Metformin before pre-surgery chemoradiotherapy to boost immune activity in oesophageal adenocarcinoma
Metformin as a Metabolic Intervention in Oesophageal Adenocarcinomas to Improve Response to Neoadjuvant Chemoradiotherapy.
This trial will try two weeks of metformin before neoadjuvant chemoradiotherapy to see if it activates the tumour immune environment in adults with stage II–III oesophageal adenocarcinoma.
Quick facts
| Phase | Phase 2 |
|---|---|
| Study type | Interventional |
| Enrollment | 14 (estimated) |
| Ages | 18 Years and up |
| Sex | All |
| Sponsor | Amsterdam UMC, location VUmc Academic / other |
| Drugs / interventions | crizotinib, radiation, cyclophosphamide |
| Locations | 2 sites (Amsterdam and 1 other locations) |
| Trial ID | NCT06687876 on ClinicalTrials.gov |
What this trial studies
This Phase 2, interventional trial gives eligible patients two weeks of metformin prior to standard neoadjuvant chemoradiotherapy and collects tumour biopsies by endoscopy to compare the tumour immune microenvironment before and after treatment. The study focuses on markers of immune activation such as intratumoral T cell levels and the CD3:CD163 ratio and explores fatty acid oxidation (FAO)–related changes that may suppress immune responses. Patients must be surgical candidates with resectable stage II–III oesophageal or gastro-oesophageal junction adenocarcinoma, have ECOG 0–1, and adequate organ function, and must not be taking anti‑diabetic drugs. Primary analyses will use tissue and molecular profiling to determine whether short-term metformin shifts the tumour microenvironment toward a more T cell–active state.
Who should consider this trial
Good fit: Adults (≥18) with histologically proven, resectable (≤T4b, N0/N+, M0) oesophageal or gastro‑oesophageal junction adenocarcinoma scheduled for neoadjuvant chemoradiotherapy, ECOG 0–1, adequate labs, willing to undergo two research endoscopies, and not taking anti‑diabetic drugs are eligible.
Not a fit: Patients with diabetes who are already treated with metformin or other anti‑diabetic drugs, those with metastatic disease, or tumours that are not driven by fatty acid oxidation are unlikely to benefit from this intervention.
Why it matters
Potential benefit: If successful, metformin could increase the proportion of patients whose tumours respond to pre-surgery chemoradiotherapy, potentially lowering recurrence risk after surgery.
How similar studies have performed: Metformin has shown observational associations and some early signals of immune or treatment-sensitising effects in other cancers, but direct evidence in oesophageal adenocarcinoma is limited, making this a relatively novel application.
Eligibility criteria
Show full inclusion / exclusion criteria
Inclusion Criteria: * Surgical resectable (\<T4b, N0 or N+, M0), and histologically proven adenocarcinoma of the oesophagus or gastro-oesophageal junction planning to undergo neoadjuvant chemoradiotherapy. * Adult patients (age ≥ 18 years). * ECOG performance status 0 or 1 (cf. Appendix A). * Adequate hematological, renal and hepatic functions defined as: * Absolute Neutrophil Count ≥ 1.5 x 10\^9/L * Platelets ≥ 100 x 10\^9/L * Hemoglobin ≥ 5.6 mmol * Total bilirubin ≤ 1.5 x upper normal limit * Creatinine clearance (Cockroft) \> 30 ml/min * Patients must be willing to undergo two endoscopies for investigational purposes. * Written, voluntary informed consent. * Patients must be accessible to follow up and management in the treatment center. Exclusion Criteria: * Patients diagnosed with diabetes mellitus type 1 or 2 receiving anti-diabetic drugs. * Patients prescribed metformin or another anti-diabetic drug for any reason. * Patients allergic or intolerant to metformin. * Excessive alcohol consumption. * Use of OCT1/OCT2 inhibitors (e.g. verapamil, cimetidine, dolutegravir, isavuonazol, trimethoprim, vandetanib, crizotinib and Olaparib). * Use of OCT1/OCT2 inducers (e.g. rifampicine). * Use of immunosuppressive medication (corticosteroids, cyclosporine, tacrolimus, sirolimus, everolimus, cyclophosphamide). * Previous systemic therapy or radiotherapy on the oesophagus. * Severe renal impairment (CLcr ≤ 30 ml/min). * Past (within 5 years) or current history of malignancy other than entry diagnosis interfering with prognosis of oesophageal cancer. * Previous systemic therapy for other forms of cancer within the last six months. * Patients with prior allogeneic stem cell or solid organ transplantation * Pregnancy (positive serum pregnancy test), planning to become pregnant, and lactation. * Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) precluding major surgery. * Pulmonary fibrosis, active, non-infectious pneumonitis and/or severely impaired lung function precluding major surgery and/or radiation. * Serious underlying medical condition which would impair the ability of the patient to receive the planned treatment, including prior allergic reactions to drugs containing Cremophor, such as teniposide or cyclosporine. * Dementia or altered mental status that would prohibit the understanding and giving of informed consent.
Where this trial is running
Amsterdam and 1 other locations
- Amsterdam UMC — Amsterdam, Netherlands (Not_yet_recruiting)
- Amsterdam UMC — Amsterdam, Netherlands (Recruiting)
Study contacts
- Principal investigator: Sarah Derks, MD PhD — Amsterdam UMC, location VUmc
- Study coordinator: Kayla Brugman, Master of Medicine
- Email: c.brugman@amsterdamumc.nl
- Phone: +3120 44 45869
How to participate
- Review the eligibility criteria above with your treating physician.
- Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
- Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.