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Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol.

Dixon-Zegeye, M., Shaw, R., Collins, L., Perez-Smith, K., Ooms, A., Qiao, M., Pantziarka, P., Izatt, L., Tischkowitz, M., Harrison, R. E., George, A., Woodward, E. R., Lord, S., Hawkes, L., Evans, D. G., Franklin, J., Hanson, H. and Blagden, S. P., 2024. Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol. Trials, 25, 103.

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s13063-024-07929-w.pdf - Published Version
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DOI: 10.1186/s13063-024-07929-w


Background: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70–100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin’s mechanism of anticancer activity in this context is unclear. Methods: Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI. Discussion: Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis. Trial registration: ISRCTN16699730. Registered on 28 November 2022. URL: EudraCT/CTIS number 2022-000165-41.

Item Type:Article
Uncontrolled Keywords:Cancer; Chemoprevention; LFS; Li-Fraumeni syndrome; Metformin; Precision-Prevention; TP53; p53; Adult; Humans; Mice; Animals; Li-Fraumeni Syndrome; Metformin; Quality of Life; Germ-Line Mutation; Magnetic Resonance Imaging; Genetic Predisposition to Disease; Randomized Controlled Trials as Topic; Clinical Trials, Phase II as Topic
Group:Faculty of Health & Social Sciences
ID Code:39580
Deposited By: Symplectic RT2
Deposited On:06 Mar 2024 16:47
Last Modified:06 Mar 2024 16:47


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