Metformin in Li Fraumeni Syndrome (MILI) Trial: A phase II randomised open-label cancer prevention study of metformin in adults with Li Fraumeni Syndrome

Research summary

The majority of invasive cancer is preceded by a latency phase characterised by the presence of a pre-invasive or an intra-epithelial lesion which is histologically non-malignant. In the LFS mouse,metformin was demonstrated to delay the emergence of invasive cancers,either because it (i) prevents pre-invasive and,later,invasive lesions from forming or (ii) because metformin extends the pre-invasive latency period. To explore this,we will compare the number and type of non-malignant “tumours” that are detected in each arm of MILI as well as the number of invasive cancers diagnosed during the 5 years of the study. To assess the side effect profile of metformin in LFS,we will be collecting safety and toxicity information during MILI,every two weeks during the titration phase and every 6 months thereafter. Acceptability will be assessed by monitoring the number of participants who remain on metformin and the total/expected intake of metformin/per participant for the 5-year duration of the study. As prevention studies have not been conducted in LFS participants before,MILI presents a unique opportunity to evaluate the impact of metformin,and of cancer prevention as a whole,on wellbeing before and during the study. We will be assessing HRQOL using questionnaires validated during UK SIGNIFY (QOL) study . As part of MILI,we will be collecting this information at baseline and correlating with outcome within the UK study set and the IPD meta-analysis. As part of MILI,we will test whether the direct or indirect effects of metformin are most responsible for its chemopreventative activities by measuring change from baseline of circulating metabolic (insulin and IGF1) and PI3K activation markers,as well as a transcriptional mitochondrial OXPHOS gene signature,after metformin treatment and which most closely corresponds to cancer-free survival. We will also be collecting plasma and cell-free DNA (cfDNA) for identification or validation of biomarkers that could be used to predict the emergence of cancer in patients with LFS. We have formed an International LFS Consortium with investigators from National Cancer Institute (NCI,USA),Hannover (Germany) and SickKids (Canada),to conduct international randomised studies to evaluate metformin as a cancer preventative. Study centres in each nation are seeking independent funding to conduct MILI in adults and/or children using a locally-adapted core protocol. Each study is sufficiently powered to address the primary objective as a standalone site. Results from all studies will be pooled in an individual participant data (IPD) meta-analysis to definitively determine the benefit of metformin at preventing cancer in this high-risk participant group and address secondary and translational endpoints. MILI is a randomised,open-label,Phase II trial evaluating the impact of metformin on cancer incidence in adults with Li Fraumeni Syndrome. . It is estimated that 224 adults with LFS will be recruited and randomised 1:1 to metformin (intervention) versus no metformin (control). Participants randomised to metformin will receive up to 2g (1000mg bd) taken daily for up to 5 years. Those in the control arm will receive no metformin. Those in both study arms will undergo yearly cancer surveillance.

Principal Investigator

Dr Lara Hawkes

Contact us

Email: crndirectdeliveryteam@ouh.nhs.uk

IRAS number

1006131