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

Oral Leukoplakia Clinical Trial

Official title:

M4OC-Prevent: Metformin for Oral Cancer Prevention

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02581137
• Other study ID #: NCI-2015-01733
• Secondary ID: NCI-2015-01733HH
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 10, 2016
• Est. completion date: December 22, 2024

Study information

• Verified date: December 2023
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 26
• Est. completion date: December 22, 2024
• Est. primary completion date: October 12, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Erythroplakia
• Erythroplasia
• Hyperplasia
• Leukoplakia
• Leukoplakia, Oral
• Mouth Neoplasms
• Oral Cavity Carcinoma
• Oral Leukoplakia

Intervention

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Metformin Hydrochloride
Given PO

Locations

Country	Name	City	State
Canada	BC Cancer Research Centre	Vancouver	British Columbia
Canada	University of British Columbia Hospital	Vancouver	British Columbia
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	UC San Diego Medical Center - Hillcrest	San Diego	California

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	Baseline to up to 14 weeks
Other	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.	Baseline to up to 14 weeks
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.	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.	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.	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.	Baseline to up to 14 weeks
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.	Up to 14 weeks
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.	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.	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.	Baseline to up to 14 weeks