Clinical Evaluation of Bioadhesive Gels for Oral Cancer Chemoprevention

• ClinicalTrials.gov Identifier: NCT01192204
• Recruitment Status: Completed
• First Posted: August 31, 2010
• Results First Posted: August 14, 2015
• Last Update Posted: August 14, 2015
• Sponsor: Ohio State University
• Collaborators: University of Louisville; University of North Carolina, Chapel Hill; National Cancer Institute (NCI)
• Information provided by (Responsible Party): Susan Mallery DDS, PhD, Ohio State University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Prevention
• Conditions: Squamous Cell Carcinoma of Mouth; Intraepithelial Neoplasia
• Interventions: Drug: 10% FBR containing bioadhesive gel; Drug: placebo gel
• Enrollment: 41

Participant Flow

Recruitment Details
Pre-assignment Details	41 patients were enrolled in this protocol. 1 patient could not keep the appointments and was referred to his private oral surgeon.

Arm/Group Title	10% FBR Gel	Placebo Gel
Arm/Group Description	Active 10% FBR containing bioadhesive gel Bioadhesive 10% freeze-dried black raspberry gel: 0.5 gm applied 4 times daily to the oral premalignant lesion site for a duration of 3 months	Color/consistency matched placebo (no black raspberry) gel Color/consistency matched placebo gel: 0.5 gm applied 4 times daily to the oral premalignant lesion site for a duration of 3 months
Period Title: Overall Study
Started	23	18
Completed	22	18
Not Completed	1	0
Reason Not Completed
could not keep recall appointments	1	0

Baseline Characteristics

Arm/Group Title		10% FBR Gel	Placebo Gel	Total
Arm/Group Description		Active 10% FBR containing bioadhesive gel Bioadhesive 10% freeze-dried black raspberry gel: 0.5 gm applied 4 times daily to the oral premalignant lesion site for a duration of 3 months	Color/consistency matched placebo (no black raspberry) gel Color/consistency matched placebo gel: 0.5 gm applied 4 times daily to the oral premalignant lesion site for a duration of 3 months	Total of all reporting groups
Overall Number of Baseline Participants		23	18	41
Baseline Analysis Population Description		[Not Specified]
Age, Categorical [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	23 participants	18 participants	41 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	17 73.9%	5 27.8%	22 53.7%
	>=65 years	6 26.1%	13 72.2%	19 46.3%
		[1] Measure Description: The patients were randomly assigned by computer generated numbers to either the BRB or the placebo gel groups.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	23 participants	18 participants	41 participants
		62.2 (1.8)	57.7 (2.9)	59.9 (2.4)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	23 participants	18 participants	41 participants
	Female	14 60.9%	9 50.0%	23 56.1%
	Male	9 39.1%	9 50.0%	18 43.9%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	23 participants	18 participants	41 participants
		23	18	41

Outcome Measures

1. Primary Outcome

Title	Light Microscopic Histologically Scored Diagnoses Pretreatment to Post Treatment
Description	A hemisection of lesional tissue will be conducted before the 3 month treatment to establish a diagnosis and provide a pretreatment baseline for the experimental parameters. Anl excisional biopsy of the treatment site including any remaining residual lesional tissue (excision of oral dysplastic lesions is consistent with current standards of care) will be obtained after 3 months of treatment to provide a posttreatment diagnosis. The 0 to 8 histologic scale was:0=normal with or without hyperkeratosis BEST OUTCOME, 1=atypia, 2=mild dysplasia, 3=mild-moderate dysplasia, 4=moderate dysplasia,5=moderate-severe dysplasia,6=severe dysplasia, 7=carcinoma in situ, 8=invasive oral squamous cell carcinoma (WORST OUTCOME).
Time Frame	Before and after the 3 month treatment.

Outcome Measure Data

Analysis Population Description

The population evaluated were as previously described i.e. 22 participants in the BRB gel cohort and 18 participants in the placebo gel cohort.

Arm/Group Title	10% FBR Gel	Placebo Gel
Arm/Group Description:	Active 10% FBR containing bioadhesive gel Bioadhesive 10% freeze-dried black raspberry gel: 0.5 gm applied 4 times daily to the oral premalignant lesion site for a duration of 3 months	Color/consistency matched placebo (no black raspberry) gel Color/consistency matched placebo gel: 0.5 gm applied 4 times daily to the oral premalignant lesion site for a duration of 3 months
Overall Number of Participants Analyzed	22	18
Mean (Standard Error); Unit of Measure: unit on histologic grade scale
Pretreatment	2.36 (0.35)	2.83 (0.34)
Posttreatment	1.9 (0.21)	2.58 (0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	10% FBR Gel
	Comments	Wilcoxon matched-pairs signed rank test (intrapatient pre versus post treatment scores)
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.048
	Comments	Statistical analyses reflect percent change intrapatient pre versus post histologic grade scores
	Method	Wilcoxon matched-pairs signed rank test
	Comments	We used a 2-tailed Mann Whitney U test to evaluate these data.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Gel
	Comments	Wilcoxon matched-pairs signed rank test (pre versus post treatment scores)
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.50
	Comments	Statistical analyses reflect percent change pre versus post histologic grade scores
	Method	Wilcoxon matched-pairs signed rank test
	Comments	[Not Specified]

