Clinical trial NCT02159248: Tolfenamic Acid, Gemcitabine and Radiation for Locally Advanced or Metastatic Pancreatic Cancer Requiring Radiation
Official title: 09.017 - A Phase I Study of Tolfenamic Acid With Gemcitabine and Radiation in Patients With Locally Advanced or Metastatic Pancreatic Cancer Requiring Definitive or Palliative Radiation Therapy
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Pancreatic Cancer
Keywords: pancreatic, gemcitabine, radiation, tolfenamic acid
Lead sponsor: Orlando Health, Inc.
Sponsor class: OTHER
First posted: 2014-06-09
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed description: This is a phase I, open-label, non-randomized, single-center, dose-escalation study which utilizes tolfenamic acid in combination with gemcitabine and radiation in patients with locally advanced or metastatic pancreatic malignancies which require definitive or palliative radiation.

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to have a variety of anti-neoplastic mechanisms, including inhibition of cell growth, promotion of apoptosis and inhibition of angiogenesis. Tolfenamic acid is an oral (NSAID) migraine medication which has demonstrated anti-tumor activity in preclinical pancreatic models when used with Gem/XRT (gemcitabine and radiation therapy) and as a single agent.

Each patient enrolled will receive tolfenamic acid in combination with Gem/XRT. Depending on cohort assignment, patients will self-administer tolfenamic acid at either 200mg, 400mg, 600mg or 800mg three times per day. Gemcitabine will be administered intravenously at 400 mg/m2, every seven days for a maximum of 5 doses, starting with the second week of tolfenamic acid administration. Radiation will be given 5 days per week (Monday-Friday) for up to 5 ½ weeks for a maximum dose of 50.4 Gy, beginning with the second week of tolfenamic acid administration.

A maximum of 24 patients will be enrolled in the dose escalation portion of the study. After the maximum tolerated dose (MTD) of tolfenamic acid has been determined, patients will be enrolled in an expansion cohort (at the MTD or the highest dose level achieved if the MTD is not reached) to further assess safety and the anti-tumor response to treatment with tolfenamic acid plus Gem/XRT.

Eligibility criteria: Primary Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed:

   1. Locally advanced (potentially resectable) pancreatic adenocarcinoma requiring neoadjuvant radiation or
   2. Locally advanced (nonresectable) or metastatic pancreatic adenocarcinoma requiring definitive or palliative radiation therapy
2. Patients may have either measurable or non-measurable disease (according to RECIST criteria, Version 1.1).
3. Age ≥ 18 years
4. ECOG performance status of 0 or 1.
5. A life expectancy of at least 12 weeks.
6. No other concurrent radiotherapy, chemotherapy or immunotherapy.
7. A minimum of 4 weeks must have elapsed since completion of any prior chemotherapy or immunotherapy.
8. Patient must have:

   1. Absolute neutrophil count (ANC) ≥1,000/mm3
   2. Platelets ≥100,000/mm3
   3. Hemoglobin ≥10 g/dL \[Transfusion to meet the hemoglobin requirement is acceptable\]
   4. Serum creatinine ≤ 1.5 X ULN
   5. Total bilirubin ≤ 1.5 X ULN
   6. Aspartate aminotransferase (AST) ≤ 2.5 X ULN
   7. Alanine aminotransferase (ALT) ≤ 2.5 X ULN
   8. Alkaline phosphatase ≤ 2.5 X ULN
   9. PT/INR ≤ 1.5 X ULN
   10. aPTT ≤ 1.5 X ULN
   11. Urine Protein ≤ Grade 1
9. For patients on warfarin: Must have maintained a stable INR on a stable dose of warfarin for at least 4 weeks prior to start of treatment.

