Clinical Evaluation of Bioadhesive Gels for Oral Cancer Chemoprevention

Summary

This is a multicenter placebo-controlled clinical trial to assess the effects of a topically applied gel on precancerous oral epithelial lesions. A total of 41 participants will be enrolled in this trial, and 22 of them will be enrolled at Ohio State. \[The remaining 19 participants will be enrolled at the University of North Carolina (9 participants) and the University of Louisville (8 participants)\]. At all three institutions, half of the participants will randomly be assigned to the 10% FBR gel (0.5 gm four times daily for 3 months), while half will enter the placebo control arm. All trial participants will have a pretreatment (including lesional and perilesional tissue) biopsy taken before and an excisional biopsy after 3 months of treatment. As pretreatment indices are compared to post treatment effects on each patient, patients serve as their own internal control. Pretreatment lesional biopsies are obtained to establish a pretreatment diagnosis and provide a pretreatment baseline for the experimental parameters.

Timeline

Start

2010-10

Primary completion

2014-02

Completion

2014-02

Publications

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• Background Lefebvre JL. Current clinical outcomes demand new treatment options for SCCHN. Ann Oncol. 2005;16 Suppl 6:vi7-vi12. doi: 10.1093/annonc/mdi452.
• Background Papadimitrakopoulou VA, Clayman GL, Shin DM, Myers JN, Gillenwater AM, Goepfert H, El-Naggar AK, Lewin JS, Lippman SM, Hong WK. Biochemoprevention for dysplastic lesions of the upper aerodigestive tract. Arch Otolaryngol Head Neck Surg. 1999 Oct;125(10):1083-9. doi: 10.1001/archotol.125.10.1083.
• Background Rudin CM, Cohen EE, Papadimitrakopoulou VA, Silverman S Jr, Recant W, El-Naggar AK, Stenson K, Lippman SM, Hong WK, Vokes EE. An attenuated adenovirus, ONYX-015, as mouthwash therapy for premalignant oral dysplasia. J Clin Oncol. 2003 Dec 15;21(24):4546-52. doi: 10.1200/JCO.2003.03.544. Epub 2003 Nov 3.
• Background Lippman SM, Lee JJ, Martin JW, El-Naggar AK, Xu X, Shin DM, Thomas M, Mao L, Fritsche HA Jr, Zhou X, Papadimitrakopoulou V, Khuri FR, Tran H, Clayman GL, Hittelman WN, Hong WK, Lotan R. Fenretinide activity in retinoid-resistant oral leukoplakia. Clin Cancer Res. 2006 May 15;12(10):3109-14. doi: 10.1158/1078-0432.CCR-05-2636.
• Background Toma S, Benso S, Albanese E, Palumbo R, Cantoni E, Nicolo G, Mangiante P. Treatment of oral leukoplakia with beta-carotene. Oncology. 1992;49(2):77-81. doi: 10.1159/000227016.
• Background Lippman SM, Batsakis JG, Toth BB, Weber RS, Lee JJ, Martin JW, Hays GL, Goepfert H, Hong WK. Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis. N Engl J Med. 1993 Jan 7;328(1):15-20. doi: 10.1056/NEJM199301073280103.
• Background Shin DM, Mao L, Papadimitrakopoulou VM, Clayman G, El-Naggar A, Shin HJ, Lee JJ, Lee JS, Gillenwater A, Myers J, Lippman SM, Hittelman WN, Hong WK. Biochemopreventive therapy for patients with premalignant lesions of the head and neck and p53 gene expression. J Natl Cancer Inst. 2000 Jan 5;92(1):69-73. doi: 10.1093/jnci/92.1.69. No abstract available.
• Background Papadimitrakopoulou VA, William WN Jr, Dannenberg AJ, Lippman SM, Lee JJ, Ondrey FG, Peterson DE, Feng L, Atwell A, El-Naggar AK, Nathan CO, Helman JI, Du B, Yueh B, Boyle JO. Pilot randomized phase II study of celecoxib in oral premalignant lesions. Clin Cancer Res. 2008 Apr 1;14(7):2095-101. doi: 10.1158/1078-0432.CCR-07-4024.
• Background William WN Jr, Lee JJ, Lippman SM, Martin JW, Chakravarti N, Tran HT, Sabichi AL, Kim ES, Feng L, Lotan R, Papadimitrakopoulou VA. High-dose fenretinide in oral leukoplakia. Cancer Prev Res (Phila). 2009 Jan;2(1):22-6. doi: 10.1158/1940-6207.CAPR-08-0100.
• Background Meyskens FL Jr. Another negative chemoprevention trial: what can we learn? Clin Cancer Res. 2008 Jan 1;14(1):2-3. doi: 10.1158/1078-0432.CCR-07-2215. No abstract available.
