A Phase 1 interventional study of Metformin and Naproxen Sodium in Fanconi Anemia, Head and Neck Cancer and Squamous Cell Carcinoma, sponsored by Rockefeller University. Recruiting at 2 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-10-28.
Sponsored by Rockefeller University · Phase 1, Interventional, and Other
Finding effective ways to slow down or prevent the development of cancer in people with Fanconi anemia (FA) is a critical medical priority. Individuals with FA are at dramatically higher risk of developing aggressive cancers, particularly of the head and neck, and these cancers are difficult to treat with standard therapies such as surgery, chemotherapy or radiation. Because options for treatment are limited and outcomes are often poor, prevention strategies are urgently needed.
In this study, the investigators will test two widely available drugs, metformin and naproxen, to evaluate whether they can lower the risk of cancer in FA patients. Metformin is commonly prescribed for type 2 diabetes, while naproxen is a nonsteroidal anti-inflammatory drug (NSAID) frequently used for pain and inflammation. Both have shown potential in previous research to influence biological pathways linked to cancer development. By repurposing these well-known drugs, this trial aims to explore a safe, practical approach to cancer prevention in this vulnerable population.
The study, conducted at the Rockefeller University and the University of Minnesota, has several goals. First, the investigators will carefully assess the safety and tolerability of metformin and naproxen when used in participants with FA. Because these individuals can be more susceptible to metabolic disorders like diabetes compared to the general population, and may have genitourinary abnormalities related to their underlying condition, monitoring for side effects and adverse events is especially important. Second, investigators will evaluate whether intervention affects visible or microscopic changes in the mouth, where cancers often arise. This will involve performing small biopsies of oral tissue to look for cancerous or pre-cancerous lesions. Third, investigators will investigate early molecular changes using an exploratory less invasive technique: collecting cells with a soft brush, similar to a toothbrush. These samples will allow the investigators to analyze biomarkers-biological signals that can indicate increased or reduced cancer risk-before and after intervention.
Together, these approaches will provide information on whether metformin or naproxen are safe and well-tolerated in the FA population. As an additional outcome, by combining direct tissue analysis with biomarker studies, the investigators aim to detect subtle changes that precede cancer, giving us an early indication of whether the drugs are working as preventive agents.
Although this is an early-phase study, its potential significance is considerable. Demonstrating that well-tolerated, inexpensive, and widely accessible drugs may have potential to reduce cancer risk would represent a major advance for FA patients, who currently face limited options for prevention and treatment. This work may also offer insights relevant to broader cancer prevention efforts in other high-risk groups. Ultimately, our study seeks to take an important step toward changing the outlook for people with Fanconi anemia by moving the focus from late-stage treatment toward early prevention.
Fanconi anemia (FA) patients have a 500-700-fold higher risk of head and neck squamous cell carcinoma (HNSCC) than the general population, with early onset and poor survival due to the aggressive nature of these tumors and intrinsic constitutional sensitivity of FA patients to chemo- and radiotherapy. Given this risk and the paucity of viable treatments, cancer prevention is a critical priority.
Metformin, a widely used anti-diabetes drug, has shown promise in FA-related cancer prevention. In preclinical studies, metformin improves defective hematopoiesis and delays tumor development in Fancd2-/-/Trp53+/- mice. Metformin also showed preventive efficacy in oral cancer in patients with oral premalignancies in a Phase IIA clinical trial (NCT02581137), with an ongoing Phase IIB randomized, placebo- controlled trial (NCT05237960) further evaluating its effectiveness. Outside FA, but in the setting of high cancer predisposition syndrome, the MILI Precision-Prevention trial (ISRCTN16699730) and a parallel NIH study will assess metformin in a non-placebo-controlled Phase II trial in adults with Li-Fraumeni Syndrome undergoing annual MRI-based cancer surveillance. Finally, a clinical trial for treatment of cytopenia in FA (NCT03398824) concluded that metformin was safe, well-tolerated, and may provide therapeutic benefit in nondiabetic patients with FA with a median age of 9.4 years.
