Fanconi AnemiaPhase 1NCT07901959
Safety and Tolerability of Metformin and Naproxen for Cancer Prevention in Fanconi Anemia
A Phase 1 study testing Metformin and Naproxen Sodium in people with Fanconi Anemia and Head and Neck Cancer, run by Rockefeller University at 2 sites in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Fanconi Anemia, Head and Neck Cancer, Squamous Cell Carcinoma
- What is being tested?
- Metformin and Naproxen Sodium
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 80 participants
- Where
- 2 sitesUnited States
- Study dates
- 14 Oct 2026to 14 Oct 2031
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
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
- 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%
Show all 35Show fewer
- 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.
Who cannot join
None listed.
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States2 sites, 2 recruiting
- Recruiting
University of MInnesota
Minneapolis, Minnesota, 55404
Rachel Uppgaard, DDS, 612-625-6976, uppg0003@umn.edu
Carla Campbell, 612-625-6976, camp2757@umn.edu
- Recruiting
The Rockefeller University
New York, New York, 10065
Francis J May, MD, 212-327-7850
Yu-Chien Lin, 212-327-7850, ylin@rockefeller.edu
About this study
Official title: A Randomized Crossover Open-Label Trial of Naproxen and Metformin Safety and Tolerability in the Setting of Prevention of Oral Cancer in Fanconi Anemia
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.
Read more
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.
Read the detailed description
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).
- Conditions
- Fanconi Anemia, Head and Neck Cancer, Squamous Cell Carcinoma, Squamous Cell Cancer of Head and Neck (SCCHN)
- Being tested
- Metformin, Naproxen Sodium
- Keywords
- metformin, naproxen, Rockefeller, Minnesota, Fanconi anemia, Cancer prevention
- Medical subject headings
- Fanconi Anemia, Head and Neck Neoplasms, Carcinoma, Squamous Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Oral metformin extended release, starting at a dose of 500mg daily and titrating up to 2000mg daily as tolerated for 6 months.
Naproxen SodiumDrug
6 months of oral naproxen sodium 440mg daily.
| Study group | Role | What they receive |
|---|---|---|
| Naproxen followed by metformin | Active comparator | 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. Receives: Drug: Metformin; Drug: Naproxen Sodium |
| Metformin followed by naproxen | Active comparator | 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. Receives: Drug: Metformin; Drug: Naproxen Sodium |
| Observational arm | No intervention | 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Duration of intervention, from month 3 to month 16 of the study for each participant.
Secondary outcomes (6)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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:
- end of pre-intervention period (3-month visit) and compared to follow up biopsy at end of first intervention period (9-months).
- end of first intervention period (9-month visit) will be compared to subsequent follow up biopsy at end of second intervention period (16-months).
- 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.
Measured: At each site visit (baseline, 3 month, 9 month, 16 month and 22 month) for the duration of the study.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Oct 2026
- Study start14 Oct 2026 (estimated)
- Primary completion14 Oct 2030 (estimated)
- Study completion14 Oct 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (16)Papers the sponsor has linked to this study.
- Other trials for Fanconi AnemiaStudies of the same condition, open and under way.
- 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 1
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Open-label randomized crossover trial.
- Masking
- None (open label)
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Rockefeller University
- Sponsor type
- University, hospital or other
- Collaborators
- University of Minnesota, The Wellcome Sanger Institute, BC Cancer Research Institute, National Institutes of Health (NIH), NewYork Presbyterian Hospital, Weill Cornell Medical Collage, USA
- Responsible party
- Principal investigator, Francis May, Rockefeller University
- Investigators
- Agata Smogorzewska, MD, PhD, Principal investigator, The Rockefeller University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07901959
- Sponsor's protocol ID
- FMA-1073
- Status last verified
- Oct 2026
- First submitted
- 13 Oct 2026
- Last updated
- 28 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: CLIA-approved labs will be reported. Exploratory and/or research results that are inconclusive or
Publications
Lawson ARJ, Abascal F, Nicola PA, Lensing SV, Roberts AL, Kalantzis G, Baez-Ortega A, Brzozowska N, El-Sayed Moustafa JS, Vaitkute D, Jakupovic B, Nessa A, Wadge S, Osterdahl MF, Paterson AL, Rassl DM, Alcantara RE, O'Neill L, Widaa S, Austin-Guest S, Neville MDC, Przybilla MJ, Cheng W, Morra M, Sykes L, Mayho M, Muller-Sienerth N, Williams N, Alexander D, Harvey LMR, Clarke T, Byrne A, Blundell JR, Young MD, Mahbubani KTA, Saeb-Parsy K, Martin HC, Stratton MR, Campbell PJ, Rahbari R, Small KS, Martincorena I. Somatic mutation and selection at population scale. Nature. 2025 Nov;647(8089):411-420. doi: 10.1038/s41586-025-09584-w. Epub 2025 Oct 8.
