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

Primary Purpose

Erythroplakia, Hyperplasia, Oral Cavity Carcinoma

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Laboratory Biomarker Analysis
Metformin Hydrochloride
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Erythroplakia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • UC San Diego Medical Center - Hillcrest
  • University of Minnesota/Masonic Cancer Center
  • BC Cancer Research Centre
  • University of British Columbia Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Prevention (extended-release metformin hydrochloride)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
October 19, 2015
Last Updated
March 29, 2023
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02581137
Brief Title
Metformin Hydrochloride in Preventing Oral Cancer in Patients With an Oral Premalignant Lesion
Official Title
M4OC-Prevent: Metformin for Oral Cancer Prevention
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 10, 2016 (Actual)
Primary Completion Date
October 12, 2017 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Erythroplakia, Hyperplasia, Oral Cavity Carcinoma, Oral Leukoplakia

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Prevention (extended-release metformin hydrochloride)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Metformin Hydrochloride
Other Intervention Name(s)
APO-Metformin, Cidophage, Dimefor, Glifage, Glucoformin, Glucophage, Glucophage ER, Metformin HCl, Riomet, Siofor
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Clinical Response to Metformin Intervention
Description
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
Secondary Outcome Measure Information:
Title
Histologic Response to Metformin Intervention
Description
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
Title
Changes in Cell Proliferation and Its Molecular Targets
Description
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
Title
Changes in Frequent Dysregulated Molecular Mechanisms and OCT Expression
Description
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
Title
Impact of Genomic Alterations on the Biological and Biochemical Consequences and Clinical Response to Metformin Hydrochloride
Description
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
Title
Change in Measurements of Metformin Hydrochloride Concentrations in Serum and Saliva
Description
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
Title
Change in Serum Metabolic Markers
Description
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
Title
Change in Serum and Saliva Inflammatory and Angiogenic Cytokines
Description
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
Other Pre-specified Outcome Measures:
Title
Change in Saliva Microbiome Analyzed Using Flow Cytometry
Description
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
Title
Microbiome Signatures Correlated With Treatment Response
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Scott M Lippman
Organizational Affiliation
The University of Arizona Medical Center-University Campus
Official's Role
Principal Investigator
Facility Information:
Facility Name
UC San Diego Medical Center - Hillcrest
City
San Diego
State/Province
California
ZIP/Postal Code
92103
Country
United States
Facility Name
University of Minnesota/Masonic Cancer Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
BC Cancer Research Centre
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V5Z 1L3
Country
Canada
Facility Name
University of British Columbia Hospital
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6T 2B5
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
34255745
Citation
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.
Results Reference
derived

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

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