Naproxen, another widely-used and well-tolerated drug, has shown promise in cancer prevention. Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to be associated with reduced metastasis across cancer types and to inhibit proliferation and drive apoptosis of cancer cells. Naproxen has shown promise in animal studies by inhibiting lung adenocarcinoma formation in mice, suggesting a chemopreventive role. In a study of 80 participants in Lynch syndrome with a predisposition to multiple cancer types, daily administration of naproxen for six months promoted immune activation, with no statistically significant difference in the total number of adverse events when comparing treatment arms to placebo, with excellent tolerance of the intervention. Another NSAID, the COX-2 selective agent celecoxib has also shown cancer preventive potential. In the FA-setting, combination of atorvastatin and celecoxib delayed tumor formation in Fancd2-/-/Trp53+/- mice. More recently, Markus Grompe's lab found that in a Fanct-/-/Trp53+/-/ADH5-/- mouse model, the number of dysplastic tongue lesions decreased following intervention with atorvastatin/celecoxib or celecoxib alone (Markus Grompe lab, SU2C team project led by Dr. Smogorzewska, unpublished). Evidence from large observational studies suggests that naproxen has a better cardiovascular safety profile compared to other NSAIDs like celecoxib.
The major innovation in this trial will be the use of molecular biomarkers to assess potential anti-mutagenic effects of these agents. Ongoing unpublished studies in our lab have shown that 55% of 38 FA patients exhibited at least one molecular alteration in normal-appearing oral mucosa. Clinically significant TP53 Single Nucleotide Variants (SNVs) were identified in 10 of 38 FA patients (26%), with 19 unique SNVs detected in 222 (8.5%) brush biopsy samples from normal-appearing, non-lesional mucosa. Copy Number Variants (CNVs) were present in 20 of 38 FA patients (53%) and detected in 56 of 171 samples (33%). These preliminary results indicate that a large proportion of FA patients are likely to have potentially oncogenic somatic genomic variants. This gives us an opportunity to follow these biomarkers, in patients without lesions and eventually forgo the use of surgical biopsies to assess efficacy of treatment.
The investigators will also incorporate buccal swab brushing followed by targeted NanoSeq analysis of variants in a panel of 239 cancer genes. This is being performed through a collaboration with Dr. Iñigo Martincorena (Sanger Institute, UK). The high sensitivity of this method for low frequency variants will give us a richer picture of mutational landscape in patients with Fanconi anemia, and by increasing sensitivity of variant detection, will increase the number of eligible participants. Some participants who may not have variants identifiable by brushing, may have variants detectable by buccal swab.
Building on these findings, the investigators propose an open-label crossover design phase 1 clinical trial testing the feasibility of metformin and naproxen, administered separately, to prevent oral cancer in FA patients. Adult FA patients with at least one oral lesion or the presence of a biomarker (described above) will be included. The investigators hypothesize that metformin and naproxen are safe, feasible, well-tolerated in patients with FA, and may reduce or reverse genetic lesions associated with cancer development in FA patients.
This is a multi-site single IRB study with Rockefeller serving as IRB of Record for the University of Minnesota (UMN) using the SMART IRB Master Reliance Agreement. The University of Minnesota site will carry out the same protocol at their site under the direction of Dr. Rachel Uppgaard, DDS (Relying Site PI).
95 studies on the registry are indexed under Fanconi Anemia; 20 are open to participants now.
This study's planned enrollment of 80 is above the median of 21 across 61 interventional studies indexed under Fanconi Anemia.
Browse Fanconi Anemia studies →Rockefeller University is the lead sponsor of 123 studies on the registry; 3 are open to participants now.
Of its 14 completed or terminated interventional studies of FDA-regulated products, 6 (43%) have results posted.
Counted across the registry records on this site, refreshed daily.
Inclusion Criteria, Participants must meet all of the following criteria to be eligible:
Confirmed Diagnosis:
Adequate Organ and Marrow Function, defined as:
Barrier method, abstinence, vasectomized partner, effective birth control, or status.
Consent - Ability to understand and willingness to sign a written form in English or an approved translated version.
Alcohol, tobacco, and marijuana abstinence
- Standard of care for oral leukoplakia is to recommend abstinence from smoking and alcohol consumption. As part of the consent, we will ask participants to agree to abstain from alcohol, tobacco, and marijuana.
Inclusion of Women and Minorities:
- This study is open to all individuals regardless of sex, race, or ethnicity. Both men and women and individuals of all racial and ethnic backgrounds are encouraged to participate.
Exclusion Criteria, Participants will be excluded if any of the following conditions are present:
Diabetes-Related Conditions
Participants with HIV infection may be included provided that they are able to provide medical records demonstrating that:
Prohibited Medications
- Current use of carbonic anhydrase inhibitors (e.g., topiramate, zonisamide, acetazolamide, dichlorphenamide) or ranolazine
Medical contraindication to NSAIDs or metformin, including:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A 0–100 scale of how well someone can carry out everyday activities. 100 is no complaints and no signs of illness; 70 is able to look after yourself but not to work or keep up normal activity; 50 is needing considerable help and frequent medical care.
