ophthalmol Vis Sci 45:2075–2082PubMedCrossRefGoogle Scholar
  24. 24.
    Calipel A, Lefebvre G, Pouponnot C et al (2003) Mutation of B-Raf in human choroidal melanoma cells mediates cell proliferation and transformation through the MEK/ERK pathway. J Biol Chem 278:42409–42418PubMedCrossRefGoogle Scholar
  25. 25.
    Thatcher N, Chang A, Parikh P et al (2005) Gefinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527–1537PubMedCrossRefGoogle Scholar
  26. 26.
    Chung KY, Shia J, Kemeny NE et al (2005) Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803–1810PubMedCrossRefGoogle Scholar
  27. 27.
    Natali PG, Nicotra MR, Winkler AB et al (1992) Progression of human cutaneous melanoma is associated with loss of expression of c-kit proto-oncogene receptor. Int J Cancer 52:197–201PubMedCrossRefGoogle Scholar
  28. 28.
    Montone KT, Van Belle P, Elenitsas R, Elder DE (1997) Proto-oncogene c-kit expression in malignant melanoma protein loss with tumor progression. Mod Pathol 10:939–944PubMedGoogle Scholar
  29. 29.
    Krug LM, Crapanzano JP, Azzoli CG et al (2005) Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: a phase II clinical trial. Cancer 103:2128–2131PubMedCrossRefGoogle Scholar
  30. 30.
    Pfeffer MR, Talmi Y, Catane R et al (2007) A phase II study of imatinib for advanced adenoid cysric carcinoma of head and neck salivary glands. Oral Oncol 43:33–36PubMedCrossRefGoogle Scholar
  31. 31.
    Alberts DS, Liu PY, Wilczynski SP et al (2007) Phase II trial of imatinib mesylate in recurrent, biomarker positive, ovarian cancer (Southwest Oncology Group Protocol SO211). Int J Gynecol Cancer 17(4):784–788PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Nicolas Penel
    • 1
    • 2
    Email author
  • Corinne Delcambre
    • 3
  • Xavier Durando
    • 4
  • Stéphanie Clisant
    • 5
  • Mohamed Hebbar
    • 6
  • Sylvie Negrier
    • 7
  • Charles Fournier
    • 8
  • Nicolas Isambert
    • 9
  • Frédéric Mascarelli
    • 10
  • Frédéric Mouriaux
    • 10
    • 11
  1. 1.Département de Cancérologie GénéraleCentre Oscar LambretLilleFrance
  2. 2.Equipe d’Accueil 2694: Santé Publique, Epidémiologie et modélisation des maladies chroniquesUniversité Lille IILilleFrance
  3. 3.Service d’Oncologie MédicaleCentre François BaclesseCaenFrance
  4. 4.Service d’Oncologie MédicaleCentre Jean PerrinClermont-FerrandFrance
  5. 5.Unité Intégrée de Recherche CliniqueCentre Oscar LambretLilleFrance
  6. 6.Service Universitaire d’Oncologie MédicaleCHRULilleFrance
  7. 7.Service d’Oncologie MédicaleCentre Léon BérardLyonFrance
  8. 8.Unité de BiostatistiquesCentre Oscar LambretLilleFrance
  9. 9.Service d’Oncologie MédicaleCentre Georges-François LeclercDijonFrance
  10. 10.Centre de Recherche des Cordeliers, UMR S 872 et INSERM U 872Université Pierre et Marie Curie et Université Paris DescartesParisFrance
  11. 11.Service Universitaire d’OphtalmologieCHRUCaenFrance

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