Metformin as a Metabolic Intervention in Oesophageal Adenocarcinomas to Improve Response to Neoadjuvant Chemoradiotherapy

NCT06687876 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 2024.09352024-511626-30-00
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 2

Brief Summary

The primary objective of this study is to investigate whether two weeks of metformin treatment can activate the tumour microenvironment in patients with stage II and III oesophageal adenocarcinomas.

Conditions

Oesophageal Adenocarcinoma; Tumor Microenvironment

Keywords

metabolic intervention; adenocarcinoma; oesophageal cancer; metformin; tumor microenvironment; neoadjuvant chemoradiotherapy

Outcome Measures

Primary Outcomes (1)

• activation of the tumour immune microenvironment after two week metformin treatment.

  Activation of the tumor immune microenvironment measured by M2 to M1 polarization, CD8 intratumoral T cell infiltration and an increase of CD3 to CD163 ratio when comparing tumor biopsies from before and after treatment.

  at enrollment and at end of metformin treatment at 2 weeks.

Secondary Outcomes (5)

• Tolerability and toxicity of metformin

  From starting treatment to end of treatment at 7 weeks.

• Metabolic change of cancer cells with SCENITH analysis.

  at enrollment and at end of metformin treatment at 2 weeks

• Pathological response

  After surgery, approximately 16 weeks after enrollment.

• Progression-free survival (PFS).

  60 months

• Overall survival (OS)

  60 months

Other Outcomes (5)

• Can metformin induce a metabolic switch in macrophages, T cells and cancer cells.

  20 months

• Change in subgroups in peripheral blood mononuclear cells (PMBCs) after metformin treatment.

  20 months

• Establish immune cell co-cultures with primary tumour cells and investigate the cell interactions and anti-tumour responses in presence of metformin.

  20 months

Study Arms (1)

Metformin

EXPERIMENTAL

1000 mg (twice a day 500 mg) metformin orally will be administered during a 2-week period. This is followed by the standard of care, which is neoadjuvant chemoradiotherapy, involving paclitaxel (50 mg/m2), carboplatin (AUC=2), and radiotherapy (23 x 1.8 Gy over five weeks) followed by surgical resection.

Drug: Metformin

Interventions

Metformin DRUG

Twice a day 500mg of metfomrin orally (1000mg/day) during a 2-week period.

Also known as: Glucient

Metformin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead
• Cancer Center Amsterdam Research Foundation: collaborator

Study Sites (2)

Amsterdam UMC

Amsterdam, Netherlands

NOT YET RECRUITING

Amsterdam UMC

Amsterdam, Netherlands

RECRUITING

MeSH Terms

Conditions

Adenocarcinoma Of Esophagus; Adenocarcinoma; Esophageal Neoplasms

Interventions

Metformin

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Sarah Derks, MD PhD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

• Hanneke W.M. van Laarhoven, MD, PhD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kayla Brugman, Master of Medicine

CONTACT

+3120 44 45869; c.brugman@amsterdamumc.nl

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD PhD

Study Record Dates

• First Submitted: November 5, 2024
• First Posted: November 14, 2024
• Study Start: March 9, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2030
• Last Updated: July 10, 2025

Record last verified: 2025-07

Locations

NL (2)