2. Secondary Outcome

Title	Changes in Lesional Sizes
Description	The remaining oral dysplasia lesion will be inspected at each follow up appointment (every 10-14 days). Biopsies will be immediately conducted on patients with any indication of malignant transformation including indurated, rolled borders, nonhealing ulcers, etc. Accordingly, these patients will withdraw from the trial. Participants will also be monitored for any changes consistent with contact mucositis e.g. soreness and erythema at application site. Clinical photographs were taken for the patients records. Pre treatment and post treatment photographs, with a ruler in place, were used for accurate pre and post treatment size measurement. NOTE: if treatment is beneficial, lesional size will decrease which will be reflected as a negative number.
Time Frame	pretreatment and posttreatment (3 months treatment duration)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	10% FBR Gel	Placebo Gel
Arm/Group Description:	Active 10% FBR containing bioadhesive gel Bioadhesive 10% freeze-dried black raspberry gel: 0.5 gm applied 4 times daily to the oral premalignant lesion site for a duration of 3 months.	Color/consistency matched placebo (no black raspberry) gel Color/consistency matched placebo gel: 0.5 gm applied 4 times daily to the oral premalignant lesion site for a duration of 3 months
Overall Number of Participants Analyzed	22	18
Mean (Standard Deviation); Unit of Measure: mm^2
	-26.12 (5.81)	18.12 (4.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	10% FBR Gel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.002
	Comments	[Not Specified]
	Method	Wilcoxon matched-pairs signed rank test
	Comments	specifically, we used the Wilcoxon matched-pairs signed rank test.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Gel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.036
	Comments	[Not Specified]
	Method	Wilcoxon matched-pairs signed rank test
	Comments	[Not Specified]

3. Secondary Outcome

Title	Treatment Changes in Loss of Heterozygosity Events
Description	Laboratory experiments will be conducted to assess the effects of gel treatment on pre and post loss of heterozygosity (LOH) events at loci associated with tumor suppressor genes.
Time Frame	Before and after the 3 month treatment duration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	10% FBR Gel	Placebo Gel
Arm/Group Description:	Active 10% FBR containing bioadhesive gel Bioadhesive 10% freeze-dried black raspberry gel: 0.5 gm applied 4 times daily to the oral premalignant lesion site for a duration of 3 months	Color/consistency matched placebo (no black raspberry) gel Color/consistency matched placebo gel: 0.5 gm applied 4 times daily to the oral premalignant lesion site for a duration of 3 months
Overall Number of Participants Analyzed	22	18
Mean (Standard Error); Unit of Measure: LOH events
	0.9 (0.02)	0.4 (0.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	10% FBR Gel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.002
	Comments	[Not Specified]
	Method	2-tailed unpaired t test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Gel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.16
	Comments	[Not Specified]
	Method	two-tailed unpaired t test
	Comments	[Not Specified]

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	10% FBR Gel	Placebo Gel
Arm/Group Description	Active 10% FBR containing bioadhesive gel Bioadhesive 10% freeze-dried black raspberry gel: 0.5 gm applied 4 times daily to the oral premalignant lesion site for a duration of 3 months No adverse events	Color/consistency matched placebo (no black raspberry) gel Color/consistency matched placebo gel: 0.5 gm applied 4 times daily to the oral premalignant lesion site for a duration of 3 months No adverse events
All-Cause Mortality
	10% FBR Gel	Placebo Gel
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	10% FBR Gel	Placebo Gel
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/22 (0.00%)	0/18 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	10% FBR Gel	Placebo Gel
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/22 (0.00%)	0/18 (0.00%)

Limitations and Caveats

While we initially planned to include microvascular densities and COX-2 analyses, there were insufficient tissue samples to collect these data. Therefore as we do not have these data we can not report them.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Susan R, Mallery DDS, PhD
• Organization: The Ohio State University
• Phone: 614 292-5892
• EMail: mallery.1@osu.edu

Publications of 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.

Other Publications:

Menzin J, Lines LM, Manning LN. The economics of squamous cell carcinoma of the head and neck. Curr Opin Otolaryngol Head Neck Surg. 2007 Apr;15(2):68-73. Review.

Lefebvre JL. Current clinical outcomes demand new treatment options for SCCHN. Ann Oncol. 2005;16 Suppl 6:vi7-vi12. Review.

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.

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. Epub 2003 Nov 3.

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.

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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.

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.

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.

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.

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.

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. Epub 2006 Jun 15.

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.

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.

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. Erratum in: Carcinogenesis 2001 May;22(5):831-3.

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.

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.

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. Epub 2006 Mar 7.

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.

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.

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.

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.

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.

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.

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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.

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.

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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.

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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.

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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.

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.

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• Responsible Party: Susan Mallery DDS, PhD, Ohio State University
• ClinicalTrials.gov Identifier: NCT01192204 History of Changes
• Other Study ID Numbers: 2009C0086; RC2CA148099 ( U.S. NIH Grant/Contract )
• First Submitted: August 30, 2010
• First Posted: August 31, 2010
• Results First Submitted: April 29, 2015
• Results First Posted: August 14, 2015
• Last Update Posted: August 14, 2015