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

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.

Eligibility

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.

Conditions3

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