Award Title: Metformin in Li Fraumeni (MILI) trial: A Phase II randomised open-label cancer prevention study of metformin in adults with Li Fraumeni Syndrome
Funder: Medical Research Council

Abstract: This clinical study is investigating the use of a drug called metformin as a way of reducing the cancer risk in people with Li Fraumeni Syndrome (LFS)._x000D_
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What is Li Fraumeni Syndrome or LFS? _x000D_
LFS is a rare genetic condition that predisposes people to develop one or more cancers. It is caused by a mutation in a gene called TP53, either inherited from a parent or occurring as a new mutation at conception.TP53 is the most important anticancer gene in the body – its job is to stop cells becoming cancerous after they become damaged or stressed. For most people with cancer the gene is only mutated in their cancer cells but, for people with LFS, it is mutated in all the cells in the body. This means there is a very high risk of developing cancer for people with LFS – a lifetime risk of 90% for women, and about 70% for men. Many  people with LFS develop  multiple cancers over their lifetimes. Cancers associated with LFS include rare bone and soft tissue sarcomas, childhood brain tumours and leukaemias, but also more common cancers such as breast cancer._x000D_
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How can people with LFS protect themselves from cancer? _x000D_
Currently there are no treatments to reduce this high risk of cancer. For LFS women there is risk-reducing mastectomy to guard against breast cancer. Other than that, people with LFS have regular health checks and imaging – like whole-body MRI scans and check-ups with specialists – to catch any new cancers early. Research shows that, for people with LFS, spotting cancer early improves survival. Currently there is an agreed protocol for such check-ups in the UK and other countries, but many people are still not getting the care and scans they need._x000D_
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Why is the MILI study testing metformin? _x000D_
Metformin is a well-known and safe drug used to treat diabetes. Laboratory experiments have shown that, in mice with LFS, metformin can reduce the risk of them developing cancer. This is because metformin alters the metabolism of cells with mutated TP53 and makes them act more like normal cells. A small study was carried out in people with LFS which showed that metformin treatment caused the same kind of cellular changes that had been seen in the treated mice. However, this is not enough to conclude that metformin will reduce the risks of cancer in people with LFS. For that, a larger clinical trial is needed – involving more patients and a much longer duration of treatment._x000D_
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How many people will take part in the MILI study?   _x000D_
The MILI study aims to enrol 224 patients with LFS in the UK, a large fraction of the approximate 600 people with it in the country. In order to get the numbers of patients needed to address more detailed questions, such as whether metformin is better at preventing certain types of cancer than others, the study will be run in US, Canada, as well as the UK and the results will be pooled together. Altogether it is expected that around 600 LFS patients from around the world will be included. Half the people on the trials will take metformin every day for up to 5 years and the other half will not – all participants will have regular check-ups for cancer, including whole-body MRI.  Five years has been estimated as long enough to give an early indication of whether differences in cancer incidence are due to treatment rather than being random (i.e., chance events) although longer follow-up may be implemented in the future._x000D_
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How will the study answer whether metformin works? _x000D_
The data from each of the trials will be put together to create one large meta-analysis to tell us definitively whether metformin reduces the risk of cancer by comparing the number of people who developed cancer in the metformin vs non-metformin participants. In addition to answering the question about reducing cancer risk, the trial will also include regular quality of life questionnaires and biological studies to better understand what it is in the cells of people with LFS that is most associated with cancer development. If the study is successful, and shows that metformin is effective, it can be licensed as a standard cancer prevention treatment for people with LFS. This trial will provide important information about LFS and give hope to families across the world who currently face the devastating impact of cancer on themselves and their children._x000D_
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How have people with LFS been involved in designing MILI? _x000D_
The idea of using metformin for cancer risk reduction was first proposed in the LFS community in 2013 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637189/) and the LFS community has been involved in the creation, development and management of this trial. In addition, money raised by the UK LFS charity, the George Pantziarka TP53 Trust, will help pay for the travel costs for participants attending clinics and taking part in the trial. All results, including interim results, will be shared with the LFS community at meetings and online.

Lay Abstract: Research Question: The purpose of the MILI study is to evaluate whether metformin can prevent or delay the emergence of cancer in people with LFS. _x000D_
Background: Li Fraumeni Syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome caused by germline or de novo pathogenic variants in TP53. Males and females with LFS have a 70% and 100% lifetime risk of cancer respectively, with around 50% having their first cancer diagnosis before the age of 46 and 31 years respectively. Typical LFS “core” malignancies include bone and soft-tissue sarcomas, breast, brain and adrenocortical cancers but less commonly lung, colon, haematological, skin, stomach and ovarian cancers. Recent evidence from LFS mouse models reveals that abnormal mitochondrial metabolism acts as a driver of cancer formation (tumorigenesis) in LFS and is reversed with the widely-used anti-diabetic drug metformin. _x000D_
Aims and Objectives: _x000D_
The primary aim is to determine the impact of metformin on the time to diagnosis of cancer in LFS, corresponding with a primary objective of comparing cancer-free survival at 5 years from randomisation between study (metformin) and control (no metformin) arms. Secondary aims are to determine the impact of metformin on: i) time to diagnosis of non-invasive/pre-cancerous lesions, ii) overall survival, iii) clinical characteristics of emerging cancers, iv) safety, tolerability and acceptability, vi) effect on quality of life and vii) lifestyle factors. Research Questions: to compare site and type of TP53 mutation with outcome, measure impact of metformin on metabolism, and investigate serum biomarkers which may correlate with tumorigenesis. Parallel studies in Canada, Germany and USA will be recruiting to a similar protocol and, upon study completion, data will be pooled in a definitive individual patient meta-analysis. This will be the world’s largest study in LFS and its first cancer prevention study. The purpose of this EME proposal is to request support for the UK MILI trial._x000D_
Methods: _x000D_
Randomised open-label Phase II trial, n=224 adults with LFS, 1:1 randomisation to metformin (intervention) versus no metformin (control). _x000D_
Timelines for Delivery: _x000D_
10/2022: Ethics/MHRA submission_x000D_
12/2022: First Trial site opens to recruitment_x000D_
01/2023: First Participant recruited_x000D_
12/2024: Recruitment completed_x000D_
12/2029: Study assessments completed_x000D_
09/2030: Data analysis completed _x000D_
12/2030: Study closed _x000D_
Impact/Dissemination:_x000D_
Trial data will support MHRA/NICE application for metformin as cancer preventative in LFS. Publications will advance understanding of tumorigenesis in LFS and somatic TP53 mutation-associated cancers.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS