Metformin for cancer prevention in Li-Fraumeni Syndrome (LFS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medizinische Hochschule Hannover

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

5 Jan 2026 → ongoing

Decision date (initial)

2025-08-27

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

German Cancer Aid (Deutsche Krebshilfe)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

The primary objective is to demonstrate superiority of metformin (daily intake) on top of close
cancer surveillance (metformin arm) regarding a prolonging of CFS compared to close cancer
surveillance alone (control arm) in adolescents and adults with LFS.

Secondary objectives 8

1. To demonstrate superiority of metformin on top of close cancer surveillance regarding a prolonging of TFS (including benign lesions) compared to close cancer surveillance alone (control arm) in adolescents and adults with LFS
2. To demonstrate superiority of metformin on top of close cancer surveillance regarding a prolonging of OS compared to close cancer surveillance alone in adolescents and adults with LFS
3. Comparison of characteristics of tumors emerging during the trial between metformin and control arm
4. Evaluation of metformin safety and tolerability
5. Evaluation of acceptability of metformin by people with LFS
6. Comparison of QoL, FOP, levels of depression and anxiety and distress between metformin and control arm
7. Change over trial participation in QoL, FOP, levels of depression and anxiety and distress
8. Analysis of impact of baseline lifestyle risk factors on cancer incidence

Conditions and MedDRA coding

Li-Fraumeni syndrome

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Male, female, inter/diverse participants (biological sex will be documented for randomization) aged ≥ 10 years
2. LFS diagnosis confirmed by detection of a TP53 germline or postzygotic somatic P/LP variant
3. Capable of understanding the consent process and participation in the trial
4. Signed written informed consent by participant and both parents/ legal representatives (if applicable)

Exclusion criteria 15

1. Currently taking metformin
2. Metformin intake for more than 3 consecutive months within 2 years before randomization
3. Current cancer diagnosis (detected previously or at baseline screening) , if feasible, rescreening should be offered at a later suitable date
4. Current completion of cancer therapy < 6 months before randomization, if feasible, rescreening should be offered at a later suitable date
5. Current type 2 DM
6. Female participants who are pregnant or breastfeeding before randomization; if feasible, re-screening should be offered at a later suitable date. Exemptions during trial participation are detailed in table 5 in chapter 13.9.
7. Gastro-intestinal condition (such as Short-Bowel Syndrome) that could affect uptake of metformin
8. Concurrent illness that could result in life expectancy of <5 years
9. History of one or more of the following cardiac conditions: a. Grade II severity according to the New York Heart Association Functional Classification (defined as symptomatic at less than ordinary levels of activity). b. Ischemic cardiac event including myocardial infarction within 3 months prior to randomization c. Uncontrolled cardiac disease, including unstable angina pectoris, uncontrolled hypertension (i.e., sustained systolic BP > 160mmHg or diastolic BP > 90mmHg); or other known acute cardio-respiratory illness like respiratory failure or recent myocardial infarction that could lead to tissue hypoxia
10. Evidence of significant renal impairment, eGFR < 45ml/min/1.73m² or conditions like dehydratation, severe infections or shock that could affect renal function
11. Liver failure, cirrhosis and/or aspartate transaminase or alanine transaminase >2.5 x upper limit of normal (ULN)
12. Elevated risk of lactic acidosis such as current moderate to severe alcohol use disorder (AUD), congenital lactic acidosis, concurrent intake of carbonic anhydrase inhibitor (e.g. acetazolamide), acute metabolic acidosis
13. Hypersensitivity to any of the components of the IMP metformin used and contained excipients
14. Unwillingness or inability of participant to take part in the cancer surveillance programme (incl. WB-MRI)
15. Participation in another clinical trial with investigational drugs within five times the half-life of the investigational drug or relevant metabolites at the time of enrolment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Cancer-free survival (CFS) as time between randomization and “cancer” event defined as histologically confirmed cancer diagnosis established during trial participation or death from any cause

Secondary endpoints 8

1. Tumor-free survival (TFS) as time between randomization and a “tumor” event including diagnosis of histologically confirmed cancer or clinically or radiologically detected benign or premalignant lesion identified during trial participation or death from any cause
2. Time from randomization to death from any cause during trial participation
3. Number and type of emerging cancers, including size, stage and histological grade at diagnosis
4. Treatment-emergent (serious) adverse events (AEs, SAEs)
5. Levels of metformin adherence described by the aggregated MARS-5 scores
6. Change of QoL, FOP, levels of depression and anxiety and distress during the trial
7. Change in QoL, FOP, levels of depression and anxiety and distress from baseline to last visit
8. Correlation of baseline weight, BMI and lifestyle factors (e. g. smoking) with outcome

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medizinische Hochschule Hannover

Sponsor organisation

Medizinische Hochschule Hannover

Address

Carl-Neuberg-Strasse 1, Gross Buchholz Gross Buchholz

City

Hanover

Postcode

30625

Country

Germany

Scientific contact point

Organisation

Medizinische Hochschule Hannover

Contact name

Klinik für pädiatrische Hämatologie und Onkologie

Public contact point

Organisation

Medizinische Hochschule Hannover

Contact name

Klinik für pädiatrische Hämatologie und Onkologie

Third parties 1

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications