Evaluation of Metformin Hydrochloride as a Metabolic Intervention in Oesophageal Adenocarcinoma to Enhance Neoadjuvant Chemoradiotherapy Response

Trial ID: 2024-511626-30-00
Protocol: MEMENTO
Sponsor: Amsterdam UMC Stichting

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Diseases & Conditions

Oesophageal adenocarcinoma

Objectives

The primary objective of this clinical trial is to evaluate the effect of a 2-week treatment with **metformin** on the activation of the tumour immune microenvironment in patients with **oesophageal adenocarcinoma**. This is assessed by measuring M2 to M1 macrophage polarization, CD8 intratumoral T cell infiltration, and the increase of the CD8:CD163 ratio in pre- and post-treatment tumour biopsies. This objective is clinically relevant as it aims to enhance the response to neoadjuvant chemoradiotherapy, potentially improving treatment outcomes for patients with this type of cancer.

Secondary objectives include:

Assessing the tolerability and toxicity of metformin.
Investigating metabolic changes in cancer cells.
Determining the utility of SCENITH in assaying the metabolic impact on cancer and immune cells.
Evaluating the pathological response according to the Mandard criteria.
Measuring progression-free survival (PFS) and overall survival (OS).
Exploring whether metformin induces a metabolic switch in macrophages, T cells, and cancer cells.
Detecting changes in the tumour immune microenvironment in subgroups of peripheral blood mononuclear cells (PBMCs).
Establishing autologous immune cell co-cultures with primary tumour cells to study immune cell-tumour cell interactions and anti-tumour responses in the presence of metformin.
Determining changes in cytokine expression in serum before and after metformin treatment.

These secondary objectives aim to provide a comprehensive understanding of metformin's impact on both the tumour and immune system, potentially leading to improved therapeutic strategies.

Participants

The clinical trial involves participants diagnosed with **oesophageal adenocarcinoma**. The study population includes both male and female adults aged 18 years and older, with an **ECOG performance status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have adequate hematological, renal, and hepatic functions. The trial does not include a vulnerable population. The total number of participants is not provided by the sponsor. Selection criteria emphasize the need for participants to be willing to undergo two endoscopies for investigational purposes and to provide written, voluntary informed consent. Participants must also be accessible for follow-up and management at the treatment center. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the effects of **metformin hydrochloride** as a metabolic intervention in patients with **oesophageal adenocarcinoma**. This is a Phase 4, randomized, double-blind, controlled trial aimed at assessing the activation of the tumour immune microenvironment following a two-week treatment with Metformin Aurobindo 500 mg film-coated tablets. The primary objective is to measure the metabolic switch in macrophages, specifically the M2 to M1 macrophage polarization, and the infiltration of CD8 intratumoral T cells, as well as the increase in the CD8:CD163 ratio in pre- and post-treatment tumour biopsies. Secondary endpoints include changes in T cell infiltration, metabolic changes in macrophages and T cells, pathological response, adverse events, progression-free survival, and overall survival.

The trial is expected to commence recruitment on September 2, 2024, and conclude by July 1, 2030. Participants will be involved in the study for a maximum treatment period of two weeks. The study visits will include an initial screening visit to confirm eligibility based on criteria such as surgical resectability, age, ECOG performance status, and adequate hematological, renal, and hepatic functions. Participants must also consent to undergo two endoscopies for investigational purposes. Follow-up visits will be scheduled to monitor the treatment's effects and any adverse events. The end-of-study visit will assess the primary and secondary endpoints and ensure the collection of all necessary data.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial will utilize a double-blind methodology to ensure unbiased results, with neither the participants nor the investigators aware of the treatment assignments. The study will adhere to rigorous ethical standards, ensuring that all participants provide written, voluntary informed consent before enrollment. The trial's findings are anticipated to contribute valuable insights into the potential role of metformin in enhancing the response to neoadjuvant chemoradiotherapy in oesophageal adenocarcinoma.

Treatment

The clinical trial involves the administration of **Metformin Aurobindo 500 mg film-coated tablets** as the experimental medication. The active substance in these tablets is **metformin hydrochloride**, a chemical compound. The pharmaceutical form of the medication is a film-coated tablet, designed for oral administration. Participants in the trial will receive a dosage of 500 mg per tablet, with a maximum daily dose of 1000 mg. The total maximum dose over the treatment period is 2000 mg. The treatment duration is set for a maximum of 2 weeks. The medication is manufactured by Aurobindo Pharma (Malta) Limited and is not a pediatric formulation. The trial aims to assess the impact of metformin on the tumor immune microenvironment in patients with oesophageal adenocarcinomas.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of metformin to evaluate its effects. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial's primary objective is to observe changes in the tumor immune microenvironment, specifically the polarization of macrophages and infiltration of CD8 intratumoral T cells, by comparing pre- and post-treatment tumor biopsies.

Efficacy

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint focuses on evaluating the **metabolic switch** in macrophages, specifically measuring M2 to M1 macrophage polarization within the tumor immune microenvironment. This will be assessed by determining the number of CD8 intratumoral T-cell infiltrations using single-cell mRNA sequencing. Secondary endpoints include measuring changes in T cell infiltration and the CD3:CD163 ratio within the spatial context by multicolor immunohistochemistry (mIHC), detecting metabolic changes in macrophages and T cells in the tumor immune microenvironment through SCENITH flow cytometry analysis, and assessing pathological response according to pTNM stage and Mandard criteria. Additionally, adverse events will be monitored based on the Common Toxicity Criteria for Adverse Events (CTCAE), along with progression-free survival and overall survival.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Surgical resectable (
Adult patients (age ≥ 18 years).
ECOG performance status 0 or 1 (cf. Appendix A).
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
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

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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.
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 esophageal 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 func-tion precluding major surgery and/or radiation.
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.
Dementia or altered mental status that would prohibit the understanding and giving of in-formed consent