Effects of Avmacol® in the Oral Mucosa of Patients Following Curative Treatment for Tobacco-related Head and Neck Cancer

Study Overview
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Brief Summary
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Avmacol is an over-the-counter dietary supplement containing broccoli seed and sprout extracts in tablet form, hypothesized to activate protective cellular pathways including detoxication. In this study, participants who have been curatively treatment for head and neck cancer, will take Avmacol twice a day for 3 months.

Detailed Description
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The broccoli seed preparation, Avmacol®, results in acute and/or sustained induction of NRF2 target gene transcripts in the oral mucosa of patients who have been curatively treated for a tobacco-related head and neck squamous cell carcinoma (HNSCC), including high grade dysplasia, carcinoma in situ, or invasive carcinoma. This study is not designed to examine the therapeutic or reparative effects of Avmacol® on premalignant lesions of the oral cavity. We will systematically assess the clinical chemopreventive potential of Avmacol® administration to patients with tobacco-related HNSCC at high risk for second primary tumor by: Conducting this phase 0 clinical study to evaluate the pharmacodynamic range of NRF2 pathway activation in the oral mucosa of HNSCC patients, in response to two tolerable and bioactive doses of Avmacol®; Determining whether the level of NRF2 pathway activation achieved in human oral epithelium is chemopreventive in the NQO1 murine model of environmental carcinogenesis; and Analyzing specimens from the Phase 0 trial to determine whether Avmacol® induces changes in alternative biomarkers of SF chemopreventive efficacy identified in the laboratory.

Official Title
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A Phase 0 Study Evaluating the Systemic Bioavailability and Pharmacodynamic Effects of Avmacol® in the Oral Mucosa of Patients Following Curative Treatment for Tobacco-related Head and Neck Cancer

Conditions
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Dysplasia, Head and Neck Cancer, Head and Neck Squamous Cell Carcinoma (HNSCC), Head and Neck Carcinoma, Head and Neck, Tobacco-Related Carcinoma, Carcinoma in Situ, Hyperplasia, Premalignant Lesion

Intervention / Treatment
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* Dietary Supplement: Avmacol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have completed curative-intent therapy (including surgery, radiation, and/or chemotherapy) for a first tobacco-related oral premalignant lesion (OPL) or HNSCC of any stage (eligible lesions include high grade dysplasia; carcinoma in situ; or stage I-IVa HNSCC). Primary site may include oral cavity, pharynx, or larynx. Oropharynx primaries must be HPV (-) as defined by routine p16 IHC at the local site. Participants may be enrolled between 3 months and 5 years AFTER completion of curative-intent therapy (including surgery, radiotherapy, and/or chemotherapy). Participants may have untreated OPLs (i.e., hyperplasia, dysplasia, carcinoma in situ) at the time of study entry, provided the index OPL or HNSCC was definitively treated. Participants must be at least 18 years old. Participants must have a Karnofsky Performance Status of 80% or higher or an ECOG of 0-1 (Appendix A). Current and former tobacco users are eligible. The tobacco use assessment form must be completed following consent, to assure eligibility (Appendix B). Patients must have ≥10 pack-year cumulative tobacco exposure or its equivalent to be eligible. This is defined as follows: Cigarette exposure: ≥10 pack-years OR Cigar exposure: ≥ 10 cigar-years, where 1 cigar year is defined as having smoked on average ≥ 1 cigar/day for a year OR Chewing tobacco: ≥10 snuff-years, where 1 snuff year is defined as using on average ≥ 1 pinch (dip) of chewing tobacco/day for a year. Able to perform written, informed consent. Women of childbearing potential (WCBP) must have a negative urine pregnancy test within 7 Days prior to the first study intervention. WCBP 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 she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and for the duration of study participation. Exclusion Criteria: Participants have a history of another malignancy within 2 years prior to starting study treatment, except for excised and cured carcinoma-in-situ of breast or cervix; non-melanomatous skin cancer; T1-2, N0, M0 differentiated thyroid carcinoma either resected or under active surveillance; superficial bladder cancer; T1a or T1b prostate cancer comprising < 5% of resected tissue with normal prostate specific antigen (PSA) since resection, or status post external beam radiation or brachytherapy with normal PSA since radiation. Primary oropharyngeal HNSCC which is HPV (+) as defined by p16 IHC. Participants with acute intercurrent illness or those who had major surgery within the preceding 4 weeks unless they have fully recovered. Participants who have a positive pregnancy test, are pregnant, or breast feeding. Patients who are not practicing adequate contraception are ineligible if they are of child bearing potential. Patients currently using anti-neoplastic or anti-tumor agents, including chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer therapy. Chronic anticoagulation with warfarin. Patients on low molecular weight heparin or fondaparinux may be enrolled. Use of chronic prescribed medications which are potent inducers or inhibitors of CYP3A4 (Appendix C). Chronic use of steroids at immunosuppressive doses. (Note, physiologic replacement doses of glucocorticoid or mineralocorticoid are acceptable, eg. prednisone 5-10 mg/day; fludrocortisone 0.1-0.2 mg/day.) History of severe food intolerance to broccoli.

