MEtformin as a MEtabolic iNTervention in Oesophageal adenocarcinomas to improve response to neoadjuvant chemoradiotherapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Amsterdam UMC Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

9 Mar 2025 → ongoing

Decision date (initial)

2024-08-05

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic

The primary objective of this clinical trial is to determine whether 2 weeks metformin treatment activates the tumour immune microenvironment measured by M2 to M1 macrophage polarization, CD8 intratumoral T cell infiltration and increase of the CD8:CD163 ratio when comparing pre- and post-treatment tumour biopsies.

Secondary objectives 10

1. Tolerability and toxicity of metformin
2. Metabolic change of cancer cells
3. Determine whether SCENITH can be used to assay the metabolic impact on cancer and im-mune cells
4. Pathological response according to the Mandard criteria.
5. Progression-free survival (PFS).
6. Overall survival (OS).
7. Determine whether metformin induces a metabolic switch in macrophages, T cells and cancer cells.
8. Determine whether changes in the tumour immune microenvironment can also be detected in subgroups of peripheral blood mononuclear cells (PBMCs) taken at the same time points.
9. To establish autologous immune cell co-cultures with primary tumour cells to investigate im-mune cell-tumour cell interactions and anti-tumour responses in the presence of metformin.
10. Determine changes in cytokine expression in serum before and after metformin treatment.

Conditions and MedDRA coding

Oesophageal adenocarcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Surgical resectable (
2. Adult patients (age ≥ 18 years).
3. ECOG performance status 0 or 1 (cf. Appendix A).
4. Adequate hematological, renal and hepatic functions defined as: o Absolute Neutrophil Count ≥ 1.5 x 109/L o platelets ≥ 100 x 109/L o haemoglobin ≥ 5.6 mmol o total bilirubin ≤ 1.5 x upper normal limit o creatinine clearance (Cockroft) > 30 ml/min
5. Patients must be willing to undergo two endoscopies for investigational purposes.
6. Written, voluntary informed consent
7. Patients must be accessible to follow up and management in the treatment center

Exclusion criteria 13

1. Patients diagnosed with diabetes mellitus type 1 or 2 receiving anti-diabetic drugs.
2. Patients prescribed metformin or another anti-diabetic drug for any reason.
3. Patients allergic or intolerant to metformin.
4. Previous systemic therapy or radiotherapy on the oesophagus.
5. Severe renal impairment (CLcr ≤ 30 ml/min).
6. Past (within 5 years) or current history of malignancy other than entry diagnosis interfering with prognosis of esophageal cancer
7. Previous systemic therapy for other forms of cancer within the last six months.
8. Patients with prior allogeneic stem cell or solid organ transplantation
9. Pregnancy (positive serum pregnancy test), planning to become pregnant, and lactation.
10. Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) precluding major surgery.
11. Pulmonary fibrosis, active, non-infectious pneumonitis and/or severely impaired lung func-tion precluding major surgery and/or radiation.
12. Serious underlying medical condition which would impair the ability of the patient to re-ceive the planned treatment, including prior allergic reactions to drugs containing Cremo-phor, such as teniposide or cyclosporine.
13. Dementia or altered mental status that would prohibit the understanding and giving of in-formed consent

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Metabolic switch in macrophages measured by M2 to M1 macrophage polarization within the tumour immune microenvironment and the number of CD8 intratumoral T-cell infiltration determined with single cell mRNA sequencing.

Secondary endpoints 6

1. Measure changes in T cell infiltration and the CD3:CD163 ratio within the spatial context by multicolor immunohistochemistry (mIHC).
2. Detect metabolic changes in macrophages and T cells in the tumour immune microenvi-ronment by SCENITH flow cytometry analysis.
3. Pathological response according to pTNM stage and Mandard criteria
4. Adverse events based on Common Toxicity Criteria for Adverse Events (CTCAE).
5. Progression free survival
6. Overall survival

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Amsterdam UMC Stichting

Sponsor organisation

Amsterdam UMC Stichting

Address

De Boelelaan 1117

City

Amsterdam

Postcode

1081 HV

Country

Netherlands

Scientific contact point

Organisation

Amsterdam UMC Stichting

Contact name

Coordinating Investigator

Public contact point

Organisation

Amsterdam UMC Stichting

Contact name

Coordinating Investigator

Locations

1 EU/EEA country · 2 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 6 files

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

Application history

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