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Trial record 7 of 1117 for:    Oral Cancer | ( Map: Canada )

Metformin Hydrochloride in Preventing Oral Cancer in Patients With an Oral Premalignant Lesion

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02581137
Recruitment Status : Active, not recruiting
First Posted : October 20, 2015
Results First Posted : May 23, 2019
Last Update Posted : June 5, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase IIa trial studies how well metformin hydrochloride works in preventing oral cancer in patients with an oral premalignant lesion (oral leukoplakia or erythroplakia). Oral premalignant lesions look like red or whitish plaques or lesions in the mouth that do not rub off and can be associated with a higher risk of cancer. Metformin hydrochloride may help prevent oral cancer from forming in patients with an oral premalignant lesion.

Condition or disease Intervention/treatment Phase
Erythroplakia Hyperplasia Mild Dysplasia Moderate Dysplasia Oral Cavity Carcinoma Oral Leukoplakia Severe Dysplasia Other: Laboratory Biomarker Analysis Drug: Metformin Hydrochloride Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the clinical response of oral premalignant lesions to 12-14 weeks of metformin (metformin hydrochloride) intervention.

SECONDARY OBJECTIVES:

I. Histologic response to metformin intervention in the target lesion. II. Tissue-based biomarkers: metformin effect on cell proliferation and its molecular targets in the target lesion and in the normal tissue (marker of cell proliferation, Ki67, molecular targets of metformin, including, in order of priority, phosphorylated ribosomal protein S6 kinase [pS6], phosphorylated v-akt murine thymoma viral oncogene homolog 1 [pAKT]S473, phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 [p4EBP], phosphorylated acetyl-CoA carboxylase alpha [pACC]).

III. Tissue-based biomarkers: expression of dysregulated molecular mechanisms and organic cation transporter 3 (OCT 3) in the target lesion and in the normal tissue, including, in order of priority, epidermal growth factor receptor (EGFR), phosphorylated (p)EGFR, tumor protein 53 (p53), phosphatase and tensin homolog (PTEN), phosphorylated mitogen-activated protein kinase 1 (pERK), cyclin-dependent kinase inhibitor 2A (p16), and OCT3.

IV. Tissue-based biomarkers: targeted analysis of cancer-associated genes in the target lesion and blood deoxyribonucleic acid (DNA).

V. Serum and saliva based biomarkers: metformin effect on serum metabolic markers (C-peptide, glycosylated hemoglobin [HbA1c]).

VI. Serum and saliva based biomarkers: metformin concentrations in serum and saliva.

VII Serum and saliva based biomarkers: metformin effect on serum and saliva inflammatory and angiogenic cytokines, including interleukin (IL)-6, IL-8, growth-related oncogene-1 (GRO-1), and vascular endothelial growth factor (VEGF).

EXPLORATORY OBJECTIVES:

I. To characterize changes in the saliva microbiome before and after metformin intervention, including both the absolute microbial load and taxonomic composition.

II. To evaluate the potential microbiome signatures that are correlated with treatment response.

OUTLINE:

Patients receive extended-release metformin hydrochloride orally (PO) once daily (QD) for 2 weeks and then twice daily (BID) for 10-12 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 2-4 weeks.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: M4OC-Prevent: Metformin for Oral Cancer Prevention
Actual Study Start Date : June 10, 2016
Actual Primary Completion Date : October 12, 2017


Arm Intervention/treatment
Experimental: Prevention (extended-release metformin hydrochloride)
Patients receive extended-release metformin hydrochloride PO QD for 2 weeks and then BID for 10-12 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Metformin Hydrochloride
Given PO
Other Names:
  • APO-Metformin
  • Cidophage
  • Dimefor
  • Glifage
  • Glucoformin
  • Glucophage
  • Glucophage ER
  • Metformin HCl
  • Riomet
  • Siofor




Primary Outcome Measures :
  1. Clinical Response to Metformin Intervention [ Time Frame: Baseline to up to 14 weeks ]

    Number of participants with complete and partial clinical response to metformin intervention.

    Criteria for complete and partial clinical response are:

    Complete Response (CR): Disappearance of all evidence of lesion(s). Partial Response (PR): Greater than or equal to 50% reduction in the sum of the products of diameters of lesion(s) measurable at baseline. Non-measurable lesion(s) may not increase greater than or equal to 25% in size and no new lesion may appear.



Secondary Outcome Measures :
  1. Histologic Response to Metformin Intervention [ Time Frame: Baseline to up to 14 weeks ]

    Number of participants with complete and partial histologic response to metformin intervention.

    Criteria for complete and partial histologic response are:

    Complete Response (CR): Complete reversal of dysplasia or hyperplasia to normal epithelium in the target lesion.

    Partial Response (PR): Improvement of the degree of dysplasia or hyperplasia in the target lesion.


  2. Changes in Cell Proliferation and Its Molecular Targets [ Time Frame: Baseline to up to 14 weeks ]
    Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers.

  3. Changes in Frequent Dysregulated Molecular Mechanisms and OCT Expression [ Time Frame: Baseline to up to 14 weeks ]
    Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers. A univariate logistic regression model with the clinical response as the outcome variable will be fitted to explore if any of the expression of frequent dysregulated mechanisms and OCT3 level are associated with the clinical response to metformin hydrochloride.