Studies often ask for 60 or 70 and above. Your doctor gives the score.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
A condition in which the immune system attacks the body’s own tissues, such as rheumatoid arthritis, lupus, psoriasis, type 1 diabetes or inflammatory bowel disease.
Immunotherapy studies often leave out active autoimmune disease, and some name exceptions, such as thyroid disease on replacement hormone. Check the exceptions this study lists.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
The number of CD4 cells, a type of white blood cell, in a given amount of blood. It is used to follow how well the immune system is doing in HIV.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Karnofsky performance status (KPS)
A 0–100 scale of how well someone can carry out everyday activities. 100 is no complaints and no signs of illness; 70 is able to look after yourself but not to work or keep up normal activity; 50 is needing considerable help and frequent medical care.
Studies often ask for 60 or 70 and above. Your doctor gives the score.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Bilirubin
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
GFR and eGFR (kidney filtering)
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis B tests
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis C tests
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Postmenopausal
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HbA1c
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Autoimmune disease
A condition in which the immune system attacks the body’s own tissues, such as rheumatoid arthritis, lupus, psoriasis, type 1 diabetes or inflammatory bowel disease.
Immunotherapy studies often leave out active autoimmune disease, and some name exceptions, such as thyroid disease on replacement hormone. Check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Adjuvant and neoadjuvant
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
CD4 count
The number of CD4 cells, a type of white blood cell, in a given amount of blood. It is used to follow how well the immune system is doing in HIV.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Participants in this arm will receive 6 months of oral naproxen sodium 440mg daily. On completion of the naproxen, participants will then have a 1 month washout period where they receive no drug intervention, followed by 6 months of oral metformin extended release, starting at a dose of 500mg daily and titrating up to 2000mg daily as tolerated.
Drug: Metformin · Drug: Naproxen Sodium
Participants in this arm will receive 6 months of oral metformin extended release, starting at a dose of 500mg daily and titrating up to 2000mg daily as tolerated. On completion of the metformin, participants will then have a 1 month washout period where they receive no drug intervention, followed by 6 months of oral naproxen sodium 440mg daily.
Drug: Metformin · Drug: Naproxen Sodium
Participants who wish to continue to participate but are unable to tolerate the metformin or naproxen intervention may be placed into this observational arm, which will include the same evaluations but will not include any drug intervention.
Oral metformin extended release, starting at a dose of 500mg daily and titrating up to 2000mg daily as tolerated for 6 months.
6 months of oral naproxen sodium 440mg daily.
Safety
The investigators will assess the primary outcome of safety and tolerability of metformin and naproxen as chemoprevention agents for head and neck squamous cell carcinoma in Fanconi anemia patients: Incidence of Grade 2 or Higher Intervention-Related Adverse Events (AEs) Description: The number and percentage of participants experiencing at least one grade ≥2 AE judged to be related to study intervention (as per CTCAE v5.0 criteria). Investigators will compare the proportion of adverse events for pre-intervention vs. metformin and pre-intervention vs. naproxen. Time Frame: Throughout the drug intervention period and up to 30 days after last intervention dose. Assessment Methods: Investigator assessment at clinic visits, participant self-reports, and clinical laboratory evaluations. Safety Goal: \<5% of participants experiencing Grade ≥3 drug-related AEs.
Time frame: For the duration of the study, 22 months for each individual participant
Tolerability of Intervention Regimen
Defined as participant retention and ability to continue intervention without dose-limiting toxicities, treatment discontinuation, or withdrawal due to side effects. Investigators will report proportion of dropout during each intervention.
Time frame: Duration of intervention, from month 3 to month 16 of the study for each participant.
Frequency of Any Adverse Events (All Grades)
Count and categorization of all reported AEs, regardless of severity or attribution. The investigators will report proportion of participant with AEs attributed to drug, subcategorized by intervention during which AE occurred and AE grade.
Time frame: Baseline visit through end of study, a weekly survey will assess AEs. Participants can report AEs to designated study staff at any point during the duration of the study,
Adherence to Intervention Regimen (Pill Counts and participant report)
Proportion of prescribed doses taken, measured via pill count and participant report via survey checklist.
Time frame: Pill counts will occur at the 9 month and 16 month site visits. Participant adherence self-report surveys will be collected at the 9 month and 16 month site visits.
