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

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ClinicalTrials.gov Identifier: NCT03268993
Recruitment Status : Completed
First Posted : August 31, 2017
Last Update Posted : April 8, 2021
Sponsor:
Collaborators:
National Cancer Institute (NCI)
University of Arizona
Information provided by (Responsible Party):
Dan Zandberg, University of Pittsburgh

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Head and Neck Cancer Head and Neck Squamous Cell Carcinoma (HNSCC) Head and Neck Carcinoma Head and Neck Tobacco-Related Carcinoma Carcinoma in Situ Dysplasia Hyperplasia Premalignant Lesion Dietary Supplement: Avmacol Not Applicable

Detailed Description:

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:

  1. 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®;
  2. Determining whether the level of NRF2 pathway activation achieved in human oral epithelium is chemopreventive in the NQO1 murine model of environmental carcinogenesis; and
  3. Analyzing specimens from the Phase 0 trial to determine whether Avmacol® induces changes in alternative biomarkers of SF chemopreventive efficacy identified in the laboratory.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention 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)
Primary Purpose: Basic Science
Official Title: 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
Actual Study Start Date : July 27, 2018
Actual Primary Completion Date : July 22, 2019
Actual Study Completion Date : July 22, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Avmacol
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
Avmacol is a dietary supplement available over the counter
Other Name: broccoli see extract




Primary Outcome Measures :
  1. Change in NRF2 target gene expression [ Time Frame: From baseline throughout treatment period, up to 4 months ]
    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.


Secondary Outcome Measures :
  1. Change in NRF2 target proteins [ Time Frame: From baseline throughout treatment period, up to 4 months ]
    Changes in NRF2 target proteins in buccal punch biopsies by immunoblotting.

  2. Change in NRF2 target gene transcripts [ Time Frame: From baseline throughout treatment period, up to 4 months ]
    Change in NRF2 target gene transcripts, between the two doses of Avmacol® by immunoblotting.

  3. Change in NRF2-independent proteins [ Time Frame: From baseline throughout treatment period, up to 4 months ]
    Change in NRF2 target gene transcripts, between the two doses of Avmacol® by immunoblotting.

  4. Alterations of Avmacol® activity in PBMCs - NK cells [ Time Frame: From baseline throughout treatment period, up to 4 months ]
    Changes in Peripheral Blood Mononuclear Cells (PBMC) gene expression and flow cytometry patterns in NK cells.

  5. Alterations of Avmacol® activity in PBMCs - T cells [ Time Frame: From baseline throughout treatment period, up to 4 months ]
    Changes in Peripheral Blood Mononuclear Cells (PBMC) gene expression and flow cytometry patterns in T cells.

  6. Change in serum cytokine levels [ Time Frame: From baseline throughout treatment period, up to 4 months ]
    Change in serum cytokine levels, as determined by multiplexed bead-based cytokine assays.

  7. Measurement of serum albumin-bound SF [ Time Frame: From baseline throughout treatment period, up to 4 months ]
    Measurement of urinary metabolites of SF using isotope dilution mass spectrometry.

  8. Safety profile in accordance with NCI CTCAE v.4 [ Time Frame: Throughout treatment period, up to 4 months ]
    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

  9. Proportion of patients primary tumors harboring genomic alteration of NRF2 related genes [ Time Frame: At baseline ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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).
  2. Primary site may include oral cavity, pharynx, or larynx. Oropharynx primaries must be HPV (-) as defined by routine p16 IHC at the local site.
  3. Participants may be enrolled between 3 months and 5 years AFTER completion of curative-intent therapy (including surgery, radiotherapy, and/or chemotherapy).
  4. 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.
  5. Participants must be at least 18 years old.
  6. Participants must have a Karnofsky Performance Status of 80% or higher or an ECOG of 0-1 (Appendix A).
  7. 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:

    1. Cigarette exposure: ≥10 pack-years OR
    2. Cigar exposure: ≥ 10 cigar-years, where 1 cigar year is defined as having smoked on average ≥ 1 cigar/day for a year OR
    3. 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.
  8. Able to perform written, informed consent.
  9. Women of childbearing potential (WCBP) must have a negative urine pregnancy test within 7 Days prior to the first study intervention.
  10. 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:

  1. 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.
  2. Primary oropharyngeal HNSCC which is HPV (+) as defined by p16 IHC.
  3. Participants with acute intercurrent illness or those who had major surgery within the preceding 4 weeks unless they have fully recovered.
  4. Participants who have a positive pregnancy test, are pregnant, or breast feeding.
  5. Patients who are not practicing adequate contraception are ineligible if they are of child bearing potential.
  6. Patients currently using anti-neoplastic or anti-tumor agents, including chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer therapy.
  7. Chronic anticoagulation with warfarin. Patients on low molecular weight heparin or fondaparinux may be enrolled.
  8. Use of chronic prescribed medications which are potent inducers or inhibitors of CYP3A4 (Appendix C).
  9. 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.)
  10. History of severe food intolerance to broccoli.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03268993


Locations
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United States, Pennsylvania
UPMC Eye Center - Eye and Ear Institute
Pittsburgh, Pennsylvania, United States, 15213
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
University of Pittsburgh
National Cancer Institute (NCI)
University of Arizona
Investigators
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Principal Investigator: Dan P Zandberg, MD University of Pittsburgh
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Responsible Party: Dan Zandberg, Principal Investigator, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT03268993    
Other Study ID Numbers: 18-028
First Posted: August 31, 2017    Key Record Dates
Last Update Posted: April 8, 2021
Last Verified: April 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dan Zandberg, University of Pittsburgh:
prevention
dietary supplement
broccoli
avmacol
Additional relevant MeSH terms:
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Carcinoma
Head and Neck Neoplasms
Squamous Cell Carcinoma of Head and Neck
Carcinoma in Situ
Hyperplasia
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Carcinoma, Squamous Cell
Neoplasms by Site
Pathologic Processes