Primary Exclusion Criteria:

1. Patients who have received prior radiation for their current malignancy at the location of interest.
2. Patients who have not recovered (to Grade 1 or less) from adverse events, other than alopecia and neuropathy, caused by previously administered chemotherapeutic agents, at the discretion of the PI/treating physician.
3. Tolfenamic acid use concurrent with, or within 8 weeks prior to the diagnosis of pancreatic cancer.
4. Current use of any non-steroidal anti-inflammatory agents (NSAIDs), including aspirin, (other than tolfenamic acid) within 4 weeks prior to the start of active treatment.
5. Previous history of hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin or other NSAIDs.
6. History of recurrent peptic ulcer/hemorrhage (two or more distinct episodes).
7. History of gastrointestinal bleeding or perforation related to previous use of NSAIDS.
8. New York Heart Association Functional Classification of 3 or 4.
9. Known autoimmune disease that could preclude the use of radiation, at the discretion of the treating physician.
10. History or evidence of CNS disease (e.g., any brain metastases, primary brain tumor, seizures not controlled with standard medical therapy, or history of stroke).
11. Known HIV positive.
12. Active systemic infection requiring parenteral antibiotic therapy.
13. Receiving systemic steroid therapy. (Inhaled steroid therapy is allowable.)
14. History of other malignancies within the last 5 years with the exception of non- melanoma skin cancer or cervical cancer in situ that has been successfully treated.