Self-Reported Adherence and Symptom Tracking
Participant-reported adherence, side effects, and symptoms logged weekly through electronic survey tools.
Time frame: Weekly for the duration of the study.
Self-Exam Completion Rate (via FAexam App)
Proportion of expected monthly oral exams completed by participants using the secure FAexam app.
Time frame: Monthly for the duration of the study.
New oral lesions
The investigators will record and compare the change in lesion number and size for participants between the start and end of the intervention period compared to between the start and end of the preintervention period. Assessment methods: Lesion status will be assessed at each study visit through oral examination, lesion mapping and measurement, and standardized, non-identifying oral cavity imaging. Comparisons will be made between pre-intervention vs after metformin, and between preintervention vs after naproxen. The investigators will compare the mean number of lesions in each time period across intervention groups.
Time frame: At each site visit (baseline, 3 month, 9 month, 16 month and 22 month) for the duration of the study.
Target Lesion Histological Grade
Histological grading (e.g., normal, hyperplasia, dysplasia, carcinoma in situ) from a target lesion selected based on clinical features at: 1. end of pre-intervention period (3-month visit) and compared to follow up biopsy at end of first intervention period (9-months). 2. end of first intervention period (9-month visit) will be compared to subsequent follow up biopsy at end of second intervention period (16-months). 3. end of second intervention period (16-month visit) will be compared to subsequent follow up biopsy at end of study (22-months). Histologic changes in that lesion will be evaluated by a trained pathologist and used to assess response to intervention. The investigators will compare the mean number of lesions in each grade category in each time period across intervention groups.
Time frame: At each site visit (baseline, 3 month, 9 month, 16 month and 22 month) for the duration of the study.
Presence of Pathogenic TP53 Variants (Oral Brush Samples) (Exploratory)
Binary variable (presence/absence) indicating whether pathogenic or likely pathogenic somatic TP53 variants are detected in oral brush samples. Somatic origin will be deduced by presence of the same variant in all tested oral sites and if necessary, confirmed by comparing results to matched germline DNA (blood or skin). The presence of TP53 variants will be tracked longitudinally and compared across timepoints pre- and post-intervention.
Time frame: Brush samples will be collected at each site visit (baseline, 3 month, 9 month, 16 month and 22 month) for the duration of the study.
Presence of Copy Number Variants (CNVs) in Oral Brush Samples (Exploratory)
Binary variable indicating detection of CNVs via genome-wide SNP genotyping. The presence of CNVs will be tracked longitudinally and compared across timepoints pre- and post-intervention. Brushing will be performed at each study visit.
Time frame: Brush samples will be collected at each site visit (baseline, 3 month, 9 month, 16 month and 22 month) for the duration of the study.
Presence of Somatic Mutations by Duplex Sequencing (NanoSeq) (Exploratory)
Binary and quantitative variables indicating somatic mutation burden (e.g., number of variants, variant allele frequency) from buccal swab samples assessed via NanoSeq 18. Changes over time will be compared between baseline and post-metformin/naproxen intervention.
Time frame: NanoSeq samples will be collected by buccal swab at each site visit (baseline, 3 month, 9month, 16 month and 22 month) for the duration of the study.
Histologic and Molecular Biomarker Changes in Target Lesion (Exploratory)
Exploratory variable assessing protein expression changes via immunohistochemistry (IHC) in biopsied tissue. Specific markers (included but not limited to Ki67 a proliferative marker, pS6 a marker of mTOR pathway activity, and COX-2 a measure of pathway activity) will be used to infer molecular mechanisms of action of metformin and naproxen. DNA and RNA sequencing may also be performed to identify changes including TP53 mutations and copy number variants or gene expression profiles in the lesion tissue.
Time frame: Assessment of biopsy samples will occur following site visits during which an oral biopsy was obtained, for the duration of the study. This may occur at each site visit except the baseline (3 month, 9month, 16 month and 22 month visits).
Plan to share: Yes — CLIA-approved labs will be reported. Exploratory and/or research results that are inconclusive or
Supporting information: Informed consent form
Time frame: Start 10/1/2026 end 10/1/2030
Access criteria: Participants will be provided with a copy of the informed consent form (ICF) electronically prior to eConsent. Additionally, participants will be provided with a paper copy of the ICF at their first study on-site visit. The ICF form is also available to participants on request.
Start is estimated for Oct 2026; primary completion for Oct 2030, 48 months later.
How these figures are worked out, and which studies are left out of them.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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Studies of the drugs tested here: Metformin · Naproxen