Bowman-Birk Inhibitor Concentrate in Preventing Cancer in Patients With Oral Leukoplakia

Bowman Birk Inhibitor Concentrate and Oral Leukoplakia: A Randomized Phase IIb Trial

This randomized phase II trial is studying how well Bowman-Birk inhibitor concentrate works in preventing cancer in patients with oral leukoplakia. Chemoprevention is the use of certain substances to keep cancer from forming, growing, or coming back. The use of Bowman-Birk inhibitor concentrate, a substance made from soy, may keep cancer from forming in patients with oral leukoplakia

Study Overview

• Status: Completed
• Conditions: Lip and Oral Cavity Cancer; Oropharyngeal Cancer; Tongue Cancer; Oral Leukoplakia
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: placebo; Drug: Bowman-Birk inhibitor concentrate

Detailed Description

PRIMARY OBJECTIVES:

I. Determine if chemoprevention by the Bowman-Birk inhibitor concentrate (BBIC) can prevent cancer in patients with oral leukoplakia (OL).

II. Determine the clinical and histologic response rate of OL to BBIC.

SECONDARY OBJECTIVES:

I. Measure the effect of BBIC on intermediate marker endpoint levels. II. Correlate the clinical and histologic responses of OL with cellular levels of proteolytic activity, erb-B2 (neu), retinioc acid receptor β, bcl-2, and mutant p53 expression, and serum levels of neu.

III. Determine the individual and group side effects of BBIC.

OUTLINE: This is a multicenter, randomized, double-blind, placebo-controlled, study. Prior to randomization, all patients receive oral placebo for 4 weeks. Patients who show good compliance (> 75% packet count) are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oral Bowman-Birk inhibitor concentrate twice daily for 6 months in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive oral placebo twice daily for 6 months in the absence of disease progression or unacceptable toxicity.

Patients complete questionnaires about diet, tobacco, and alcohol usage at baseline and at the completion of study treatment. Blood, urine, and biopsy tissue are collected at baseline and at the completion of study treatment. Oral mucosal cells are collected at baseline, during the run-in phase, at randomization, after completion of study treatment, and at 3 months after completion of study treatment. Samples are examined for protease activity, levels of bcl-2 and erbB-2, mutant p53 oncogene expression and epidermal growth factor receptor, and retinoic acid receptor-β expression.

After completion of study treatment, patients are followed at 3 months.

• Study Type: Interventional
• Enrollment (Actual): 325
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Orange, California, United States, 92868
      • University of California Medical Center At Irvine-Orange Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically and clinically confirmed oral leukoplakia and/or erythroplakia
• Bidimensionally measurable disease (≥ 100 mm^2 for total area of all lesions) after biopsy
• No presence of obvious head and neck aerodigestive tract cancer, carcinoma in situ, or previously treated head and neck cancer within the past 2 years
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of allergic reaction to soybeans, sorbitol, sucrose, artificial flavorings, aspartame, saccharin, or lidocaine
• At least 6 months since prior Bowman-Birk inhibitor concentrate
• At least 6 months since prior participation in another randomized clinical trail

• At least 3 months since prior systemic steroids or topical oral steroid preparations

  • Topical nasal steroid sprays or cutaneous preparations with minimal systemic absorption for nasal or dermatologic disorders allowed
• More than 6 months since prior beta carotene capsules

• At least 2 years since prior retinoid or other beta carotene therapy, including > 25,000 IU of vitamin A for any reason

