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.

Study Overview

• Status: Active, not recruiting
• Conditions: Hyperplasia; Oral Cavity Carcinoma; Oral Leukoplakia; Erythroplakia
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Metformin Hydrochloride

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.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6T 2B5
      • University of British Columbia Hospital
    • Vancouver, British Columbia, Canada, V5Z 1L3
      • BC Cancer Research Centre
• United States
  • California
    • San Diego, California, United States, 92103
      • UC San Diego Medical Center - Hillcrest
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota/Masonic Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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: Glucophage; Riomet; Cidophage; Metformin HCl; Glifage; Siofor; APO-Metformin; Dimefor; Glucoformin; Glucophage ER

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Scott M Lippman, The University of Arizona Medical Center-University Campus

Publications and helpful links

General Publications

• Gutkind JS, Molinolo AA, Wu X, Wang Z, Nachmanson D, Harismendy O, Alexandrov LB, Wuertz BR, Ondrey FG, Laronde D, Rock LD, Rosin M, Coffey C, Butler VD, Bengtson L, Hsu CH, Bauman JE, Hewitt SM, Cohen EE, Chow HS, Lippman SM, Szabo E. Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions. JCI Insight. 2021 Sep 8;6(17):e147096. doi: 10.1172/jci.insight.147096.

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2016
• Primary Completion (Actual): October 12, 2017
• Study Completion (Estimated): December 22, 2024

Study Registration Dates

• First Submitted: October 19, 2015
• First Submitted That Met QC Criteria: October 19, 2015
• First Posted (Estimated): October 20, 2015

Study Record Updates

• Last Update Posted (Actual): January 17, 2024
• Last Update Submitted That Met QC Criteria: December 23, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Stomatognathic Diseases; Mouth Diseases; Pathological Conditions, Anatomical; Precancerous Conditions; Hyperplasia; Mouth Neoplasms; Leukoplakia; Leukoplakia, Oral; Erythroplasia; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: NCI-2015-01733 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA023074 (U.S. NIH Grant/Contract); HHSN2612012000311; N01-CN-2012-00031; N01CN00031 (U.S. NIH Grant/Contract); 1510157567 (Other Identifier: Banner University Medical Center - Tucson); UAZ2015-05-02 (Other Identifier: DCP)