Potential Sites: Being a Principal Investigator for MILI

Full Title of Trial:

Metformin in Li Fraumeni (MILI) Trial: A Phase II Randomised open-label cancer prevention trial of Metformin in adults with Li Fraumeni Syndrome

Short Title:

Metformin in LFS (MILI) Trial

Trial Acronym:

MILI

Clinical Phase:

II

Trial Design:

Open label, randomised control phase II trial

Countries of Recruitment  

UK

Objectives

Endpoints

Primary Endpoint:

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 

Secondary Endpoints:

1. Comparison of cumulative tumour-free survival at 5 years from randomisation between intervention (metformin) and control (no metformin) arms

1. Tumour free survival – with a “tumour” event including pathologically confirmed diagnosis of malignant cancer or clinically/scan detected benign or premalignant lesion (e.g. ductal carcinoma in situ - DCIS) identified during trial participation or death from any cause.

2. Comparison of overall survival between trial and control arms at 5 years between intervention (metformin) and control (no metformin) arms

2. Time from randomisation to death from any cause. 

3. To compare the impact of taking metformin on the clinical characteristics of emerging cancers. 

3. Number and type of emerging cancers, including size, stage and histological grade at diagnosis.

4. To determine the safety and toxicity of metformin 

4. Relevant treatment-emergent adverse events and clinically significant laboratory changes (per NCI CTCAE V5.0) or changes in physical exam and/or vital signs in intervention arm compared to baseline. 

5. To assess the acceptability of metformin 

5. MARS-5 questionnaire score

6. To compare impact of metformin and cancer prevention on quality of life (QOL)

6. Comparison of change in 12-item short form survey (SF12v2), Cancer Worry Scale, between intervention and control arms and compared to baseline. Treatment Burden Questionnaire (TBQ) compared between arms (collected from year 1)

7. To determine the impact of baseline lifestyle risk factors on cancer incidence

7. Correlation of baseline weight, BMI and lifestyle factors (e.g., smoking and diet) with cancer-free survival. 

            Objectives

            Endpoints

1. To establish the mechanism of action of metformin as a cancer preventative

1. Whether baseline insulin sensitivity predicts cancer-free survival in LFS

2. Whether metformin’s chemoprevention effects are indirect via insulin sensitivity in LFS using HOMA-IR as surrogate marker.

3. Whether metformin’s chemoprevention effects are indirect via changes in circulating PI3K/AKT/mTOR signalling in LFS. 

4. Whether metformin’s chemoprevention effects are direct via alterations to oxidative phosphorylation in LFS using OXPHOS gene signature as surrogate marker. 

2. To identify biomarkers of response/ cancer

i Surrogate genetic markers of cancer-free survival or metformin response. 

ii Proteomic markers of cancer-free survival or metformin response.

iii Penetrance of germline TP53 mutation in tumour tissue

 iv Retrospective identification or validation of circulating cancer biomarkers

3. To assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS.

i. Yield and diagnostic accuracy of WB-MRI

Planned enrolment:

224 adults with LFS will be enrolled into MILI with 1:1 randomisation to active (yearly) cancer surveillance with metformin (intervention) versus active (yearly) cancer surveillance without metformin (control). 

Target Population:

Inclusion: 

To be eligible to enter the trial participants must fulfil all of the following: 

1. Diagnosis of LFS from confirmed pathogenic TP53 variant (class IV or V by CanVIG-UK criteria (see appendix 2)
2. Aged ≥16 years
3. Capable of understanding the consent process and participating in the trial and according to the investigators’ discretion.

Exclusion:

1. Currently taking metformin 
2. Metformin intake for more than 3 months in total, within the 2 years antecedent to the date of trial enrolment 
3. Completion of cancer systemic therapy within the 6 months antecedent to the date of trial enrolment
4. Current type 1 or 2 diabetes mellitus
5. Presence of active ongoing cancer /or currently receiving cancer treatment (excluding maintenance treatments e.g., hormones) 
6. Current pregnancy or lactation
7. Gastro-intestinal condition (such as short-bowel syndrome) that would affect absorption of metformin
8. Concurrent medical condition (other than LFS) that could result in life expectancy of <5 years
9. History of the following cardiac conditions:
   1. 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).
   2. Ischaemic cardiac event including myocardial infarction within 3 months prior to date of enrolment. 
   3. Uncontrolled cardiac disease, including unstable angina pectoris, uncontrolled hypertension (i.e., sustained systolic BP > 160 mmHg or diastolic BP > 90 mm Hg) 
10. Evidence of significant renal impairment eGFR < 50ml/minute/1.73m2 
11. Liver cirrhosis and/or alkaline phosphatase, aspartate transaminase or alanine transaminase >2.5 x upper limit of normal (ULN) 
12. Elevated risk of lactic acidosis such as current chronic alcoholism, congenital lactic acidosis, concurrent intake of carbonic anhydrase inhibitor (e.g. acetazolamide)
13. Known allergy to metformin
14. 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.

Name of drug

Formulation, dose, route of administration

Investigational Medicinal Product(s)

Metformin (N,N-dimethylbiguanide) hydrochloride

Immediate-release tablets, given initially as 500 mg once daily and dose increased every 14 days by 500 mg increments to up to 2g/daily (1000 mg bd) given orally. Final dose selected for individual participants according to tolerability.

Treatment Duration

Treatment for up to 5 years from randomisation

Follow-up duration

Participants will be followed-up for 5 years from randomisation.

End of trial

Defined by the completion of the planned statistical analyses and the completion of the translational research analysis (whichever comes last).