  • Up to 2 multivitamins per day allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (Bowman-Birk inhibitor concentrate); Patients receive oral Bowman-Birk inhibitor concentrate twice daily for 6 months	Other: laboratory biomarker analysis; Correlative studies; Drug: Bowman-Birk inhibitor concentrate; Given orally; Other Names: BBIC
Placebo Comparator: Arm II (placebo); Patients receive oral placebo twice daily for 6 months	Other: laboratory biomarker analysis; Correlative studies; Other: placebo; Given orally; Other Names: PLCB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Percent Change in Total Lesion Area After 6 Months on Study	Relative percent change in total lesion area was defined as 100 times (area posttreatment minus area pretreatment) all divided by pretreatment area.	6 months
Number of Participants by Category of Clinical Response at 6 Months	Category of clinical response was based on the magnitude of relative percent change in total lesion area. A complete response (CR) was declared if the relative percent change in total lesion area was minus 100 percent. A partial response (PR) was a relative percent decrease in total lesion area of 50% or more, without being a CR. Disease progression was a relative percent increase in total lesion area of at least 50%. Remaining cases were declared to be stable disease.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Difference in Rated Degree of Malignancy Between Randomization and 6-month Specimen	The reviewer was blinded to study-arm assignment (drug or placebo), but not to time point of specimen. For each specimen, the reviewer marked a continuum to indicate degree of tissue abnormality. The continuum was 140 mm long, and anchored by the word 'Normal' on the left and 'Malignant' on the right. The distance from the left edge of the continuum to the reviewer's mark, in mm, was determined. For analyses, a score was formed by subtracting the pretreatment value from the 6-month value. Thus, a retreat from 'Malignancy' over time produces a negative score, a score of zero denotes no change, and a positive score denotes a worsening situation. Positive values indicate histologic worsening, whereas negative scores denote improvement over the 6-month study period.	Baselie to 6 months
Clinical Impression From Photographs	A secondary clinical response measure was bsaed on blinded, comparative judgments of pairs of photographs of the same lesion at baseline and 6 months on study. Picture pairs were assigned to album page, one pair per page, at random. Five physicians experienced with evaluation of oral mucosal tissue abnormalities, but blinded to study arm and time point, independently compared the pictures in each pair using a 7-point scale. The scale ranged from, "top photo shows a complete response relative to the bottom photo," through, "the same degree of disease is shown by top photo and bottom photo," to "bottom photo shows a complete response relative to the top photo." Raw scores were transformed to account for relative position of the earlier and later photo, and averaged across the 5 reviewers. Final scores ranged from one, denoting a CR at 6 months, to 4, which indicated no change, through 7, which indicated that the 6-month photo depicted a much worse situation than the pretreatment photo.	Baseline to 6 months
Relative Percent Change in Buccal-Cell Neu Protein (ng/mg)	100% x (Posttreatment value - pretreatment value)/(pretreatment value)	Baseline to 6 months
Relative Percent Change in Serum Neu Protein (ng/ml)	100% x (Posttreatment value - pretreatment value)/(pretreatment value)	Baseline to 6 months
Relative Percent Change in Protease Activity (Delta RFU/Min/µg)	100% x (Posttreatment value - pretreatment value)/(pretreatment value)	Baseline to 6 months
Number of Participants Report at Least 1 Adverse Event During the Study	The onset of adverse event is between the randomizaiton date and off-study date	Randomized date to Off-study date, up to 21 months
Combined Percentage Change From Baseline in Proteolytic Activity, Buccal-cell Erb-B2 (Neu) and Serum Levels of Neu at 6 Months		Baseline to 6 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Frank Meyskens, University of California Medical Center At Irvine-Orange Campus

Publications and helpful links

General Publications

• Meyskens FL. Development of Bowman-Birk inhibitor for chemoprevention of oral head and neck cancer. Ann N Y Acad Sci. 2001 Dec;952:116-23. doi: 10.1111/j.1749-6632.2001.tb02732.x.
• Meyskens FL Jr. Development of difluoromethyl-ornithine and Bowman-Birk inhibitor as chemopreventive agents by assessment of relevant biomarker modulation: some lessons learned. IARC Sci Publ. 2001;154:49-55.
• Armstrong WB, Taylor TH, Kennedy AR, Melrose RJ, Messadi DV, Gu M, Le AD, Perloff M, Civantos F, Goodwin WJ, Wirth LJ, Kerr AR, Meyskens FL Jr. Bowman birk inhibitor concentrate and oral leukoplakia: a randomized phase IIb trial. Cancer Prev Res (Phila). 2013 May;6(5):410-8. doi: 10.1158/1940-6207.CAPR-13-0004.
• Armstrong WB, Wan XS, Kennedy AR, Taylor TH, Meyskens FL Jr. Development of the Bowman-Birk inhibitor for oral cancer chemoprevention and analysis of Neu immunohistochemical staining intensity with Bowman-Birk inhibitor concentrate treatment. Laryngoscope. 2003 Oct;113(10):1687-702. doi: 10.1097/00005537-200310000-00007.

Study record dates

Study Major Dates

• Study Start: January 1, 1999
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: May 25, 2006
• First Submitted That Met QC Criteria: May 25, 2006
• First Posted (Estimate): May 26, 2006

Study Record Updates

• Last Update Posted (Estimate): December 19, 2014
• Last Update Submitted That Met QC Criteria: December 16, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Mouth Diseases; Pathological Conditions, Anatomical; Precancerous Conditions; Tongue Diseases; Mouth Neoplasms; Oropharyngeal Neoplasms; Leukoplakia; Leukoplakia, Oral; Tongue Neoplasms
• Other Study ID Numbers: NCI-2009-00888; 98-34; U01CA072294 (U.S. NIH Grant/Contract)