NCT01981525

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

Completed Phase 1 Last updated 14 December 2020

What this trial tests

Phase 1 trial testing Metformin in Li-Fraumeni Syndrome in 26 participants. Completed in 11 December 2020.

Timeline

27 January 2014

Primary endpoint
30 June 2016

11 December 2020

Quick facts

Lead sponsor	National Cancer Institute (NCI)
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	26
Start date	27 January 2014
Primary completion	30 June 2016
Estimated completion	11 December 2020
Sites	1 location across United States

Drugs / interventions tested

• Metformin (metformin) — full drug profile →

Conditions studied

• Li-Fraumeni Syndrome — all drugs for Li-Fraumeni Syndrome →

Sponsor

National Cancer Institute (NCI)

Who can join

18 and older, any sex, with Li-Fraumeni Syndrome. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Tumour predisposition and cancer syndromes as models to study gene-environment interactions.
   Carbone M, Arron ST, Beutler B, Bononi A, et al · · 2020 · cited 118× · PMID 32472073 · DOI 10.1038/s41568-020-0265-y
2. Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome.
   Wang PY, Li J, Walcott FL, Kang JG, et al · · 2017 · cited 50× · PMID 27869650 · DOI 10.1172/jci88668
3. Cancer Stemness: p53 at the Wheel.
   Ghatak D, Das Ghosh D, Roychoudhury S. · · 2020 · cited 48× · PMID 33505918 · DOI 10.3389/fonc.2020.604124
4. Repurposing old drugs to chemoprevention: the case of metformin.
   Heckman-Stoddard BM, Gandini S, Puntoni M, Dunn BK, et al · · 2016 · cited 47× · PMID 26970131 · DOI 10.1053/j.seminoncol.2015.09.009
5. Mitochondrial metabolism and cancer therapeutic innovation.
   Du H, Xu T, Yu S, Wu S, et al · · 2025 · cited 43× · PMID 40754534 · DOI 10.1038/s41392-025-02311-x
6. Li-Fraumeni Syndrome: Mutation of <i>TP53</i> Is a Biomarker of Hereditary Predisposition to Tumor: New Insights and Advances in the Treatment.
   Rocca V, Blandino G, D'Antona L, Iuliano R, et al · · 2022 · cited 27× · PMID 35954327 · DOI 10.3390/cancers14153664
7. Role of mitochondria in physiological activities, diseases, and therapy.
   Wang L, Zhou X, Lu T. · · 2025 · cited 23× · PMID 40536597 · DOI 10.1186/s43556-025-00284-5
8. Heritable genetic variants in key cancer genes link cancer risk with anthropometric traits.
   Di Giovannantonio M, Harris BH, Zhang P, Kitchen-Smith I, et al · · 2021 · cited 17× · PMID 32591342 · DOI 10.1136/jmedgenet-2019-106799