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Thirty-six individuals who have previously been treated for tobacco-related, HPV-negative HNSCC will be recruited for this study. After being deemed eligible, subjects will be assigned a patient number and be registered into the CTMA database. At registration, they will be randomized to receive either 4 tablets/day in Cycle 1 or 8 tablets/day in Cycle 1 (and the other dose in Cycle 2). This randomization is not blinded. Randomization will be stratified by history of head and neck radiation therapy (yes or no).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Avmacol<br>You will be given a higher dose of Avmacol® each month, taking 2 Avmacol® tablets per day the first month (Cycle 1), 4 Avmacol® tablets per day the second month (Cycle 2), and 8 Avmacol® tablets per day the third month (Cycle 3). Investigators will study how Avmacol® affects your body by collecting three different tissues: 1) your cheek cells (buccal cells); 2) your urine; and 3) your blood. After you have finished three months of Avmacol®, you will return one month later for an end-of-study visit. | Dietary Supplement: Avmacol<br>* Avmacol is a dietary supplement available over the counter<br>* Other names: broccoli see extract;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in NRF2 target gene expression | Quantitative changes in NRF2 target gene transcripts expression (i.e. NQO1 and GCLC) in oral mucosa (buccal cytobrush) by quantitative polymerase chain reaction (qPCR) according to a linear mixed model framework. | From baseline throughout treatment period, up to 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in NRF2 target proteins | Changes in NRF2 target proteins in buccal punch biopsies by immunoblotting. | From baseline throughout treatment period, up to 4 months | 
| Change in NRF2 target gene transcripts | Change in NRF2 target gene transcripts, between the two doses of Avmacol® by immunoblotting. | From baseline throughout treatment period, up to 4 months | 
| Change in NRF2-independent proteins | Change in NRF2 target gene transcripts, between the two doses of Avmacol® by immunoblotting. | From baseline throughout treatment period, up to 4 months | 
| Alterations of Avmacol® activity in PBMCs - NK cells | Changes in Peripheral Blood Mononuclear Cells (PBMC) gene expression and flow cytometry patterns in NK cells. | From baseline throughout treatment period, up to 4 months | 
| Alterations of Avmacol® activity in PBMCs - T cells | Changes in Peripheral Blood Mononuclear Cells (PBMC) gene expression and flow cytometry patterns in T cells. | From baseline throughout treatment period, up to 4 months | 
| Change in serum cytokine levels | Change in serum cytokine levels, as determined by multiplexed bead-based cytokine assays. | From baseline throughout treatment period, up to 4 months | 
| Measurement of serum albumin-bound SF | Measurement of urinary metabolites of SF using isotope dilution mass spectrometry. | From baseline throughout treatment period, up to 4 months | 
| Safety profile in accordance with NCI CTCAE v.4 | Patients will receive a diary for daily logging of adverse events. This will tabulated by Avmacol dose and type and grade of adverse events. The mean frequency and grade of events will be calculated by dose, and between-dose differences compared by means | Throughout treatment period, up to 4 months | 
| Proportion of patients primary tumors harboring genomic alteration of NRF2 related genes | Genomic alterations in primary tumors will be characterized and the proportion determined by number of patients with NRF2 related genes per the total number of patients studied. | At baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prevention, dietary supplement, broccoli, avmacol