Lip and Oral Cavity Cancer, Oral Leukoplakia, Oropharyngeal Cancer, Tongue Cancer
Conditions
Brief summary
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
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.
Interventions
Given orally
OTHERplacebo
Given orally
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Percent Change in Total Lesion Area After 6 Months on Study | 6 months | Relative percent change in total lesion area was defined as 100 times (area posttreatment minus area pretreatment) all divided by pretreatment area. |
| Number of Participants by Category of Clinical Response at 6 Months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative Percent Change in Buccal-Cell Neu Protein (ng/mg) | Baseline to 6 months | 100% x (Posttreatment value - pretreatment value)/(pretreatment value) |
| Relative Percent Change in Serum Neu Protein (ng/ml) | Baseline to 6 months | 100% x (Posttreatment value - pretreatment value)/(pretreatment value) |
| The Difference in Rated Degree of Malignancy Between Randomization and 6-month Specimen | Baselie to 6 months | 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. |
| Number of Participants Report at Least 1 Adverse Event During the Study | Randomized date to Off-study date, up to 21 months | The onset of adverse event is between the randomizaiton date and off-study date |
| 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 | — |
| Relative Percent Change in Protease Activity (Delta RFU/Min/µg) | Baseline to 6 months | 100% x (Posttreatment value - pretreatment value)/(pretreatment value) |
| Clinical Impression From Photographs | Baseline to 6 months | 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. |
Countries
United States
Participant flow
Recruitment details
A total of 513 people were screened for participation across all 8 performance sites, of which 188 (37%) were ineligible and 325 were consented.
Pre-assignment details
Of 325 consented, 157 (48%) completed the run-in period but 25 declined to continue, resulting in 132 randomized patients.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Bowman-Birk Inhibitor Concentrate) Patients receive oral Bowman-Birk inhibitor concentrate twice daily for 6 months
Bowman-Birk inhibitor concentrate: Given orally
laboratory biomarker analysis: Correlative studies | 67 |
| Arm II (Placebo) Patients receive oral placebo twice daily for 6 months
placebo: Given orally
laboratory biomarker analysis: Correlative studies | 65 |
| Total | 132 |
Baseline characteristics
| Characteristic | Arm I (Bowman-Birk Inhibitor Concentrate) | Arm II (Placebo) | Total |
|---|---|---|---|
| Age, Continuous | 58.25 years STANDARD_DEVIATION 13.63 | 60.64 years STANDARD_DEVIATION 12.01 | 59.42 years STANDARD_DEVIATION 12.87 |
| Sex: Female, Male Female | 26 Participants | 25 Participants | 51 Participants |
| Sex: Female, Male Male | 41 Participants | 40 Participants | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 30 / 67 | 25 / 65 |
| serious Total, serious adverse events | 5 / 67 | 0 / 65 |
Outcome results
Primary
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.
Time frame: 6 months
Population: The participants who have complete data are analyzed in this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Bowman-Birk Inhibitor Concentrate) | Number of Participants by Category of Clinical Response at 6 Months | Complete response (CR) | 2 participants |
| Arm I (Bowman-Birk Inhibitor Concentrate) | Number of Participants by Category of Clinical Response at 6 Months | Partial response (PR) | 10 participants |
| Arm I (Bowman-Birk Inhibitor Concentrate) | Number of Participants by Category of Clinical Response at 6 Months | Stable disease | 27 participants |
| Arm I (Bowman-Birk Inhibitor Concentrate) | Number of Participants by Category of Clinical Response at 6 Months | Disease progression | 4 participants |
| Arm II (Placebo) | Number of Participants by Category of Clinical Response at 6 Months | Disease progression | 6 participants |
| Arm II (Placebo) | Number of Participants by Category of Clinical Response at 6 Months | Complete response (CR) | 2 participants |
| Arm II (Placebo) | Number of Participants by Category of Clinical Response at 6 Months | Stable disease | 26 participants |
| Arm II (Placebo) | Number of Participants by Category of Clinical Response at 6 Months | Partial response (PR) | 12 participants |
Primary
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.
Time frame: 6 months
Population: The participants who have complete data are analyzed in this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Bowman-Birk Inhibitor Concentrate) | Relative Percent Change in Total Lesion Area After 6 Months on Study | -20.6 percentage change | Standard Deviation 52.4 |
| Arm II (Placebo) | Relative Percent Change in Total Lesion Area After 6 Months on Study | -17.1 percentage change | Standard Deviation 66.4 |
Secondary
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.