• Background Rodrigo KA, Rawal Y, Renner RJ, Schwartz SJ, Tian Q, Larsen PE, Mallery SR. Suppression of the tumorigenic phenotype in human oral squamous cell carcinoma cells by an ethanol extract derived from freeze-dried black raspberries. Nutr Cancer. 2006;54(1):58-68. doi: 10.1207/s15327914nc5401_7.
• Background Chen T, Rose ME, Hwang H, Nines RG, Stoner GD. Black raspberries inhibit N-nitrosomethylbenzylamine (NMBA)-induced angiogenesis in rat esophagus parallel to the suppression of COX-2 and iNOS. Carcinogenesis. 2006 Nov;27(11):2301-7. doi: 10.1093/carcin/bgl109. Epub 2006 Jun 15.
• Background Chen T, Hwang H, Rose ME, Nines RG, Stoner GD. Chemopreventive properties of black raspberries in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis: down-regulation of cyclooxygenase-2, inducible nitric oxide synthase, and c-Jun. Cancer Res. 2006 Mar 1;66(5):2853-9. doi: 10.1158/0008-5472.CAN-05-3279.
• Background Kresty LA, Morse MA, Morgan C, Carlton PS, Lu J, Gupta A, Blackwood M, Stoner GD. Chemoprevention of esophageal tumorigenesis by dietary administration of lyophilized black raspberries. Cancer Res. 2001 Aug 15;61(16):6112-9.
• Background Xue H, Aziz RM, Sun N, Cassady JM, Kamendulis LM, Xu Y, Stoner GD, Klaunig JE. Inhibition of cellular transformation by berry extracts. Carcinogenesis. 2001 Feb;22(2):351-6. doi: 10.1093/carcin/22.2.351.
• Background Huang C, Huang Y, Li J, Hu W, Aziz R, Tang MS, Sun N, Cassady J, Stoner GD. Inhibition of benzo(a)pyrene diol-epoxide-induced transactivation of activated protein 1 and nuclear factor kappaB by black raspberry extracts. Cancer Res. 2002 Dec 1;62(23):6857-63.
• Background Huang C, Li J, Song L, Zhang D, Tong Q, Ding M, Bowman L, Aziz R, Stoner GD. Black raspberry extracts inhibit benzo(a)pyrene diol-epoxide-induced activator protein 1 activation and VEGF transcription by targeting the phosphotidylinositol 3-kinase/Akt pathway. Cancer Res. 2006 Jan 1;66(1):581-7. doi: 10.1158/0008-5472.CAN-05-1951.
• Background Hecht SS, Huang C, Stoner GD, Li J, Kenney PM, Sturla SJ, Carmella SG. Identification of cyanidin glycosides as constituents of freeze-dried black raspberries which inhibit anti-benzo[a]pyrene-7,8-diol-9,10-epoxide induced NFkappaB and AP-1 activity. Carcinogenesis. 2006 Aug;27(8):1617-26. doi: 10.1093/carcin/bgi366. Epub 2006 Mar 7.
• Background Stoner GD. Foodstuffs for preventing cancer: the preclinical and clinical development of berries. Cancer Prev Res (Phila). 2009 Mar;2(3):187-94. doi: 10.1158/1940-6207.CAPR-08-0226. Epub 2009 Mar 3.
• Background Wang LS, Hecht SS, Carmella SG, Yu N, Larue B, Henry C, McIntyre C, Rocha C, Lechner JF, Stoner GD. Anthocyanins in black raspberries prevent esophageal tumors in rats. Cancer Prev Res (Phila). 2009 Jan;2(1):84-93. doi: 10.1158/1940-6207.CAPR-08-0155.
• Background Shumway BS, Kresty LA, Larsen PE, Zwick JC, Lu B, Fields HW, Mumper RJ, Stoner GD, Mallery SR. Effects of a topically applied bioadhesive berry gel on loss of heterozygosity indices in premalignant oral lesions. Clin Cancer Res. 2008 Apr 15;14(8):2421-30. doi: 10.1158/1078-0432.CCR-07-4096.
• Background Mallery SR, Zwick JC, Pei P, Tong M, Larsen PE, Shumway BS, Lu B, Fields HW, Mumper RJ, Stoner GD. Topical application of a bioadhesive black raspberry gel modulates gene expression and reduces cyclooxygenase 2 protein in human premalignant oral lesions. Cancer Res. 2008 Jun 15;68(12):4945-57. doi: 10.1158/0008-5472.CAN-08-0568.
• Background Ugalde CM, Liu Z, Ren C, Chan KK, Rodrigo KA, Ling Y, Larsen PE, Chacon GE, Stoner GD, Mumper RJ, Fields HW, Mallery SR. Distribution of anthocyanins delivered from a bioadhesive black raspberry gel following topical intraoral application in normal healthy volunteers. Pharm Res. 2009 Apr;26(4):977-86. doi: 10.1007/s11095-008-9806-x. Epub 2009 Jan 10.
