Combination of Metformin to Neoadjuvant Radiochemotherapy in the Treatment of Locally Advanced Rectal Cancer (METCAP).

Study Overview
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Brief Summary
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Metformin is an oral antidiabetic of the biguanide class derived from galega officinalis. Historical cohort of patients with diabetes have shown that diabetics on Metformin had a better chance of survival than diabetics not on Metformin. These observations have led to in vitro studies of metformin on cancer cells. It was thus demonstrated that Metformin has anti-proliferative properties. The aim of our study is to evaluate the efficacy of metformin in combination with neoadjuvant radiochemotherapy in the treatment of locally advanced rectal cancer.

Detailed Description
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Patients eligible for the trial and having signed their consent to participate will undergo a dosimetric scan at baseline. 48 hours later (minimum), a Metformin therapy will be started at a dosage of 850 mg 2 times / day ( = 1700 mg / day). Seven days later (minimum) and up to 48 hours before surgery, the dosage of Metformin will be increased to 850 mg 3 times / day ( = 2550 mg / day). This very same day (J10), patients will start a radiochemotherapy. For 5 weeks, 5 days out of 7, patients will receive 800 mg/m² of Capecitabine 2 times / day (on morning and evening) ( = 1600 mg / m² / day) and a 3D irradiation or an Intensity-Modulated Radiation Therapy (IMRT) of a total dose of 50 Gy (5 sessions of 2 Gy per week). 6 to 8 weeks after completion of the chemoradiotherapy, surgery will be scheduled. It will consist of a tumor resection with total resection of the meso rectum. Prior to the start of treatment, patients will have a clinical and a paraclinical examination and will undergo a laboratory examination. Once a week during the radiochemotherapy, patients will have a clinical examination and will undergo a laboratory examination. Three weeks after the end of the radiochemotherapy, patients will have a clinical examination. Before surgery, patients will have a clinical and a paraclinical examination. Finally, at the end of the study, patients will have a clinical examination.

Official Title
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Phase II Study Evaluating the Efficacy of the Combination of Metformin to Neoadjuvant Radiochemotherapy in the Treatment of Locally Advanced Rectal Cancer.

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with an adenocarcinoma of the low or middle rectum. T3 or T4 stage (T evaluated by MRI and / or echo-endoscopy). Absence of distant metastasis. Patient requiring a radiochemotherapy. Correct hematological conditions : Neutrophils ≥ 1500 G / L, platelets ≥ 100 000 G / L. Age ≥ 18 years Performance status (WHO) ≤ 2 Lactatemia ≤ Higher standard of the sampling laboratory. For women of childbearing age, a contraceptive method is mandatory for the entire duration of the study. Exclusion Criteria: Other histologies such as squamous cell carcinoma, neuroendocrine tumors, melanomas, etc. History of lactic acidosis. Any diabetes (According to the WHO definition : fasting plasma glucose (FPG) > 1.26 g / L-1). Ongoing antidiabetic treatment such as Biguanides, hypoglycemic sulfamides, glinides, GLP-1 analogue, gliptins, alpha-glucosidase inhibitors Insulin or insulin analogues Hypersensitivity to capecitabine or to any of the excipients or to fluorouracil. History of severe and unexpected reactions to a fluoropyrimidine therapy. Patient with known deficiency to the dihydropyrimidine dehydrogenase (DPD). Hypersensitivity to metformin or to any of the excipients. Renal failure or impaired renal function (creatinine clearance < 60 ml / min). Severe infection. Acute or chronic disease which may cause tissue hypoxia such as heart or respiratory failure or recent myocardial infarction (< 6 months). Hepatic insufficiency, acute alcohol intoxication, alcoholism. Psychiatric inability to give consent. Contraindication to radiation therapy and/or chemotherapy. Treatment with sorivudine or its chemically related analogues, such as brivudine. Patient under tutorship or guardianship. Pregnant or breastfeeding women.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin treatment<br>J1 : dosimetric scan J3 : initiation of the Metformin therapy (at a dosage of 1700 mg / day) J10 : increasing the dose of Metformin (2550 mg / day) + initiation of the radiochemotherapy J44 : end of the radiochemotherapy Between J86 and J100 : surgery (discontinuation of the Metformin therapy 48 hours before surgery) | Drug: Metformin<br>* J3 - J10 (7 days minimum) : 850 mg 2 times / day J10 - 48h before surgery : 850 mg 3 times / day<br>* Other names: Stagid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The efficacy will be assessed on the operative specimen by the complete histological response rate (absence of tumor cells : pCR). |  | within 30 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity will be assessed according to NCI-CTCAE v4.0. Grades ≥ 3 related to metformin will be collected by the clinician. |  | up to 30 days after the end of the treatments (metformin and radiochemotherapy) | 
| Sphincter preservation rate and downstaging rate |  | within 30 days after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiochemotherapy, Metformin, Rectal cancer