PubMed 41062696Davis KAS, Bishara D, Molokhia M, Mueller C, Perera G, Stewart RJ. Aspirin in people with dementia, long-term benefits, and harms: a systematic review. Eur J Clin Pharmacol. 2021 Jul;77(7):943-954. doi: 10.1007/s00228-021-03089-x. Epub 2021 Jan 22.
PubMed 33483830Zhang QS, Deater M, Phan N, Marcogliese A, Major A, Guinan EC, Grompe M. Combination therapy with atorvastatin and celecoxib delays tumor formation in a Fanconi anemia mouse model. Pediatr Blood Cancer. 2019 Jan;66(1):e27460. doi: 10.1002/pbc.27460. Epub 2018 Sep 25.
PubMed 30255556Reyes-Uribe L, Wu W, Gelincik O, Bommi PV, Francisco-Cruz A, Solis LM, Lynch PM, Lim R, Stoffel EM, Kanth P, Samadder NJ, Mork ME, Taggart MW, Milne GL, Marnett LJ, Vornik L, Liu DD, Revuelta M, Chang K, You YN, Kopelovich L, Wistuba II, Lee JJ, Sei S, Shoemaker RH, Szabo E, Richmond E, Umar A, Perloff M, Brown PH, Lipkin SM, Vilar E. Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa. Gut. 2021 Mar;70(3):555-566. doi: 10.1136/gutjnl-2020-320946. Epub 2020 Jul 8.
PubMed 32641470Kumar G, Madka V, Singh A, Farooqui M, Stratton N, Lightfoot S, Mohammed A, Rao CV. Naproxen inhibits spontaneous lung adenocarcinoma formation in KrasG12V mice. Neoplasia. 2021 Jun;23(6):574-583. doi: 10.1016/j.neo.2021.05.010. Epub 2021 Jun 3.
PubMed 34091121Smith ML, Hawcroft G, Hull MA. The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action. Eur J Cancer. 2000 Mar;36(5):664-74. doi: 10.1016/s0959-8049(99)00333-0.
PubMed 10738133Bowen CM, Deng N, Reyes-Uribe L, Parra ER, Rocha P, Solis LM, Wistuba II, Sepeda VO, Vornik L, Perloff M, Szabo E, Umar A, Sinha KM, Brown PH, Vilar E. Naproxen chemoprevention induces proliferation of cytotoxic lymphocytes in Lynch Syndrome colorectal mucosa. Front Immunol. 2023 May 3;14:1162669. doi: 10.3389/fimmu.2023.1162669. eCollection 2023.
PubMed 37207208Pollard JA, Furutani E, Liu S, Esrick E, Cohen LE, Bledsoe J, Liu CW, Lu K, de Haro MJR, Surralles J, Malsch M, Kuniholm A, Galvin A, Armant M, Kim AS, Ballotti K, Moreau L, Zhou Y, Babushok D, Boulad F, Carroll C, Hartung H, Hont A, Nakano T, Olson T, Sze SG, Thompson AA, Wlodarski MW, Gu X, Libermann TA, D'Andrea A, Grompe M, Weller E, Shimamura A. Metformin for treatment of cytopenias in children and young adults with Fanconi anemia. Blood Adv. 2022 Jun 28;6(12):3803-3811. doi: 10.1182/bloodadvances.2021006490.
PubMed 35500223Dixon-Zegeye M, Shaw R, Collins L, Perez-Smith K, Ooms A, Qiao M, Pantziarka P, Izatt L, Tischkowitz M, Harrison RE, George A, Woodward ER, Lord S, Hawkes L, Evans DG, Franklin J, Hanson H, Blagden SP. Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol. Trials. 2024 Feb 3;25(1):103. doi: 10.1186/s13063-024-07929-w.
PubMed 38308321Gutkind 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 34255745Zhang QS, Tang W, Deater M, Phan N, Marcogliese AN, Li H, Al-Dhalimy M, Major A, Olson S, Monnat RJ Jr, Grompe M. Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice. Blood. 2016 Dec 15;128(24):2774-2784. doi: 10.1182/blood-2015-11-683490. Epub 2016 Oct 18.
PubMed 27756748Beckham TH, Leeman J, Jillian Tsai C, Riaz N, Sherman E, Singh B, Lee N, McBride S, Higginson DS. Treatment modalities and outcomes of Fanconi anemia patients with head and neck squamous cell carcinoma: Series of 9 cases and review of the literature. Head Neck. 2019 May;41(5):1418-1426. doi: 10.1002/hed.25577. Epub 2019 Jan 11.
PubMed 30633423Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica. 2018 Jan;103(1):30-39. doi: 10.3324/haematol.2017.178111. Epub 2017 Oct 19.
