Metformin and 5-fluorouracil for Refractory Colorectal Cancer.

Primary Outcomes Measures:

• Disease control Rate at 8 weeks according to RECIST 1.1 (Tumor response was defined as the percentage of patients with complete response, partial response or stable disease as best overall response).

Secondary Outcome Measures:

• Progression-free Survival
• Overall Survival
• Adverse Events (assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0)

Inclusion criteria

• Histological diagnosis of metastatic colorectal adenocarcioma previously treated with at least two lines of chemotherapy (oxaliplatin and irinotecan regimens) if mutated KRAS or treated with at least 3 lines of chemotherapy (oxaliplatin, irinotecan and cetuximab) if KRAS wild type.
• Disease progression according to radiological or clinical assessment.
• Measurable disease.
• ECOG Performance 0-1.
• Age above 16 years.
• Normal organic function as defined for the following criteria:

• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 times the upper normal limit of the local laboratory (LSN-LL);
• Total serum bilirubin ≤ 2.0 x ULN-LL;
• Absolute neutrophil count ≥ 1,500 / mm3;
• Platelet count ≥ 100,000 / mm3;
• Hemoglobin ≥ 8.0 g / dl;
• Serum creatinine ≤ 1.5 x ULN-LL
• Written informed consent before enrollment

Exclusion criteria

• Diabetic patients taking metformin.
• Patients already treated with mTOR inhibitors.
• Hypersensitivity to metformin, renal or hepatic impairment or other conditions that predispose to lactic acidosis.
• History of acute myocardial infarction in the last 6 months
• Serious illness or psychiatric condition.
• Current participation in other protocols with experimental drugs.
• Suspicion of dihidropirimida dehydrogenase(DPD)deficiency.
• Presence of active infection.
• No ability to ingest food orally.
• Patients with metastatic disease to CNS.
• Patients who underwent major surgery in the last 4 weeks.
• Patients who received chemotherapy in the last three weeks.
• Patients who underwent radiotherapy in the last 2 weeks or who received radiotherapy in the target lesion, if this is the only target lesion.
• Patients using oral anticoagulation (warfarin).
• Pregnant or lactating patients