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A Pilot Study of Metformin in Patients With a Diagnosis of Li-Fraumeni Syndrome

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National Institutes of Health Clinical Center (CC)
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ) Identifier:
First received: November 7, 2013
Last updated: September 30, 2014
Last verified: July 2014


  • Li Fraumeni Syndrome (LFS) is a highly penetrant, autosomal dominant cancer predisposition disorder. Four main cancer types including sarcoma, adrenocortical carcinoma, breast cancer, and malignant brain tumors commonly characterize LFS but the syndrome can include other cancers.
  • Sixty to eighty percent of classic LFS families have detectable germline TP53 mutations.
  • TP53 encodes p53 protein. Among many other functions p53 is involved in the regulation of mitochondrial respiration and energy homeostasis.
  • Metformin is an oral biguanide drug that is approved by the FDA for the treatment of type II diabetes. Metformin has been associated with reduced cancer risk in several epidemiologic studies and reduced cancer mortality in patients with type 2 diabetes.
  • Metformin decreases circulating insulin and IGF1, and promotes glucose uptake in skeletal muscle and inhibits gluconeogenesis in the liver. Elevations in circulating insulin and IGF1 levels have been associated with increased cancer risk.
  • Metformin and p53 both have effects on the mitochondria. One effect of metformin is inhibition of mitochondrial respiratory complex I, thereby decreasing ATP production via oxidative phosphorylation.
  • It is proposed that in the absence of a normal functioning p53, metformin may modulate mitochondrial function by inhibiting oxidative phosphorylation in turn inducing a bioenergetic crisis in rapidly proliferating cells and cellular senescence or apoptosis.
  • Data obtained using oxygen consumption studies of blood lymphocytes and phosphorus-31 magnetic resonance spectroscopy (31P-MRS) to assess the phosphocreatine (PCr) recovery time constant (Tc) in skeletal muscle of LFS patients harboring germline mutations in TP53 suggest that LFS patients may have increased oxidative phosphorylation capacity. The implication of this is unclear, but increased ATP production and improved mitochondrial function may provide growth advantages to rapidly proliferating cancer cells.
  • Preclinical research in animal models shows that metformin may be more toxic in cancer cells that have lost p53 function.
  • Lifetime risk of cancer in LFS patients with germline TP53 mutations is estimated to be up to 70% by age 60, with women having excess lifetime cancer risk (up to 100%) compared to men (up to 80%). There are currently no approved chemopreventive agents for patients with LFS.
  • Metformin has been shown to be safe and tolerable in diabetic and non-diabetics, and may be an ideal candidate for chemoprevention of cancer in this population.


  • Determine the tolerability of oral daily metformin in patients with LFS caused by germline TP53 mutations.
  • Determine if 8 weeks of daily metformin administration has any effect on circulating IGF-1, insulin, and IGFBP3


  • Must have a germline TP53 mutation and provide documentation of testing.
  • Must have adequate organ function.
  • Age greater than or equal to 18 years.


  • This is a pilot study to assess the tolerability of daily oral metformin administration in patients with LFS caused by germline TP53 mutations and to study the effect of metformin on biomarker levels in these subjects.
  • In the absence of intolerable toxicity, a minimum of 22 patients will take metformin by mouth for 2 weeks at 500 mg once per day, then 2 weeks at 500 mg twice per day (1000 mg/day) then 2 weeks a 500 mg three times per day (1500 mg/day), then 2 weeks at 1000 mg twice per day (2000 mg/day, maximum dose). Patients will be on the maximum tolerated dose (maintenance dose) for 6 more weeks, before stopping the drug. Patients unable to undergo full dose escalation (to 2000 mg/day) may be replaced, therefore the IRB accrual ceiling will be set at 36 to allow for a small number of patients that may be unable to undergo scheduled dose escalation.
  • Patients will be assessed for biomarker levels (IGF-1, insulin, IGFBP3) by blood sample at baseline, and weeks 2 and 8.
  • Patients will also undergo optional 13 C-MBT and 31 P-MRS testing while enrolled on the study.

Condition Intervention Phase
Li-Fraumeni Syndrome
Drug: Metformin
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of Metformin in Patients With a Diagnosis of Li-Fraumeni Syndrome

Resource links provided by NLM:

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Determine the tolerability of 500, 1000, 1500, and 2000 mg metformin by mouth daily in patients with LFS caused by germline TP53 mutations [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Determine if 8 weeks of daily metformin administration has any effect on circulating IGF-1, insulin, and IGFBP3 [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Determine if daily metformin administration has any effect on circulating IGF-1, insulin, and IGFBP3 levels, two weeks after the start of metformin administration and six weeks after discontinuing metformin (week 20) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Determine if daily metformin administration has any effect on hepaticmitochondrial function using a 13C-methionine breath test (13C- BT) two and eight weeks after the start of metformin administration. If there is a change between week 0 and ... [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Determine if daily metformin administration has any effect on skeletalmuscle mitochondrial function using phosphorous-31 magnetic resonance spectroscopy (31P-MRS) two and eight weeks after the start of metformin. If there is a change between ... [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • If warranted by results of either 13C-MBT or 31P-MRS testing at weeks 2, 8, and possibly also week 20, will correlate changes in tissue mitochondrial function with blood mononuclear cell oxygen consumption and/or oxidative stress markers by exam... [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 36
Study Start Date: October 2013
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single Arm
Patients will receive metformin at level 1 dose for 2 weeks. If dose is tolerated, patient will receive level 2 dose for 2 weeks and if tolerated will escalate to level 3 dose, and if tolerated will escalate to level 4 dose.
Drug: Metformin
Treatment will be administered primarily on an outpatient basis. Patients will be instructed to take 500 mg metformin by mouth 1, 2 or 3 times a day or 1000 mg twice per day depending on dose level. Patients will receive metformin at level 1 dose for 2 weeks. If dose is tolerated, patient will receive level 2 dose for 2 weeks and if tolerated will escalate to level 3 dose, and if tolerated will escalate to level 4 dose. Metformin will be taken for 14 weeks.

  Show Detailed Description


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
  • All TP53 germline mutation positive adult patients will be eligible for this study. All patients must have a documented TP53 germline mutation.
  • Patients with history of cancer must be in remission, with surgery completed at least 6 months prior to enrollment and chemotherapy completed at least 1 year prior to enrollment (except for basel cell carcinoma of the skin).
  • Age greater than or equal to 18 years. The doses of metformin used in this study exceed the maximum recommended daily dose for the pediatric population.
  • ECOG performance status 0 or 1 or Karnofsky greater than or equal to 70%.
  • Patients must have normal organ and marrow function as defined below:

    • Leukocytes greater than or equal to 3,000/microL
    • Absolute neutrophil count greater than or equal to 1,500/microL
    • Platelets greater than or equal to 100,000/microL
    • Total bilirubin: Within normal institutional limits
    • AST(SGOT) / ALT(SGPT): less than or equal to 2.5 times institutional upper limit of normal
    • Creatinine: Within normal institutional limits OR
    • Creatinine clearance: greater than or equal to 60 mL/min/1.73m(2) if serum creatinine > institutional normal

Note: If leukopenia is idiopathic and no other significant co-morbidities exist patients will not be excluded on the basis of their WBC.

-Metformin is a category B drug and can be used to treat gestational diabetes. Levels of metformin excreted in breast milk appear to be low and not clinically significant.

However, for protocol safety reasons, we will not be enrolling pregnant and/or nursing women in this study as metformin as has not been extensively evaluated in non-diabetic pregnant and nursing women. For this reason, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Women who are nursing will be advised to discontinue breastfeeding if the mother is treated with metformin. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform Drs. Fojo or Walcott, or protocol physicians/study team at NCI and her primary care provider immediately.

-Ability of subject to understand and the willingness to sign a written informed consent document.