Primary outcomes:
measure: Evaluate safety and toxicity
timeFrame: Approximately 16 weeks
Secondary outcomes:
measure: Assess the anti-tumor response.
timeFrame: Approximately 16 weeks
Other outcomes:
Locations:
city: Orlando
country: United States
facility: UF Health Cancer Center at Orlando Health
state: Florida
Study officials:
affiliation: Orlando Health
name: Omar R Kayaleh, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Rich TA, Shepard RC, Mosley ST. Four decades of continuing innovation with fluorouracil: current and future approaches to fluorouracil chemoradiation therapy. J Clin Oncol. 2004 Jun 1;22(11):2214-32. doi: 10.1200/JCO.2004.08.009.
citation: 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.
citation: 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.
citation: Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW, Vauthey JN, Wang H, Cleary KR, Staerkel GA, Charnsangavej C, Lano EA, Ho L, Lenzi R, Abbruzzese JL, Wolff RA. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008 Jul 20;26(21):3496-502. doi: 10.1200/JCO.2007.15.8634.
citation: Joensuu TK, Kiviluoto T, Karkkainen P, Vento P, Kivisaari L, Tenhunen M, Westberg R, Elomaa I. Phase I-II trial of twice-weekly gemcitabine and concomitant irradiation in patients undergoing pancreaticoduodenectomy with extended lymphadenectomy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004 Oct 1;60(2):444-52. doi: 10.1016/j.ijrobp.2004.03.026.
citation: Moertel CG, Frytak S, Hahn RG, O'Connell MJ, Reitemeier RJ, Rubin J, Schutt AJ, Weiland LH, Childs DS, Holbrook MA, Lavin PT, Livstone E, Spiro H, Knowlton A, Kalser M, Barkin J, Lessner H, Mann-Kaplan R, Ramming K, Douglas HO Jr, Thomas P, Nave H, Bateman J, Lokich J, Brooks J, Chaffey J, Corson JM, Zamcheck N, Novak JW. Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer. 1981 Oct 15;48(8):1705-10. doi: 10.1002/1097-0142(19811015)48:83.0.co;2-4.
citation: Tarnawski AS, Jones MK. Inhibition of angiogenesis by NSAIDs: molecular mechanisms and clinical implications. J Mol Med (Berl). 2003 Oct;81(10):627-36. doi: 10.1007/s00109-003-0479-y. Epub 2003 Sep 6.
citation: Fan F, Wey JS, McCarty MF, Belcheva A, Liu W, Bauer TW, Somcio RJ, Wu Y, Hooper A, Hicklin DJ, Ellis LM. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene. 2005 Apr 14;24(16):2647-53. doi: 10.1038/sj.onc.1208246.
citation: Wey JS, Fan F, Gray MJ, Bauer TW, McCarty MF, Somcio R, Liu W, Evans DB, Wu Y, Hicklin DJ, Ellis LM. Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer. 2005 Jul 15;104(2):427-38. doi: 10.1002/cncr.21145.
citation: Yang AD, Camp ER, Fan F, Shen L, Gray MJ, Liu W, Somcio R, Bauer TW, Wu Y, Hicklin DJ, Ellis LM. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res. 2006 Jan 1;66(1):46-51. doi: 10.1158/0008-5472.CAN-05-3086.
citation: Beebe JS, Jani JP, Knauth E, Goodwin P, Higdon C, Rossi AM, Emerson E, Finkelstein M, Floyd E, Harriman S, Atherton J, Hillerman S, Soderstrom C, Kou K, Gant T, Noe MC, Foster B, Rastinejad F, Marx MA, Schaeffer T, Whalen PM, Roberts WG. Pharmacological characterization of CP-547,632, a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy. Cancer Res. 2003 Nov 1;63(21):7301-9.
citation: Brekken RA, Overholser JP, Stastny VA, Waltenberger J, Minna JD, Thorpe PE. Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice. Cancer Res. 2000 Sep 15;60(18):5117-24.
citation: Cooke SP, Boxer GM, Lawrence L, Pedley RB, Spencer DI, Begent RH, Chester KA. A strategy for antitumor vascular therapy by targeting the vascular endothelial growth factor: receptor complex. Cancer Res. 2001 May 1;61(9):3653-9.
citation: 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.
citation: 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.
citation: 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.
citation: Schlaeppi JM, Wood JM. Targeting vascular endothelial growth factor (VEGF) for anti-tumor therapy, by anti-VEGF neutralizing monoclonal antibodies or by VEGF receptor tyrosine-kinase inhibitors. Cancer Metastasis Rev. 1999;18(4):473-81. doi: 10.1023/a:1006358220123.
citation: 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.
citation: Rahimi N, Dayanir V, Lashkari K. Receptor chimeras indicate that the vascular endothelial growth factor receptor-1 (VEGFR-1) modulates mitogenic activity of VEGFR-2 in endothelial cells. J Biol Chem. 2000 Jun 2;275(22):16986-92. doi: 10.1074/jbc.M000528200.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Bouwman P, Philipsen S. Regulation of the activity of Sp1-related transcription factors. Mol Cell Endocrinol. 2002 Sep 30;195(1-2):27-38. doi: 10.1016/s0303-7207(02)00221-6.
citation: Safe S, Kim K. Nuclear receptor-mediated transactivation through interaction with Sp proteins. Prog Nucleic Acid Res Mol Biol. 2004;77:1-36. doi: 10.1016/S0079-6603(04)77001-4. No abstract available.
citation: Wang L, Wei D, Huang S, Peng Z, Le X, Wu TT, Yao J, Ajani J, Xie K. Transcription factor Sp1 expression is a significant predictor of survival in human gastric cancer. Clin Cancer Res. 2003 Dec 15;9(17):6371-80.
citation: Yao JC, Wang L, Wei D, Gong W, Hassan M, Wu TT, Mansfield P, Ajani J, Xie K. Association between expression of transcription factor Sp1 and increased vascular endothelial growth factor expression, advanced stage, and poor survival in patients with resected gastric cancer. Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):4109-17. doi: 10.1158/1078-0432.CCR-03-0628.
citation: Corell T. Pharmacology of tolfenamic acid. Pharmacol Toxicol. 1994;75 Suppl 2:14-21. doi: 10.1111/j.1600-0773.1994.tb01991.x. No abstract available.
citation: Pedersen SB. Biopharmaceutical aspects of tolfenamic acid. Pharmacol Toxicol. 1994;75 Suppl 2:22-32. doi: 10.1111/j.1600-0773.1994.tb01992.x.
citation: Pentikainen PJ, Penttila A, Neuvonen PJ, Khalifah RG, Hignite CE. Human metabolism of tolfenamic acid. I. Isolation, preliminary characterization and pharmacokinetics of tolfenamic acid and its metabolites. Eur J Drug Metab Pharmacokinet. 1982 Oct-Dec;7(4):259-67. doi: 10.1007/BF03189628. No abstract available.
citation: Rozencweig M, Von Hoff DD, Staquet MJ, Schein PS, Penta JS, Goldin A, Muggia FM, Freireich EJ, DeVita VT Jr. Animal toxicology for early clinical trials with anticancer agents. Cancer Clin Trials. 1981;4(1):21-8.