Tolfenamic Acid, Gemcitabine and Radiation for Locally Advanced or Metastatic Pancreatic Cancer Requiring Radiation

Summary

The purposes of this study are to: * Evaluate the safety and toxicity of tolfenamic acid when used with gemcitabine and radiation therapy in patients with locally advanced or metastatic pancreatic cancer. * Determine the maximum-tolerated dose (MTD) of tolfenamic acid when used with gemcitabine and radiation in pancreatic cancer. * Characterize the pharmacokinetic profile of tolfenamic acid when used with gemcitabine and radiation. * Assess the anti-tumor response to tolfenamic acid when used with gemcitabine and radiation in patients with advanced pancreatic malignancies.

Timeline

Start

2014-03

Primary completion

2017-08

Completion

2019-12

Outcome

Outcome not reported

Stopped (Enrollment): “The study closed prior to enrolling any participants.”

Publications

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• Background Jutooru I, Chadalapaka G, Abdelrahim M, Basha MR, Samudio I, Konopleva M, Andreeff M, Safe S. Methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate decreases specificity protein transcription factors and inhibits pancreatic tumor growth: role of microRNA-27a. Mol Pharmacol. 2010 Aug;78(2):226-36. doi: 10.1124/mol.110.064451. Epub 2010 May 20.
• Background Abdelrahim M, Baker CH, Abbruzzese JL, Safe S. Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. J Natl Cancer Inst. 2006 Jun 21;98(12):855-68. doi: 10.1093/jnci/djj232.
• Background Abdelrahim M, Baker CH, Abbruzzese JL, Sheikh-Hamad D, Liu S, Cho SD, Yoon K, Safe S. Regulation of vascular endothelial growth factor receptor-1 expression by specificity proteins 1, 3, and 4 in pancreatic cancer cells. Cancer Res. 2007 Apr 1;67(7):3286-94. doi: 10.1158/0008-5472.CAN-06-3831.
• Background Konduri S, Colon J, Baker CH, Safe S, Abbruzzese JL, Abudayyeh A, Basha MR, Abdelrahim M. Tolfenamic acid enhances pancreatic cancer cell and tumor response to radiation therapy by inhibiting survivin protein expression. Mol Cancer Ther. 2009 Mar;8(3):533-42. doi: 10.1158/1535-7163.MCT-08-0405. Epub 2009 Mar 3.
• Background Maliakal P, Abdelrahim M, Sankpal UT, Maliakal C, Baker CH, Safe S, Herrera LJ, Abudayyeh A, Kaja S, Basha R. Chemopreventive effects of tolfenamic acid against esophageal tumorigenesis in rats. Invest New Drugs. 2012 Jun;30(3):853-61. doi: 10.1007/s10637-010-9622-0. Epub 2011 Jan 4.
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• Background A multi-institutional comparative trial of radiation therapy alone and in combination with 5-fluorouracil for locally unresectable pancreatic carcinoma. The Gastrointestinal Tumor Study Group. Ann Surg. 1979 Feb;189(2):205-8.
• Background Atasoy BM, Dane F, Ucuncu Kefeli A, Caglar H, Cingi A, Turhal NS, Abacioglu U, Yegen C. Concomitant chemoradiotherapy with low-dose weekly gemcitabine for nonmetastatic unresectable pancreatic cancer. Turk J Gastroenterol. 2011 Feb;22(1):60-4. doi: 10.4318/tjg.2011.0158.
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• Background Davis DW, Inoue K, Dinney CP, Hicklin DJ, Abbruzzese JL, McConkey DJ. Regional effects of an antivascular endothelial growth factor receptor monoclonal antibody on receptor phosphorylation and apoptosis in human 253J B-V bladder cancer xenografts. Cancer Res. 2004 Jul 1;64(13):4601-10. doi: 10.1158/0008-5472.CAN-2879-2.
• Background Kozin SV, Boucher Y, Hicklin DJ, Bohlen P, Jain RK, Suit HD. Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. Cancer Res. 2001 Jan 1;61(1):39-44.
• Background Laird AD, Christensen JG, Li G, Carver J, Smith K, Xin X, Moss KG, Louie SG, Mendel DB, Cherrington JM. SU6668 inhibits Flk-1/KDR and PDGFRbeta in vivo, resulting in rapid apoptosis of tumor vasculature and tumor regression in mice. FASEB J. 2002 May;16(7):681-90. doi: 10.1096/fj.01-0700com.
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• Background Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J, Plaisance S, De Mol M, Bono F, Kliche S, Fellbrich G, Ballmer-Hofer K, Maglione D, Mayr-Beyrle U, Dewerchin M, Dombrowski S, Stanimirovic D, Van Hummelen P, Dehio C, Hicklin DJ, Persico G, Herbert JM, Communi D, Shibuya M, Collen D, Conway EM, Carmeliet P. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med. 2003 Jul;9(7):936-43. doi: 10.1038/nm884.
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• Background Andre T, Kotelevets L, Vaillant JC, Coudray AM, Weber L, Prevot S, Parc R, Gespach C, Chastre E. Vegf, Vegf-B, Vegf-C and their receptors KDR, FLT-1 and FLT-4 during the neoplastic progression of human colonic mucosa. Int J Cancer. 2000 Apr 15;86(2):174-81. doi: 10.1002/(sici)1097-0215(20000415)86:23.0.co;2-e.
• Background Abdelrahim M, Smith R 3rd, Burghardt R, Safe S. Role of Sp proteins in regulation of vascular endothelial growth factor expression and proliferation of pancreatic cancer cells. Cancer Res. 2004 Sep 15;64(18):6740-9. doi: 10.1158/0008-5472.CAN-04-0713.
• Background Shi Q, Le X, Abbruzzese JL, Peng Z, Qian CN, Tang H, Xiong Q, Wang B, Li XC, Xie K. Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res. 2001 May 15;61(10):4143-54.
• Background Abdelrahim M, Safe S. Cyclooxygenase-2 inhibitors decrease vascular endothelial growth factor expression in colon cancer cells by enhanced degradation of Sp1 and Sp4 proteins. Mol Pharmacol. 2005 Aug;68(2):317-29. doi: 10.1124/mol.105.011825. Epub 2005 May 9.
• Background Wei D, Wang L, He Y, Xiong HQ, Abbruzzese JL, Xie K. Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res. 2004 Mar 15;64(6):2030-8. doi: 10.1158/0008-5472.can-03-1945.
• Background Black AR, Black JD, Azizkhan-Clifford J. Sp1 and kruppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol. 2001 Aug;188(2):143-60. doi: 10.1002/jcp.1111.
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Indications