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

dc.citation.epageTrials. 2024 Feb 3;25(1):103. doi: 10.1186/s13063-024-07929-w.
dc.contributor.authorDixon-Zegeye, M.
dc.contributor.authorShaw, R.
dc.contributor.authorCollins, L.
dc.contributor.authorPerez-Smith, K.
dc.contributor.authorOoms, A.
dc.contributor.authorQiao, M.
dc.contributor.authorPantziarka, P.
dc.contributor.authorIzatt, L.
dc.contributor.authorTischkowitz, M.
dc.contributor.authorHarrison, R. E.
dc.contributor.authorGeorge, A.
dc.contributor.authorWoodward, E. R.
dc.contributor.authorLord, S.
dc.contributor.authorHawkes, L.
dc.contributor.authorEvans, D. G.
dc.contributor.authorFranklin, J.
dc.contributor.authorHanson, H.
dc.contributor.authorBlagden, S. P.
dc.description.abstractBACKGROUND: 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.
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dc.identifier.citationDixon-Zegeye M, Shaw R, Collins L, Perez-Smith K, Ooms A, Qiao M, et al. Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol. Trials. 2024;25(1):103.
dc.publisherBioMed Central
dc.rights© 2024. The Author(s).
dc.subject*Li-Fraumeni Syndrome/diagnostic imaging/genetics/prevention & control
dc.subject*Metformin/adverse effects
dc.subjectQuality of Life
dc.subjectGerm-Line Mutation
dc.subjectMagnetic Resonance Imaging
dc.subjectGenetic Predisposition to Disease
dc.subjectRandomized Controlled Trials as Topic
dc.subjectClinical Trials, Phase II as Topic
dc.subjectLi-Fraumeni syndrome
dc.titleCancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol
dc.typeJournal Article