  4. Impact of Genomic Alterations on the Biological and Biochemical Consequences and Clinical Response to Metformin Hydrochloride [ Time Frame: Up to 14 weeks ]
    Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers. A univariate logistic regression model with the clinical response as the outcome variable will be fitted to explore if any genomic alterations are associated with the clinical response to metformin hydrochloride.

  5. Change in Measurements of Metformin Hydrochloride Concentrations in Serum and Saliva [ Time Frame: Baseline to up to 14 weeks ]
    Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers.

  6. Change in Serum Metabolic Markers [ Time Frame: Baseline to up to 14 weeks ]
    Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers.

  7. Change in Serum and Saliva Inflammatory and Angiogenic Cytokines [ Time Frame: Baseline to up to 14 weeks ]
    Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers.


Other Outcome Measures:
  1. Change in Saliva Microbiome Analyzed Using Flow Cytometry [ Time Frame: Baseline to up to 14 weeks ]
    This will characterize changes in the saliva microbiome before and after metformin intervention, including both the absolute microbial load and taxonomic composition. Will first evaluate changes in alpha diversity among matched pairs using non-parametric analogous Wilcoxon rank-sum test (Mann-Whitney test). To test for significant differences in beta diversity (e.g. if pretreatment and post-treatment samples cluster in principle coordinates analysis space), permutational multivariate analysis of variance (PERMANOVA) will be used.

  2. Microbiome Signatures Correlated With Treatment Response [ Time Frame: Baseline to up to 14 weeks ]
    Will first evaluate changes in alpha diversity among matched pairs using non-parametric analogous Wilcoxon rank-sum test (Mann-Whitney test). To test for significant differences in beta diversity (e.g. if pretreatment and post-treatment samples cluster in principle coordinates analysis space), PERMANOVA will be used.



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:

  • Participants with oral leukoplakia or erythroplakia with mild, moderate, or severe histologic dysplasia, or hyperplasia not associated with mechanical factors such as ill-fitted dentures
  • Measurable disease - minimum lesion size of 8 x 3 mm before initial biopsy
  • Karnofsky performance status >= 70%
  • Leukocytes >= 3,000/microliter
  • Absolute neutrophil count >= 1,000/microliter
  • Platelets >= 100,000/microliter
  • Total bilirubin =< 1.5 × institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =<1.5 × institutional ULN
  • eGFR > 40 mL/min using the Cockcroft-Gault equation
  • Life expectancy > 3 months
  • Willing to use adequate contraception (barrier method, abstinence, subject has had a vasectomy or partner is using effective birth control or is postmenopausal) for the duration of study participation
  • Ability to take oral medication
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients with diabetes who are taking insulin or oral agents
  • History of diabetic ketoacidosis
  • Participants may not be receiving any other investigational agents within past 3 months
  • History of allergic reactions attributed to compounds of similar chemical composition to metformin or prior use of metformin within the last year
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, human immunodeficiency virus (HIV)-positive, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Oral carcinoma in situ
  • History of chronic alcohol use or abuse defined as any one of the following: a) average consumption of 3 or more alcohol containing beverages daily in the past 12 months; b) consumption of 7 or more alcoholic beverages within a 24 hour (hr) period in the past 12 months
  • Glycated hemoglobin (HbA1c) > 8%
  • Pregnancy or nursing women
  • Acute or chronic liver disease, evidence of hepatitis (infectious or autoimmune), cirrhosis or portal hypertension
  • History of renal disease
  • History of prior head and neck squamous cell carcinoma (HNSCC) unless curatively treated for >= 1 year
  • Have received chemotherapy and/or radiation for any malignancy (excluding non-melanoma skin cancer and cancers confined to organs with removal as only treatment) in the past 2 years; ongoing adjuvant hormonal therapy for breast cancer is allowed

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): NCT02581137


Locations
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United States, California
University of California San Diego
San Diego, California, United States, 92103
United States, Minnesota
University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota, United States, 55455
Canada, British Columbia
BC Cancer Research Centre
Vancouver, British Columbia, Canada, V5Z 1L3
University of British Columbia Hospital
Vancouver, British Columbia, Canada, V6T 2B5
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Scott M Lippman The University of Arizona Medical Center-University Campus
  Study Documents (Full-Text)

Documents provided by National Cancer Institute (NCI):

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02581137     History of Changes
Other Study ID Numbers: NCI-2015-01733
NCI-2015-01733 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
N01-CN-2012-00031
HHSN2612012000311
1510157567 ( Other Identifier: Banner University Medical Center - Tucson )
UAZ2015-05-02 ( Other Identifier: DCP )
N01CN00031 ( U.S. NIH Grant/Contract )
P30CA023074 ( U.S. NIH Grant/Contract )
First Posted: October 20, 2015    Key Record Dates
Results First Posted: May 23, 2019
Last Update Posted: June 5, 2019
Last Verified: February 2019

Additional relevant MeSH terms:
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Mouth Neoplasms
Leukoplakia, Oral
Head and Neck Neoplasms
Neoplasms by Site
Neoplasms
Mouth Diseases
Hyperplasia
Leukoplakia
Erythroplasia
Pathologic Processes
Stomatognathic Diseases
Precancerous Conditions
Pathological Conditions, Anatomical
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs