Erythroplakia, Hyperplasia, Oral Cavity Carcinoma, Oral Leukoplakia
Conditions
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.
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.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGMetformin Hydrochloride
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response to Metformin Intervention | 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
| Measure | Time frame | Description |
|---|---|---|
| Histologic Response to Metformin Intervention | 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. |
| Changes in Cell Proliferation and Its Molecular Targets | 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 | 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 | 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 | 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 | 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 | 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. |
Countries
Canada, United States
Contacts
PRINCIPAL_INVESTIGATORScott M Lippman
The University of Arizona Medical Center-University Campus
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Laboratory Biomarker Analysis: Correlative studies
Metformin Hydrochloride: Given PO | 26 |
| Total | 26 |
Baseline characteristics
| Characteristic | Prevention (Extended-release Metformin Hydrochloride) |
|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 23 Participants |
| Region of Enrollment Canada | 12 Participants |
| Region of Enrollment United States | 14 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 26 |
| other Total, other adverse events | 24 / 26 |
| serious Total, serious adverse events | 1 / 26 |
Outcome results
Primary
Clinical Response to Metformin Intervention
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.
Time frame: Baseline to up to 14 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prevention (Extended-release Metformin Hydrochloride) | Clinical Response to Metformin Intervention | 4 Participants |
Secondary
Change in Measurements of Metformin Hydrochloride Concentrations in Serum and Saliva
Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers.
Time frame: Baseline to up to 14 weeks
Secondary
Change in Serum and Saliva Inflammatory and Angiogenic Cytokines
Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers.
Time frame: Baseline to up to 14 weeks
Secondary
Change in Serum Metabolic Markers
Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers.
Time frame: Baseline to up to 14 weeks
Secondary
Changes in Cell Proliferation and Its Molecular Targets
Nonparametric methods, e.g. signed rank test, will be performed to evaluate each of the changes in tissue, serum, and saliva markers.
Time frame: Baseline to up to 14 weeks
Secondary
Changes in Frequent Dysregulated Molecular Mechanisms and OCT Expression
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.
Time frame: Baseline to up to 14 weeks
Secondary
Histologic Response to Metformin Intervention
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.
Time frame: Baseline to up to 14 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prevention (Extended-release Metformin Hydrochloride) | Histologic Response to Metformin Intervention | 14 Participants |
Secondary
Impact of Genomic Alterations on the Biological and Biochemical Consequences and Clinical Response to Metformin Hydrochloride
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.
Time frame: Up to 14 weeks
Other Pre-specified
Change in Saliva Microbiome Analyzed Using Flow Cytometry
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.
Time frame: Baseline to up to 14 weeks
Other Pre-specified
Microbiome Signatures Correlated With Treatment Response
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.
Time frame: Baseline to up to 14 weeks