Testing the Effect of the Broccoli Seed and Sprout Extract, Avmacol ES, on the Cancer Causing Substances of Tobacco in Heavy Smokers

Study Overview
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Brief Summary
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This phase II trial tests whether broccoli seed and sprout extract works to break down cancer causing substances of tobacco in heavy smokers. Smokers are at increased risk for developing lung, head and neck, and other cancers. Broccoli seed and sprout extract may help break down and remove toxic substances caused by tobacco use and possibly produce substances that may protect cells from tobacco smoke-induced damage in current smokers.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine whether broccoli sprout/broccoli seed extract supplement (broccoli seed and sprout extract [BSSE]) sustainably increases the urinary excretion of the mercapturic acids of the tobacco carcinogens benzene and/or acrolein over a 12-week exposure period in otherwise healthy, current smokers. SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of BSSE over a 12-week exposure period. II. To evaluate whether BSSE sustainably increases the urinary excretion of the mercapturic acid of the tobacco carcinogen crotonaldehyde. III. To evaluate the bioavailability of BSSE measured as sulforaphane (SF) metabolites and assess for a dose-response relationship between the effective SF dose delivered by BSSE and the detoxification of benzene and acrolein. IV. To determine whether the GSTM1 and GSTT1 genotypes are important genetic modulators of detoxification of tobacco carcinogens in the setting of prolonged exposure to BSSE. EXPLORATORY OBJECTIVES: I. To evaluate modulation of mucosal signatures of nuclear factor-erythroid factor 2-related factor 2 (NRF2) activation, inflammation, and innate immunity. II. To evaluate modulation of nasal epithelial gene signatures including smoking, lung cancer, and squamous dysplasia. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I: Patients receive broccoli seed and sprout extract orally (PO) once daily (QD) for 12 weeks in the absence of unacceptable toxicity. Patients undergo the collection of blood and nasal epithelial cell samples at visits 2 and 6 and the collection of buccal cell samples at visits 2, 3, and 6. GROUP II: Patients receive placebo PO QD for 12 weeks in the absence of unacceptable toxicity. Patients undergo the collection of blood and nasal epithelial cell samples at visits 2 and 6 and the collection of buccal cell samples at visits 2, 3, and 6. After completion of study, patients are followed up at 2-4 weeks.

Official Title
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Phase II Randomized, Double Blind, Placebo-Controlled Trial of Broccoli Seed and Sprout Extract (BSSE), Avmacol ES, to Evaluate Sustained Detoxification of Tobacco Carcinogens in Heavy Smokers

Conditions
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Cigarette Smoking-Related Carcinoma

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Dietary Supplement: Broccoli Sprout/Broccoli Seed Extract Supplement
* Drug: Placebo Administration
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female current tobacco smokers with >= 20 pack years of self-reported smoking exposure and a current average use of >= 10 cigarettes/day Age >= 18 years. No upper age limit Karnofsky performance scale >= 70% Absolute neutrophil count >= 1,000/microliter Platelets >= 100,000/microliter Total bilirubin =< 2 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN Creatinine =< 1.5 x ULN Participants with known human immunodeficiency virus (HIV) infection are not eligible for this trial due to potential interaction between sulforaphane and anti-retroviral therapy Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment are not eligible due to potential interaction between sulforaphane and anti-retroviral therapy The effects of BSSE on the developing human fetus at the recommended therapeutic dose are unknown. For this reason,, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately Ability to understand and the willingness to sign a written informed consent document Participants with known chronic hepatitis B virus (HBV) infection are not eligible for this trial due to potential interaction between sulforaphane and suppressive anti-viral therapy Exclusion Criteria: History of invasive cancer within the past 2 years, except for excised and cured non-melanoma skin cancer or carcinoma in situ of the cervix. Participants who continue adjuvant treatment for an index cancer occurring > 2 years ago, such as adjuvant hormonal therapy for breast cancer, are excluded. Participants who are on anti-neoplastic treatment for a chronic malignancy, such as multiple myeloma or chronic myelogenous leukemia, are excluded Ongoing use of a nutraceutical or dietary supplement containing glucoraphanin or sulforaphane Note, participants will be eligible if they agree to stop the glucoraphanin or sulforaphane product at least 7 days prior to the baseline visit (7-day washout) Participants may not be receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to Avmacol ES (BSSE) Uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia Any other condition or lifestyle factor, that, in the opinion of the principal investigator, may adversely affect the participant's ability to complete the study or its measures or pose significant risk to the participant Pregnant or lactating women. Pregnant women are excluded from this study because the effects of BSSE on the developing human fetus are unknown. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with BSSE, Breastfeeding should be discontinued if the mother is treated with BSSE

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (broccoli seed and sprout extract)<br>Patients receive broccoli seed and sprout extract PO QD for 12 weeks in the absence of unacceptable toxicity. Patients undergo the collection of blood and nasal epithelial cell samples at visits 2 and 6 and the collection of buccal cell samples at visits 2, 3, and 6. | Procedure: Biospecimen Collection<br>* Undergo collection of blood, buccal cell, and nasal epithelial cell samples<br>* Other names: Specimen Collection;Dietary Supplement: Broccoli Sprout/Broccoli Seed Extract Supplement<br>* Given PO<br>* Other names: Avmacol;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Active Comparator: Group II (placebo)<br>Patients receive placebo PO QD for 12 weeks in the absence of unacceptable toxicity. Patients undergo the collection of blood and nasal epithelial cell samples at visits 2 and 6 and the collection of buccal cell samples at visits 2, 3, and 6. | Procedure: Biospecimen Collection<br>* Undergo collection of blood, buccal cell, and nasal epithelial cell samples<br>* Other names: Specimen Collection;Drug: Placebo Administration<br>* Given PO<br>Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Detoxification of benzene and acrolein | Measured by changes in the urinary levels of their respective mercapturic acids, SPMA and 3-HPMA, from baseline. | At baseline and 2, 4, 8, and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AE)s | Measured by National Cancer Institute Common Terminology Criteria for Adverse Events version 5. The frequency and associated percentage of each specific AE will be tabulated by the treatment group and then compared via Fisher's exact test. The tolerability will be measured by the adherence rate and will be compared between the broccoli seed and sprout extract (BSSE) and placebo groups via Fisher's exact test. | Up to 12 weeks | 
| Increases in detoxification of crotonaldehyde | Will determine whether BSSE sustainably increases the detoxification of crotonaldehyde, as measured by changes in the creatinine-normalized urinary levels of its mercapturic acid metabolite, 3-HMPMA, over time. Similar to the carcinogens, benzene and acrolein, the detoxification of crotonaldehyde will be measured by change at 2 weeks, 4 weeks, 8 weeks and 12 weeks in the urinary excretion of 3-HMPMA from baseline, and a linear mixed effects model will be fit to changes in log-transformed urinary 3-HMPMA levels from baseline. | At baseline and 2, 4, 8, and 12 weeks | 
| Bioavailability of BSSE | Measured by urinary sulforaphane (SF) metabolites. | At baseline and 2, 4, 8, and 12 weeks | 
| Dose-response relationship between effective SF dose and the detoxification of benzene and acrolein | A dose-response relationship between SF metabolites and detoxification of benzene and/or acrolein will be assessed by a linear mixed effects model with random intercepts, in which changes from baseline in each of the log-transformed urinary mercapturic acid levels as the dependent variable (response) and changes from baseline in SF metabolites as the independent variable (dose). | Baseline up to 12 weeks | 
| Genetic modulators of detoxification of tobacco carcinogens | Will assess whether the GSTM1 and GSTT1 genotypes are important genetic modulators of detoxification of tobacco carcinogens in the setting of prolonged exposure to BSSE. The association of GSTM1 and GSTT1 genotypes with detoxification of benzene and/or acrolein will be assessed by a linear mixed effects model with random intercepts for changes from baseline in each of the log transformed mercapturic acid levels, in which the fixed effects include BSSE, genotype and time indicators and two-way and three-way interactions of BSSE, genotype and time indicators. This will allow us to study whether 1) the BSSE effect if significant is modulated by the genotypes, 2) the time effect if significant is modulated by the genotypes, or 3) the interaction effect between BSSE and time if significant is modulated by the genotypes. | Up to 12 weeks |