A Pilot Study of Metformin in Patients With a Diagnosis of Li-Fraumeni Syndrome
Status:
Completed
Trial end date:
2020-12-11
Target enrollment:
Participant gender:
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 any effect on circulating
IGF-1, insulin, and IGFBP3
Eligibility:
- Must have a germline TP53 mutation and provide documentation of testing.
- Must have adequate organ function.
- Age greater than or equal to 18 years.
Design:
- 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 a total of 14 weeks and then discontinue metformin for 6 weeks. The total time
on study will be 20 weeks.
- Patients will be assessed for biomarker levels (IGF-1, insulin, IGFBP3) by blood sample
at baseline, and weeks 0 and 8.