PubMed 29051281Rosenberg PS, Socie G, Alter BP, Gluckman E. Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants. Blood. 2005 Jan 1;105(1):67-73. doi: 10.1182/blood-2004-04-1652. Epub 2004 Aug 26.
PubMed 15331448Kutler DI, Patel KR, Auerbach AD, Kennedy J, Lach FP, Sanborn E, Cohen MA, Kuhel WI, Smogorzewska A. Natural history and management of Fanconi anemia patients with head and neck cancer: A 10-year follow-up. Laryngoscope. 2016 Apr;126(4):870-9. doi: 10.1002/lary.25726. Epub 2015 Oct 20.
PubMed 26484938
Study at a glance
From the registry record, last updated by the sponsor on 28 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Crossover Open-Label Trial of Naproxen and Metformin Safety and Tolerability in the Setting of Prevention of Oral Cancer in Fanconi Anemia
- ClinicalTrials.gov ID
- NCT07901959
- Acronym / sponsor ID
- FMA-1073
- Conditions
- Fanconi Anemia, Head and Neck Cancer, Squamous Cell Carcinoma, Squamous Cell Cancer of Head and Neck (SCCHN)
- Keywords
- metformin, naproxen, Rockefeller, Minnesota, Fanconi anemia, Cancer prevention
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Rockefeller UniversityUniversity, hospital or other
- Collaborators
- University of Minnesota, The Wellcome Sanger Institute, BC Cancer Research Institute, National Institutes of Health (NIH), NewYork Presbyterian Hospital, Weill Cornell Medical Collage, USA
- Study start
- 14 Oct 2026 (estimated)
- Primary completion
- 14 Oct 2030 (estimated)
- Study completion
- 14 Oct 2031 (estimated)
- First posted
- 28 Oct 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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).
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Open-label randomized crossover trial.
| Arm | Type | Receives |
|---|---|---|
| Naproxen followed by metformin | Active comparator | Drug: Metformin, Drug: Naproxen SodiumParticipants 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. |
| Metformin followed by naproxen | Active comparator | Drug: Metformin, Drug: Naproxen SodiumParticipants 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. |
| Observational arm | No intervention | –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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (35 listed)
- 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
Key exclusion criteria (0 listed)
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 |
|---|---|---|
| MetforminOral metformin extended release, starting at a dose of 500mg daily and titrating up to 2000mg daily as tolerated for 6 months. | Drug | Metformin followed by naproxen, Naproxen followed by metformin |
| Naproxen Sodium6 months of oral naproxen sodium 440mg daily. | Drug | Metformin followed by naproxen, Naproxen followed by metformin |
Primary outcome
Safety
Time frame: For the duration of the study, 22 months for each individual participant
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.
Tolerability of Intervention Regimen
Time frame: Duration of intervention, from month 3 to month 16 of the study for each participant.
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.
6 secondary outcomes
Frequency of Any Adverse Events (All Grades)
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)
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
Time frame: Weekly for the duration of the study.
Self-Exam Completion Rate (via FAexam App)
Time frame: Monthly for the duration of the study.
New oral lesions
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
Time frame: At each site visit (baseline, 3 month, 9 month, 16 month and 22 month) for the duration of the study.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Oct 2026.
- Background: PubMed 41062696Lawson ARJ, Abascal F, Nicola PA, Lensing SV, Roberts AL, Kalantzis G, Baez-Ortega A, Brzozowska N, El-Sayed Moustafa JS, Vaitkute D, Jakupovic B, Nessa A, Wadge S, Osterdahl MF, Paterson AL, Rassl DM, Alcantara RE, O'Neill L, Widaa S, Austin-Guest S, Neville MDC, Przybilla MJ, Cheng W, Morra M, Sykes L, Mayho M, Muller-Sienerth N, Williams N, Alexander D, Harvey LMR, Clarke T, Byrne A, Blundell JR, Young MD, Mahbubani KTA, Saeb-Parsy K, Martin HC, Stratton MR, Campbell PJ, Rahbari R, Small KS, Martincorena I. Somatic mutation and selection at population scale. Nature. 2025 Nov;647(8089):411-420. doi: 10.1038/s41586-025-09584-w. Epub 2025 Oct 8.
- Background: PubMed 33483830Davis KAS, Bishara D, Molokhia M, Mueller C, Perera G, Stewart RJ. Aspirin in people with dementia, long-term benefits, and harms: a systematic review. Eur J Clin Pharmacol. 2021 Jul;77(7):943-954. doi: 10.1007/s00228-021-03089-x. Epub 2021 Jan 22.