Time frame: Baseline to 6 months
Population: The participants who have complete data are analyzed in this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Bowman-Birk Inhibitor Concentrate) | Clinical Impression From Photographs | 4.0 score | Standard Deviation 1 |
| Arm II (Placebo) | Clinical Impression From Photographs | 3.6 score | Standard Deviation 0.9 |
Secondary
Combined Percentage Change From Baseline in Proteolytic Activity, Buccal-cell Erb-B2 (Neu) and Serum Levels of Neu at 6 Months
Time frame: Baseline to 6 months
Population: The participants whose data are available and complete are included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I (Bowman-Birk Inhibitor Concentrate) | Combined Percentage Change From Baseline in Proteolytic Activity, Buccal-cell Erb-B2 (Neu) and Serum Levels of Neu at 6 Months | Buccal-Cell New | -8.9 percentage change |
| Arm I (Bowman-Birk Inhibitor Concentrate) | Combined Percentage Change From Baseline in Proteolytic Activity, Buccal-cell Erb-B2 (Neu) and Serum Levels of Neu at 6 Months | Protease Activity | 16.2 percentage change |
| Arm I (Bowman-Birk Inhibitor Concentrate) | Combined Percentage Change From Baseline in Proteolytic Activity, Buccal-cell Erb-B2 (Neu) and Serum Levels of Neu at 6 Months | Serum Neu (n=41) | -4.1 percentage change |
Comparison: Correlation of percent change in buccal-cell Neu with relative percent change in total lesion areap-value: >0.45Spearman Rank Correlation
Comparison: Correlation of percent change in protease activity with relative percent change in total lesion areap-value: >0.88Spearman Rank Correlation
Comparison: Correlation of percent change in serum Neu with relative percent change in total lesion areap-value: >0.66Spearman Rank Correlation
Secondary
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
Time frame: Randomized date to Off-study date, up to 21 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Bowman-Birk Inhibitor Concentrate) | Number of Participants Report at Least 1 Adverse Event During the Study | Yes: report at least 1 AE | 33 participants |
| Arm I (Bowman-Birk Inhibitor Concentrate) | Number of Participants Report at Least 1 Adverse Event During the Study | No: no AE reported | 34 participants |
| Arm II (Placebo) | Number of Participants Report at Least 1 Adverse Event During the Study | Yes: report at least 1 AE | 25 participants |
| Arm II (Placebo) | Number of Participants Report at Least 1 Adverse Event During the Study | No: no AE reported | 40 participants |
Secondary
Relative Percent Change in Buccal-Cell Neu Protein (ng/mg)
100% x (Posttreatment value - pretreatment value)/(pretreatment value)
Time frame: Baseline to 6 months
Population: The participants who have complete data are analyzed in this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Bowman-Birk Inhibitor Concentrate) | Relative Percent Change in Buccal-Cell Neu Protein (ng/mg) | -10.1 percentage change |
| Arm II (Placebo) | Relative Percent Change in Buccal-Cell Neu Protein (ng/mg) | -4.2 percentage change |
Secondary
Relative Percent Change in Protease Activity (Delta RFU/Min/µg)
100% x (Posttreatment value - pretreatment value)/(pretreatment value)
Time frame: Baseline to 6 months
Population: The participants who have complete data are analyzed in this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Bowman-Birk Inhibitor Concentrate) | Relative Percent Change in Protease Activity (Delta RFU/Min/µg) | 15.7 percentage change |
| Arm II (Placebo) | Relative Percent Change in Protease Activity (Delta RFU/Min/µg) | 17.2 percentage change |
Secondary
Relative Percent Change in Serum Neu Protein (ng/ml)
100% x (Posttreatment value - pretreatment value)/(pretreatment value)
Time frame: Baseline to 6 months
Population: The participants who have complete data are analyzed in this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Bowman-Birk Inhibitor Concentrate) | Relative Percent Change in Serum Neu Protein (ng/ml) | -3.9 percentage change |
| Arm II (Placebo) | Relative Percent Change in Serum Neu Protein (ng/ml) | -8.1 percentage change |
Secondary
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.
Time frame: Baselie to 6 months
Population: The participants who have complete data are analyzed in this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Bowman-Birk Inhibitor Concentrate) | The Difference in Rated Degree of Malignancy Between Randomization and 6-month Specimen | 1.2 score | Standard Deviation 23.7 |
| Arm II (Placebo) | The Difference in Rated Degree of Malignancy Between Randomization and 6-month Specimen | 3.6 score | Standard Deviation 15.4 |