Evaluation of Metformin and Metformin Hydrochloride for Cancer Prevention in Adolescents and Adults with Li-Fraumeni Syndrome: A Phase IIIb Randomized Open-Label Trial

Trial ID: 2025-520714-63-00
Protocol: LFS-Metformin-Trial
Sponsor: Medizinische Hochschule Hannover

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Diseases & Conditions

Li-Fraumeni syndrome

Objectives

The primary objective of this Phase IIIb randomized open-label trial is to demonstrate the superiority of **metformin** (daily intake) in conjunction with close cancer surveillance over close cancer surveillance alone in prolonging cancer-free survival (CFS) in adolescents and adults with **Li-Fraumeni syndrome** (LFS). This is clinically relevant as it aims to provide a potential preventive strategy for individuals with LFS, a condition associated with a high risk of developing multiple types of cancer.

Secondary objectives include:

Demonstrating the superiority of metformin in prolonging time to first symptom (TFS), including benign lesions, and overall survival (OS) compared to surveillance alone.
Comparing tumor characteristics emerging during the trial between the metformin and control arms.
Evaluating the safety, tolerability, and acceptability of metformin in individuals with LFS.
Comparing quality of life (QoL), fear of progression (FOP), and levels of depression, anxiety, and distress between the metformin and control arms.
Assessing changes in QoL, FOP, and psychological distress over the course of the trial.
Analyzing the impact of baseline lifestyle risk factors on cancer incidence.

Participants

The clinical trial involves participants diagnosed with **Li-Fraumeni syndrome** (LFS), a hereditary condition associated with a higher risk of developing certain cancers. The study population includes male, female, and inter/diverse participants aged 10 years and older. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants were selected based on a confirmed diagnosis of LFS through the detection of a TP53 germline or postzygotic somatic pathogenic/likely pathogenic variant. The trial includes individuals capable of understanding the consent process, with signed informed consent obtained from the participant and both parents or legal representatives, if applicable. The study population is characterized by a diverse age range and includes both genders, with a focus on a vulnerable population due to the genetic nature of the condition. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

Plans and Procedures

The clinical trial is designed as a **randomized**, open-label study to evaluate the efficacy of **metformin** in cancer prevention among adolescents and adults diagnosed with **Li-Fraumeni syndrome**. The trial aims to demonstrate the superiority of daily **metformin** intake in conjunction with close cancer surveillance compared to surveillance alone. Participants will be randomly assigned to either the **metformin** arm or the control arm, with the primary endpoint being cancer-free survival (CFS), defined as the time from randomization to a histologically confirmed cancer diagnosis or death from any cause. Secondary endpoints include tumor-free survival, time to death from any cause, and the number and type of emerging cancers.

The trial is expected to commence recruitment on August 25, 2025, and conclude by August 25, 2032. The study will involve multiple visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥10 years), confirmed **Li-Fraumeni syndrome** diagnosis, and the ability to understand the consent process. Participants will be required to provide signed informed consent. Follow-up visits will be scheduled to monitor adherence to **metformin**, assess adverse events, and evaluate changes in quality of life, fear of progression, and psychological distress. The end-of-study visit will occur at the conclusion of the participant's involvement, which is anticipated to last up to 84 weeks, corresponding to the maximum treatment period of **metformin** administration.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the treatment regimen, or withdraw consent. The trial will ensure rigorous monitoring of treatment-emergent adverse events and adherence levels, with the latter assessed using the MARS-5 scores. The study will also explore correlations between baseline characteristics such as weight, BMI, and lifestyle factors with trial outcomes. The trial's design and procedures are structured to provide robust data on the potential benefits of **metformin** in reducing cancer risk in this high-risk population.

Treatment

The clinical trial involves the administration of **metformin hydrochloride** as an **oral solution**. The active substance, metformin hydrochloride, is of chemical origin. Participants will receive a maximum daily dose of 2000 mg, with a total maximum dose of 5110 g over the course of the study. The treatment period is set for a maximum of 84 days. The oral solution is administered daily, and the trial aims to assess its efficacy in cancer prevention for individuals with Li-Fraumeni syndrome. Compliance with the dosing schedule will be monitored throughout the study.

Additionally, the trial includes the use of **metformin** in the form of **film-coated tablets**. This formulation also contains metformin as the active substance, derived chemically. The dosage regimen mirrors that of the oral solution, with a maximum daily dose of 2000 mg and a total maximum dose of 5110 g over 84 days. The tablets are administered orally on a daily basis. The study will monitor participant adherence to the dosing schedule to ensure accurate assessment of the treatment's effectiveness.

Both formulations of metformin are classified as antidiabetic medications and are not designated as orphan drugs. The trial does not include any pediatric formulations. The primary objective is to evaluate the superiority of metformin, in conjunction with close cancer surveillance, compared to surveillance alone in prolonging cancer-free survival in adolescents and adults with Li-Fraumeni syndrome. No placebo or comparator treatment is used in this study, as the focus is on the experimental use of metformin in the specified population.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the measurement of **cancer-free survival (CFS)**. This endpoint is defined as the time between randomization and the occurrence of a "cancer" event, which includes a histologically confirmed cancer diagnosis or death from any cause during trial participation. Secondary endpoints will include **tumor-free survival (TFS)**, which measures the time from randomization to a "tumor" event, including the diagnosis of histologically confirmed cancer or clinically or radiologically detected benign or premalignant lesions, as well as death from any cause.

Additional secondary endpoints will evaluate the number and type of emerging cancers, including their size, stage, and histological grade at diagnosis. The trial will also monitor treatment-emergent serious adverse events (AEs, SAEs) and assess levels of metformin adherence using the aggregated MARS-5 scores. Changes in quality of life (QoL), fear of progression (FOP), levels of depression, anxiety, and distress will be measured during the trial and from baseline to the last visit. Furthermore, the correlation of baseline weight, body mass index (BMI), and lifestyle factors such as smoking with trial outcomes will be analyzed.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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

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Exclusion Criteria

Currently taking metformin
Metformin intake for more than 3 consecutive months within 2 years before randomization
Current cancer diagnosis (detected previously or at baseline screening) , if feasible, rescreening should be offered at a later suitable date
Current completion of cancer therapy < 6 months before randomization, if feasible, rescreening should be offered at a later suitable date
Current type 2 DM
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.
Gastro-intestinal condition (such as Short-Bowel Syndrome) that could affect uptake of metformin
Concurrent illness that could result in life expectancy of <5 years
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
Evidence of significant renal impairment, eGFR < 45ml/min/1.73m² or conditions like dehydratation, severe infections or shock that could affect renal function
Liver failure, cirrhosis and/or aspartate transaminase or alanine transaminase >2.5 x upper limit of normal (ULN)
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
Hypersensitivity to any of the components of the IMP metformin used and contained excipients
Unwillingness or inability of participant to take part in the cancer surveillance programme (incl. WB-MRI)
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