- Background: PubMed 30255556Zhang QS, Deater M, Phan N, Marcogliese A, Major A, Guinan EC, Grompe M. Combination therapy with atorvastatin and celecoxib delays tumor formation in a Fanconi anemia mouse model. Pediatr Blood Cancer. 2019 Jan;66(1):e27460. doi: 10.1002/pbc.27460. Epub 2018 Sep 25.
- Background: PubMed 32641470Reyes-Uribe L, Wu W, Gelincik O, Bommi PV, Francisco-Cruz A, Solis LM, Lynch PM, Lim R, Stoffel EM, Kanth P, Samadder NJ, Mork ME, Taggart MW, Milne GL, Marnett LJ, Vornik L, Liu DD, Revuelta M, Chang K, You YN, Kopelovich L, Wistuba II, Lee JJ, Sei S, Shoemaker RH, Szabo E, Richmond E, Umar A, Perloff M, Brown PH, Lipkin SM, Vilar E. Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa. Gut. 2021 Mar;70(3):555-566. doi: 10.1136/gutjnl-2020-320946. Epub 2020 Jul 8.
- Background: PubMed 34091121Kumar G, Madka V, Singh A, Farooqui M, Stratton N, Lightfoot S, Mohammed A, Rao CV. Naproxen inhibits spontaneous lung adenocarcinoma formation in KrasG12V mice. Neoplasia. 2021 Jun;23(6):574-583. doi: 10.1016/j.neo.2021.05.010. Epub 2021 Jun 3.
- Background: PubMed 10738133Smith ML, Hawcroft G, Hull MA. The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action. Eur J Cancer. 2000 Mar;36(5):664-74. doi: 10.1016/s0959-8049(99)00333-0.
- Background: PubMed 37207208Bowen CM, Deng N, Reyes-Uribe L, Parra ER, Rocha P, Solis LM, Wistuba II, Sepeda VO, Vornik L, Perloff M, Szabo E, Umar A, Sinha KM, Brown PH, Vilar E. Naproxen chemoprevention induces proliferation of cytotoxic lymphocytes in Lynch Syndrome colorectal mucosa. Front Immunol. 2023 May 3;14:1162669. doi: 10.3389/fimmu.2023.1162669. eCollection 2023.
- Background: PubMed 35500223Pollard JA, Furutani E, Liu S, Esrick E, Cohen LE, Bledsoe J, Liu CW, Lu K, de Haro MJR, Surralles J, Malsch M, Kuniholm A, Galvin A, Armant M, Kim AS, Ballotti K, Moreau L, Zhou Y, Babushok D, Boulad F, Carroll C, Hartung H, Hont A, Nakano T, Olson T, Sze SG, Thompson AA, Wlodarski MW, Gu X, Libermann TA, D'Andrea A, Grompe M, Weller E, Shimamura A. Metformin for treatment of cytopenias in children and young adults with Fanconi anemia. Blood Adv. 2022 Jun 28;6(12):3803-3811. doi: 10.1182/bloodadvances.2021006490.
- Background: PubMed 38308321Dixon-Zegeye M, Shaw R, Collins L, Perez-Smith K, Ooms A, Qiao M, Pantziarka P, Izatt L, Tischkowitz M, Harrison RE, George A, Woodward ER, Lord S, Hawkes L, Evans DG, Franklin J, Hanson H, Blagden SP. Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol. Trials. 2024 Feb 3;25(1):103. doi: 10.1186/s13063-024-07929-w.
- Background: 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.
- Background: PubMed 27756748Zhang QS, Tang W, Deater M, Phan N, Marcogliese AN, Li H, Al-Dhalimy M, Major A, Olson S, Monnat RJ Jr, Grompe M. Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice. Blood. 2016 Dec 15;128(24):2774-2784. doi: 10.1182/blood-2015-11-683490. Epub 2016 Oct 18.
- Background: PubMed 30633423Beckham TH, Leeman J, Jillian Tsai C, Riaz N, Sherman E, Singh B, Lee N, McBride S, Higginson DS. Treatment modalities and outcomes of Fanconi anemia patients with head and neck squamous cell carcinoma: Series of 9 cases and review of the literature. Head Neck. 2019 May;41(5):1418-1426. doi: 10.1002/hed.25577. Epub 2019 Jan 11.
- Related InfoLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. CLIA-approved labs will be reported. Exploratory and/or research results that are inconclusive or
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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.
Agata Smogorzewska, MD, PhD principal investigator
The Rockefeller University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Metformin and Naproxen Sodium in people with Fanconi Anemia and Head and Neck Cancer, run by Rockefeller University at 2 sites in United States.
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 35 inclusion and 0 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: looking for participants now, as of the sponsor's last update on 28 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Francis J May, MD (212-327-7850, fmay@rockefeller.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety (time frame: For the duration of the study, 22 months for each individual participant). The study lists 2 primary outcomes in all. 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 NCT07901959, which also lists 16 linked publications.
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 28 Oct 2026.