• Background Lang K, Menzin J, Earle CC, Jacobson J, Hsu MA. The economic cost of squamous cell cancer of the head and neck: findings from linked SEER-Medicare data. Arch Otolaryngol Head Neck Surg. 2004 Nov;130(11):1269-75. doi: 10.1001/archotol.130.11.1269.
• Background Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96. doi: 10.3322/CA.2007.0010. Epub 2008 Feb 20.
• Background Silverman S Jr, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer. 1984 Feb 1;53(3):563-8. doi: 10.1002/1097-0142(19840201)53:33.0.co;2-f.
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• Background Speight PM. Update on oral epithelial dysplasia and progression to cancer. Head Neck Pathol. 2007 Sep;1(1):61-6. doi: 10.1007/s12105-007-0014-5. Epub 2007 Nov 30. No abstract available.
• Background Helzer LJ, Heitkamp KM, Shein M, Etzel RA. Pilot study of methods to measure saliva cotinine in Alaska Native women during pregnancy. Int J Circumpolar Health. 2007;66 Suppl 1:29-38.
• Background Mao L, Lee JS, Fan YH, Ro JY, Batsakis JG, Lippman S, Hittelman W, Hong WK. Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment. Nat Med. 1996 Jun;2(6):682-5. doi: 10.1038/nm0696-682.
• Background Chan G, Boyle JO, Yang EK, Zhang F, Sacks PG, Shah JP, Edelstein D, Soslow RA, Koki AT, Woerner BM, Masferrer JL, Dannenberg AJ. Cyclooxygenase-2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res. 1999 Mar 1;59(5):991-4.
• Background Connelly ST, Macabeo-Ong M, Dekker N, Jordan RC, Schmidt BL. Increased nitric oxide levels and iNOS over-expression in oral squamous cell carcinoma. Oral Oncol. 2005 Mar;41(3):261-7. doi: 10.1016/j.oraloncology.2004.09.007.
• Background Kawanishi S, Hiraku Y, Pinlaor S, Ma N. Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. Biol Chem. 2006 Apr;387(4):365-72. doi: 10.1515/BC.2006.049.
• Background Mann JR, Backlund MG, DuBois RN. Mechanisms of disease: Inflammatory mediators and cancer prevention. Nat Clin Pract Oncol. 2005 Apr;2(4):202-10. doi: 10.1038/ncponc0140.
• Background Joshi N, Johnson LL, Wei WQ, Abnet CC, Dong ZW, Taylor PR, Limburg PJ, Dawsey SM, Hawk ET, Qiao YL, Kirsch IR. Gene expression differences in normal esophageal mucosa associated with regression and progression of mild and moderate squamous dysplasia in a high-risk Chinese population. Cancer Res. 2006 Jul 1;66(13):6851-60. doi: 10.1158/0008-5472.CAN-06-0662.
• Background Otrock ZK, Mahfouz RA, Makarem JA, Shamseddine AI. Understanding the biology of angiogenesis: review of the most important molecular mechanisms. Blood Cells Mol Dis. 2007 Sep-Oct;39(2):212-20. doi: 10.1016/j.bcmd.2007.04.001. Epub 2007 Jun 6.
• Background Tong M, Lloyd B, Pei P, Mallery SR. Human head and neck squamous cell carcinoma cells are both targets and effectors for the angiogenic cytokine, VEGF. J Cell Biochem. 2008 Dec 1;105(5):1202-10. doi: 10.1002/jcb.21920.
• Background Kannan R, Bijur GN, Mallery SR, Beck FM, Sabourin CL, Jewell SD, Schuller DE, Stoner GD. Transforming growth factor-alpha overexpression in proliferative verrucous leukoplakia and oral squamous cell carcinoma: an immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996 Jul;82(1):69-74. doi: 10.1016/s1079-2104(96)80379-9.
• Background Wang LS, Stoner GD. Anthocyanins and their role in cancer prevention. Cancer Lett. 2008 Oct 8;269(2):281-90. doi: 10.1016/j.canlet.2008.05.020. Epub 2008 Jun 20.
• Results Mallery SR, Tong M, Shumway BS, Curran AE, Larsen PE, Ness GM, Kennedy KS, Blakey GH, Kushner GM, Vickers AM, Han B, Pei P, Stoner GD. Topical application of a mucoadhesive freeze-dried black raspberry gel induces clinical and histologic regression and reduces loss of heterozygosity events in premalignant oral intraepithelial lesions: results from a multicentered, placebo-controlled clinical trial. Clin Cancer Res. 2014 Apr 1;20(7):1910-24. doi: 10.1158/1078-0432.CCR-13-3159. Epub 2014 Jan 31.

Drugs

Indications