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Trial record 4 of 2090 for:    Oral Cancer | NIH

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

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ClinicalTrials.gov Identifier: NCT02581137
Recruitment Status : Active, not recruiting
First Posted : October 20, 2015
Last Update Posted : July 31, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

October 19, 2015
October 20, 2015
July 31, 2018
June 10, 2016
February 28, 2019   (Final data collection date for primary outcome measure)
Change in clinical response of oral premalignant lesions [ Time Frame: Baseline to up to 14 weeks ]
Clinical response will be categorized into complete response (CR), partial response (PR), no change or progressive disease. A participant with CR or PR is considered as a respondent. A one-sided one-sample binomial exact test at a significance level of 5% will be performed to see if the clinical response rate is greater than 30% (poor treatment).
Same as current
Complete list of historical versions of study NCT02581137 on ClinicalTrials.gov Archive Site
  • Change in histologic response [ Time Frame: Baseline to up to 14 weeks ]
    The histologic response rate will be calculated and a one-sided 95% confidence interval based on the exact method will be derived.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Change in histologic response [ Time Frame: Baseline to up to 14 weeks ]
    The histologic response rate will be calculated and a one-sided 95% confidence interval based on the exact method will be derived.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Not Provided
 
Metformin Hydrochloride in Preventing Oral Cancer in Patients With an Oral Premalignant Lesion
M4OC-Prevent: Metformin for Oral Cancer Prevention
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.

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.

Interventional
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
  • Erythroplakia
  • Hyperplasia
  • Mild Dysplasia
  • Moderate Dysplasia
  • Oral Cavity Carcinoma
  • Oral Leukoplakia
  • Severe Dysplasia
  • 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
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.
Interventions:
  • Other: Laboratory Biomarker Analysis
  • Drug: Metformin Hydrochloride
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
26
Same as current
Not Provided
February 28, 2019   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Canada,   United States
 
 
NCT02581137
NCI-2015-01733
NCI-2015-01733 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
N01-CN-2012-00031
HHSN2612012000311
1510157567 ( Other Identifier: The University of Arizona Medical Center-University Campus )
UAZ2015-05-02 ( Other Identifier: DCP )
N01CN00031 ( U.S. NIH Grant/Contract )
P30CA023074 ( U.S. NIH Grant/Contract )
Yes
Not Provided
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Scott Lippman The University of Arizona Medical Center-University Campus
National Cancer Institute (NCI)
July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP