Combination of Gemcitabine and Imatinib Mesylate in Pemetrexed-pretreated Patients With Pleural Mesothelioma

Summary

This is a phase II, monocentric study of the combination of gemcitabine and imatinib mesylate in pemetrexed-pretreated patients with MPM expressing PDGFR-beta and/or C-kit by Immunohistochemistry (IHC). Treatment will be done until disease progression, or patient refusal or withdrawal of patient consent, or unacceptable toxicity

Timeline

Start

2014-11

Primary completion

2015-12

Completion

2017-12

Publications

• Background Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003 Jul 15;21(14):2636-44. doi: 10.1200/JCO.2003.11.136.
• Background Ceresoli GL, Zucali PA, Favaretto AG, Grossi F, Bidoli P, Del Conte G, Ceribelli A, Bearz A, Morenghi E, Cavina R, Marangolo M, Parra HJ, Santoro A. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol. 2006 Mar 20;24(9):1443-8. doi: 10.1200/JCO.2005.04.3190.
• Background Castagneto B, Botta M, Aitini E, Spigno F, Degiovanni D, Alabiso O, Serra M, Muzio A, Carbone R, Buosi R, Galbusera V, Piccolini E, Giaretto L, Rebella L, Mencoboni M. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM). Ann Oncol. 2008 Feb;19(2):370-3. doi: 10.1093/annonc/mdm501. Epub 2007 Dec 20.
• Background Santoro A, O'Brien ME, Stahel RA, Nackaerts K, Baas P, Karthaus M, Eberhardt W, Paz-Ares L, Sundstrom S, Liu Y, Ripoche V, Blatter J, Visseren-Grul CM, Manegold C. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaive patients with malignant pleural mesothelioma: results of the International Expanded Access Program. J Thorac Oncol. 2008 Jul;3(7):756-63. doi: 10.1097/JTO.0b013e31817c73d6.
• Background Ceresoli GL, Zucali PA, Gianoncelli L, Lorenzi E, Santoro A. Second-line treatment for malignant pleural mesothelioma. Cancer Treat Rev. 2010 Feb;36(1):24-32. doi: 10.1016/j.ctrv.2009.09.003. Epub 2009 Oct 29.
• Background Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, Rubin K. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res. 2001 Apr 1;61(7):2929-34.
• Background Pietras K, Rubin K, Sjoblom T, Buchdunger E, Sjoquist M, Heldin CH, Ostman A. Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res. 2002 Oct 1;62(19):5476-84.
• Background Pietras K, Stumm M, Hubert M, Buchdunger E, Rubin K, Heldin CH, McSheehy P, Wartmann M, Ostman A. STI571 enhances the therapeutic index of epothilone B by a tumor-selective increase of drug uptake. Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3779-87.
• Background Garlepp MJ, Leong CC. Biological and immunological aspects of malignant mesothelioma. Eur Respir J. 1995 Apr;8(4):643-50.
• Background Langerak AW, van der Linden-van Beurden CA, Versnel MA. Regulation of differential expression of platelet-derived growth factor alpha- and beta-receptor mRNA in normal and malignant human mesothelial cell lines. Biochim Biophys Acta. 1996 Feb 7;1305(1-2):63-70. doi: 10.1016/0167-4781(95)00196-4.
• Background Pogrebniak HW, Lubensky IA, Pass HI. Differential expression of platelet derived growth factor-beta in malignant mesothelioma: a clue to future therapies? Surg Oncol. 1993 Aug;2(4):235-40. doi: 10.1016/0960-7404(93)90012-n.
• Background Klominek J, Baskin B, Hauzenberger D. Platelet-derived growth factor (PDGF) BB acts as a chemoattractant for human malignant mesothelioma cells via PDGF receptor beta-integrin alpha3beta1 interaction. Clin Exp Metastasis. 1998 Aug;16(6):529-39. doi: 10.1023/a:1006542301794.
• Background Sawyers C. Targeted cancer therapy. Nature. 2004 Nov 18;432(7015):294-7. doi: 10.1038/nature03095.
• Background Shih AH, Holland EC. Platelet-derived growth factor (PDGF) and glial tumorigenesis. Cancer Lett. 2006 Feb 8;232(2):139-47. doi: 10.1016/j.canlet.2005.02.002. Epub 2005 Aug 31.
• Background Yu J, Ustach C, Kim HR. Platelet-derived growth factor signaling and human cancer. J Biochem Mol Biol. 2003 Jan 31;36(1):49-59. doi: 10.5483/bmbrep.2003.36.1.049.
• Background Johnson MD, Okedli E, Woodard A, Toms SA, Allen GS. Evidence for phosphatidylinositol 3-kinase-Akt-p7S6K pathway activation and transduction of mitogenic signals by platelet-derived growth factor in meningioma cells. J Neurosurg. 2002 Sep;97(3):668-75. doi: 10.3171/jns.2002.97.3.0668.
• Background Porta C, Mutti L, Tassi G. Negative results of an Italian Group for Mesothelioma (G.I.Me.) pilot study of single-agent imatinib mesylate in malignant pleural mesothelioma. Cancer Chemother Pharmacol. 2007 Jan;59(1):149-50. doi: 10.1007/s00280-006-0243-4. Epub 2006 Apr 25. No abstract available.
• Background Roberts F, Harper CM, Downie I, Burnett RA. Immunohistochemical analysis still has a limited role in the diagnosis of malignant mesothelioma. A study of thirteen antibodies. Am J Clin Pathol. 2001 Aug;116(2):253-62. doi: 10.1309/XL6K-8E62-9FLD-V8Q8.
• Background George D. Platelet-derived growth factor receptors: a therapeutic target in solid tumors. Semin Oncol. 2001 Oct;28(5 Suppl 17):27-33.
• Background Taylor JR, Brownlow N, Domin J, Dibb NJ. FMS receptor for M-CSF (CSF-1) is sensitive to the kinase inhibitor imatinib and mutation of Asp-802 to Val confers resistance. Oncogene. 2006 Jan 5;25(1):147-51. doi: 10.1038/sj.onc.1209007.
• Background Mathy A, Baas P, Dalesio O, van Zandwijk N. Limited efficacy of imatinib mesylate in malignant mesothelioma: a phase II trial. Lung Cancer. 2005 Oct;50(1):83-6. doi: 10.1016/j.lungcan.2005.04.010.
• Background Bertino P, Porta C, Barbone D, Germano S, Busacca S, Pinato S, Tassi G, Favoni R, Gaudino G, Mutti L. Preliminary data suggestive of a novel translational approach to mesothelioma treatment: imatinib mesylate with gemcitabine or pemetrexed. Thorax. 2007 Aug;62(8):690-5. doi: 10.1136/thx.2006.069872. Epub 2007 Feb 20.
• Background Bertino P, Piccardi F, Porta C, Favoni R, Cilli M, Mutti L, Gaudino G. Imatinib mesylate enhances therapeutic effects of gemcitabine in human malignant mesothelioma xenografts. Clin Cancer Res. 2008 Jan 15;14(2):541-8. doi: 10.1158/1078-0432.CCR-07-1388.
• Background George S, Desai J, Paul Eder J, Manola J, Ryan DP, Appleman LJ, Demetri GD. Selective kinase inhibition with daily imatinib intensifies toxicity of chemotherapy in patients with solid tumours. Eur J Cancer. 2006 May;42(7):864-70. doi: 10.1016/j.ejca.2005.12.010. Epub 2006 Feb 28.
• Background Ali Y, Lin Y, Gharibo MM, Gounder MK, Stein MN, Lagattuta TF, Egorin MJ, Rubin EH, Poplin EA. Phase I and pharmacokinetic study of imatinib mesylate (Gleevec) and gemcitabine in patients with refractory solid tumors. Clin Cancer Res. 2007 Oct 1;13(19):5876-82. doi: 10.1158/1078-0432.CCR-07-0883.
• Background Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol. 2004 Feb;15(2):257-60. doi: 10.1093/annonc/mdh059.

Drugs

Indications