ErythroplakiaPhase 2NCT02581137
Metformin Hydrochloride in Preventing Oral Cancer in Patients With an Oral Premalignant Lesion
A Phase 2 study testing Laboratory Biomarker Analysis and Metformin Hydrochloride in people with Erythroplakia and Hyperplasia, run by National Cancer Institute (NCI) at 4 sites in 2 countries.
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Erythroplakia, Hyperplasia, Oral Cavity Carcinoma
- What is being tested?
- Laboratory Biomarker Analysis and Metformin Hydrochloride
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 26 participants
- Where
- 4 sitesin 2 countries
- Study dates
- 10 Jun 2016to 19 Dec 2026
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
4 sites in 2 countries.
4 sites in 2 countries
United States2 sites
University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota, 55455
UC San Diego Medical Center - Hillcrest
San Diego, California, 92103
Canada2 sites
BC Cancer Research Centre
Vancouver, British Columbia, V5Z 1L3
University of British Columbia Hospital
Vancouver, British Columbia, V6T 2B5
About this study
Official title: 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.
Read the detailed description
PRIMARY OBJECTIVES:
- To determine the clinical response of oral premalignant lesions to 12-14 weeks of metformin (metformin hydrochloride) intervention.
SECONDARY OBJECTIVES:
- 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).
- 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:
- 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.
- Conditions
- Erythroplakia, Hyperplasia, Oral Cavity Carcinoma, Oral Leukoplakia
- Being tested
- Laboratory Biomarker Analysis, Metformin Hydrochloride
- Medical subject headings
- Erythroplasia, Hyperplasia, Mouth Neoplasms, Leukoplakia, Oral
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Laboratory Biomarker AnalysisOther
Correlative studies
Metformin HydrochlorideDrug
Also called APO-Metformin, Cidophage, Dimefor, Glifage
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Prevention (extended-release metformin hydrochloride) | Experimental | 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. Receives: Other: Laboratory Biomarker Analysis; Drug: Metformin Hydrochloride |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline to up to 14 weeks
Secondary outcomes (7)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline to up to 14 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Oct 2015 (estimated)
- Study start10 Jun 2016
- Primary completion12 Oct 2017
- Study completion19 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for ErythroplakiaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 26 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Scott M Lippman, Principal investigator, The University of Arizona Medical Center-University Campus
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02581137
- Sponsor's protocol ID
- NCI-2015-01733
- Other IDs
- NCI-2015-01733, HHSN2612012000311, N01-CN-2012-00031, 1510157567, UAZ2015-05-02, N01CN00031, P30CA023074
- Status last verified
- Jun 2026
- First submitted
- 19 Oct 2015
- Last updated
- 26 Jun 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
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.
PubMed 34255745
Study at a glance
From the registry record, last updated by the sponsor on 26 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- M4OC-Prevent: Metformin for Oral Cancer Prevention
- ClinicalTrials.gov ID
- NCT02581137
- Acronym / sponsor ID
- NCI-2015-01733
- Conditions
- Erythroplakia, Hyperplasia, Oral Cavity Carcinoma, Oral Leukoplakia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 26 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 10 Jun 2016 (actual)
- Primary completion
- 12 Oct 2017 (actual)
- Study completion
- 19 Dec 2026 (estimated)
- First posted
- 20 Oct 2015 (estimated)
- Results
- Posted 23 May 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- To determine the clinical response of oral premalignant lesions to 12-14 weeks of metformin (metformin hydrochloride) intervention.
SECONDARY OBJECTIVES:
- 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).
- 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:
- 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 design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Prevention (extended-release metformin hydrochloride) | Experimental | Other: Laboratory Biomarker Analysis, Drug: Metformin HydrochloridePatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Laboratory Biomarker AnalysisCorrelative studies | Other | Prevention (extended-release metformin hydrochloride) |
| Metformin HydrochlorideAlso: APO-Metformin, Cidophage, Dimefor, GlifageGiven PO | Drug | Prevention (extended-release metformin hydrochloride) |
Primary outcome
Clinical Response to Metformin Intervention
Time frame: 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.
7 secondary outcomes
Histologic Response to Metformin Intervention
Time frame: Baseline to up to 14 weeks
Changes in Cell Proliferation and Its Molecular Targets
Time frame: Baseline to up to 14 weeks
Changes in Frequent Dysregulated Molecular Mechanisms and OCT Expression
Time frame: Baseline to up to 14 weeks
Impact of Genomic Alterations on the Biological and Biochemical Consequences and Clinical Response to Metformin Hydrochloride
Time frame: Up to 14 weeks
Change in Measurements of Metformin Hydrochloride Concentrations in Serum and Saliva
Time frame: Baseline to up to 14 weeks
Change in Serum Metabolic Markers
Time frame: Baseline to up to 14 weeks
Change in Serum and Saliva Inflammatory and Angiogenic Cytokines
Time frame: Baseline to up to 14 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jun 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34255745Gutkind 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Scott M Lippman principal investigator
The University of Arizona Medical Center-University Campus
4 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Laboratory Biomarker Analysis and Metformin Hydrochloride in people with Erythroplakia and Hyperplasia, run by National Cancer Institute (NCI) at 4 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 26 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 May 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Clinical Response to Metformin Intervention (time frame: Baseline to up to 14 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02581137, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jun 2026.