Metformin in Li Fraumeni (MILI) Trial: A Phase II Randomised open-label cancer prevention study of Metformin in adults with Li Fraumeni Syndrome
MILI is sponsored by the University of Oxford and funded by the NIHR Efficacy and Mechanism Evaluation (EME) Programme (NIHR131239) , an MRC and NIHR partnership.
The translational research is funded by the Cancer Research UK (CRUK) (PRCPJT-May22\100018). Statistical support is provided by the Centre for Statistics in Medicine (CSM).
Metformin in Li Fraumeni (MILI) Trial: A Phase II Randomised open-label cancer prevention trial of Metformin in adults with Li Fraumeni Syndrome
Chief Investigator: Prof Sarah Blagden
Sponsor: University of Oxford
Trial is in set up.
Recruitment Target : 224 participants
Recruitment Duration : 24 months
trial Duration: 84 months
Planning to open 6 sites. MILI will use a “hub and spoke” design whereby local genetics centres (spokes) will refer participants to one of the investigator sites (hubs) for trial assessments. Spoke sites will also continue to carry out some Standard of Care activities and data from which will be used in the trial.
Background and trial Relevance
The Metformin in Li Fraumeni (MILI) trial. This clinical trial is investigating the use of a drug called metformin as a way of reducing the cancer risk in people with Li Fraumeni Syndrome (LFS).
What is Li Fraumeni Syndrome or LFS? 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.
How can people with LFS protect themselves from cancer? 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.
Why is the MILI trial testing metformin? 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.
How many people will take part in the MILI trial? The MILI trial 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 trial 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.
How will the trial answer whether metformin works? 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 trial 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.
How have people with LFS been involved in designing MILI? 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.
To compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between intervention (metformin) and control (no metformin) arms
Cancer free survival – with “cancer” event defined as pathologically confirmed diagnosis of malignant cancer identified during trial participation or death from any cause
To be eligible to enter the trial participants must fulfil all of the following:
- Diagnosis of LFS from confirmed pathogenic TP53 variant (class IV or V by CanVIG-UK criteria (see appendix 2)
- Aged ≥16 years
- Capable of understanding the consent process and participating in the trial and according to the investigators’ discretion.
- Currently taking metformin
- Metformin intake for more than 3 months in total, within the 2 years antecedent to the date of trial enrolment
- Completion of cancer systemic therapy within the 6 months antecedent to the date of trial enrolment
- Current type 1 or 2 diabetes mellitus
- Presence of active ongoing cancer (detected previously or at baseline scanning)
- Current pregnancy or lactation
- Gastro-intestinal condition (such as short-bowel syndrome) that could affect absorption of metformin
- Concurrent medical condition (other than LFS) that could result in life expectancy of <5 years
- History of the following cardiac conditions:
- Congestive cardiac failure of > Grade II severity according to the New York Heart Association Functional Classification (defined as symptomatic at less than ordinary levels of activity).
- Ischaemic cardiac event including myocardial infarction within 3 months prior to date of enrolment.
- Uncontrolled cardiac disease, including unstable angina pectoris, uncontrolled hypertension (i.e., sustained systolic BP > 160 mmHg or diastolic BP > 90 mm Hg)
- Evidence of significant renal impairment eGFR < 50ml/minute/1.73m2
- Liver cirrhosis and/or alkaline phosphatase, aspartate transaminase or alanine transaminase >2.5 x upper limit of normal (ULN)
- Elevated risk of lactic acidosis such as current chronic alcoholism, congenital lactic acidosis, concurrent intake of carbonic anhydrase inhibitor (e.g. acetazolamide)
- Known allergy to metformin
- Does not fulfil MRI Safety Screening criteria (e.g. implanted cardiac pacemaker, post-surgical metal hardware – plates etc) and/or unable to undergo baseline scan.