  • Patients who have had stem-cell transplantation.
  • Current use of metformin or other anti-diabetic agents, or hypersensitivity or allergy to metformin.
  • Patients who are receiving any other investigational agents.
  • Patients with history of chronic alcohol use
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin or other agents used in study.
  • Patients with congestive heart failure requiring pharmacological management.
  • Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.


Exclusion criteria for (13)C-MBT studies in addition to general exclusion criteria (pertaining to effects of oral uptake of the administered substrate or mitochondrial function in the liver):

  • Gastric paresis
  • Short gut syndrome
  • Inflammatory bowel disease*
  • Celiac sprue
  • Pancreatic insufficiency or disease
  • Any malabsorption disease/syndrome
  • Chronic PPI use or H2 blocker use that cannot be temporarily discontinued (at least 48 hours)
  • Any acetaminophen, aspirin, NSAID, or statin use within 2 days of testing (known to affect mitochondrial function)
  • Drugs that interfere with mitochondrial function if they are unable to be discontinued 48 hours prior to (13)MBT testing will be excluded for this test only but eligible for the rest of the protocol.
  • Any oral steroid use within 2 weeks of testing
  • Chronic alcohol use** defined as > 2 standard drinks per day (more than 2 beers, 2 glasses of wine, or 2 shots of liquor per day)

    • Inflammatory bowel disease will be exclusion for the (13)C-MBT only, because even if well controlled we do not know the effect chronic inflammation in the bowel and steroid use may have on the test. The test analyzes exhaled CO(2) in the breath and this can be affected by diet (carbohydrate heavy), exercise, and certain pathologies like liver disease. Also pro-inflammatory mediators have been shown to cause hepatocellular injury that may also interfere with results of the test.

      • The test is currently being studied as an early detection, non-invasive method for liver cirrhosis. Therefore, patients who have had chronic alcohol use consistent with a regular pattern of alcohol consumption may have underlying liver disease that may affect the CO(2) measurement.

Further, alcohol changes the NADH/NAD ratio intracellularly and studies have shown that alcohol can inhibit methionine oxidation. Previous protocols utilizing the 13C-MBT have excluded patients who consume greater than 20 g/day of alcohol. A standard drink is equivalent to approximately 14 g/day of alcohol (one 12 oz beer, one 5 oz glass of wine, or one shot of liquor). This information was obtained from the National Institute of Health/National Institute of

Alcohol Abuse and Alcoholism (NIAAA): We will also evaluate LFTs and should clinical concern arise, check PT/PTT and albumin. Patients with normal liver function and no substantial history of alcohol abuse will be eligible.

EXCLUSION CRITERIA FOR 31P-MRS STUDIES (eligibility to be determined by Dr. Hwang):

Although patients will need to sign a separate informed consent to undergo the (31)P-MRS studies the list below includes some of the general exclusion criteria as information for the caring physician.


  • Inability to perform exercise with dominant leg
  • Claustrophobia and/or inability to lie flat in MRI machine
  • Metal medical implantable device or other MRI incompatible materials
  • Body mass index under 19 or over 45
  • Prior stem cell transplantation
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01981525

Contact: Farzana L Walcott, M.D. (240) 276-7661

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Contact: Robin Eisch    (301) 402-5958   
Sponsors and Collaborators
Principal Investigator: Antonio T Fojo, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ) Identifier: NCT01981525     History of Changes
Other Study ID Numbers: 140005, 14-C-0005
Study First Received: November 7, 2013
Last Updated: September 30, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
TP53 Mutation
Autosomal Dominant Hereditary Disorder

Additional relevant MeSH terms:
Li-Fraumeni Syndrome
DNA Repair-Deficiency Disorders
Genetic Diseases, Inborn
Metabolic Diseases
Neoplastic Syndromes, Hereditary
Pathologic Processes
Hypoglycemic Agents
Pharmacologic Actions
Physiological Effects of Drugs processed this record on March 01, 2015