Safe use of metformin and naproxen to help prevent cancer in people with Fanconi anemia

Inclusion Criteria, Participants must meet all of the following criteria to be eligible:

Confirmed Diagnosis:

* Fanconi anemia confirmed by review of past molecular testing (including chromosomal breakage testing results) Age
* Age ≥18 years. Functional Status
* Karnofsky performance scale ≥70%.

Adequate Organ and Marrow Function, defined as:

* Leukocytes ≥3,000/µL
* Absolute neutrophil count ≥1,000/µL
* Platelets ≥40,000/µL
* Total bilirubin ≤1.5 × institutional upper limit of normal (ULN) unless with Gilberts syndrome
* AST (SGOT) / ALT (SGPT) ≤3 × institutional ULN
* eGFR \>45 mL/min (using CKD-EPI equation: https://www.mdcalc.com/ckd-epi-equations-glomerular-filtration-rate-gfr) Viral Infection Status
* HIV-infected patients are eligible if on effective antiretroviral therapy with undetectable viral load within 6 months.
* Chronic HBV infection is permitted if viral load is undetectable on suppressive therapy.
* History of HCV infection is allowed if patient has been treated and cured, or if currently being treated and has undetectable viral load.
* Patients on chronic suppressive antiviral therapy for HSV are eligible. Medication and Intervention Requirements
* Ability to take oral medication. Contraception Agreement
* Willing to use adequate contraception during the study, including:

Barrier method, abstinence, vasectomized partner, effective birth control, or postmenopausal status.

* Women of childbearing potential and men must agree to use contraception prior to study entry and throughout participation.
* Female participants who become pregnant or suspect pregnancy must inform the study physician immediately.

Consent - Ability to understand and willingness to sign a written informed consent 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

* Diagnosed diabetes treated with insulin or other anti-diabetic medication
* History of diabetic ketoacidosis
* HbA1c greater than or equal to 6.5%
* Prior use of metformin within the past year Recent Investigational Drug Use
* Receipt of any investigational agents within the past 3 months Drug Hypersensitivity
* History of allergic reaction to metformin, naproxen or chemically similar compounds Medical Comorbidities
* Uncontrolled intercurrent illness (e.g., active infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, psychiatric/social issues limiting compliance)
* Oral carcinoma in situ on baseline exam or biopsy Pregnancy and Nursing
* Pregnant or breastfeeding women are excluded due to unknown risks of metformin and potential risk of naproxen on the fetus and nursing infant Liver Disease
* Acute or chronic liver disease including elevated liver enzymes \>3x ULN as described above, or diagnosis of infectious or autoimmune hepatitis, cirrhosis, portal hypertension, or hepatocellular carcinoma Active Cancer Treatment
* Current course of chemotherapy, immunotherapy, or radiation for any malignancy (excluding non-melanoma skin cancer or surgically cured organ-confined cancers)
* Prior curatively treated cancers are allowed if treatment is completed within 6 months of study start.
* Ongoing adjuvant hormonal therapy (e.g., for breast cancer) is allowed
* Chronic Medical Conditions do not exclude participants from the trial unless they meet one of the other listed exclusion criteria.

Participants with HIV infection may be included provided that they are able to provide medical records demonstrating that:

* HIV infection is documented and the participant has been on a stable antiretroviral regimen for at least 6 months.
* HIV RNA is below the limit of quantification (e.g., \<50 copies/mL) on the most recent measurement and there is no history of virologic failure within the past 12 months.
* CD4+ T-cell count is ≥200 cells/µL within 6 months prior to enrollment.
* There has been no AIDS-defining illness or active opportunistic infection within the past 12 months.
* The participant's current antiretroviral regimen has no known clinically significant drug-drug interactions with the study intervention.
* The participant is otherwise clinically stable in the judgment of the investigator.

Prohibited Medications

\- Current use of carbonic anhydrase inhibitors (e.g., topiramate, zonisamide, acetazolamide, dichlorphenamide) or ranolazine Contraindications

Medical contraindication to NSAIDs or metformin, including:

* NSAID hypersensitivity
* NSAID-induced asthma
* Previous NSAID-induced peptic ulcer
* Other active peptic ulcers
* Renal impairment (eGFR \<45 mL/min)
* Bleeding/clotting disorders (e.g. hemophilia, thrombophilia)
* Current use of systemic (not topical) NSAID or Steroid
* Taking NSAIDs or steroids regularly at time of screening Note: Participants requiring NSAIDs during the trial will be encouraged to use acetaminophen, and can continue in the study as long as the acetaminophen use is temporary and intermittent. Participants who take additional NSAIDs (2 doses or more in a one week period) will be temporarily withdrawn from both intervention arms until they are no longer regularly taking NSAIDs.