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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

Brief Summary:

Background:

• 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.
• 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.
• 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.

Objectives:

• 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 a
  

  Detailed Summary:

  Background:

  • 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.
  • 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.
  • 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.

  Objectives:

  • 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 a
    Sponsor: National Cancer Institute (NCI)
    

    Current Primary Outcome:

    • Determine the tolerability of metformin in patients with LFS caused by germline TP53 mutations [ Time Frame: 2 years ]
    • Determine if 8 weeks of daily metformin administration has any effect on circulating IGF-1, insulin, and IGFBP3 [ Time Frame: 2 years ]
    
    
    

    Original Primary Outcome:

    • Determine the tolerability of oral daily metformin in patients with LFS caused by germline TP53 mutations. [ Time Frame: 12 months ]
    • Determine if 8 weeks of daily metformin administration has any effect on circulating IGF-1, insulin, and IGFBP3 [ Time Frame: 12 months ]
    
    
    

    Current Secondary Outcome:

    • 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 ]
    • Determine if daily metformin administration has any effect on skeletalmuscle mitochondrial function using phosphorous-31 magnetic resonance spectroscopy (31P-MRS) baseline and eight weeks after the start of metformin. If there is a change bet... [ Time Frame: 2 years ]
    
    
    

    Original Secondary Outcome:
    
    Information By: National Institutes of Health Clinical Center (CC)
    

    Dates:
    Date Received: November 7, 2013
    Date Started: October 22, 2013
    Date Completion:
    Last Updated: May 12, 2017
    Last Verified: April 21, 2017