This is a phase II trial to evaluate efficacy and safety of Metformin and Fluorouracil in patients with metastatic colorectal cancer (CRC) who have progressed after Oxaliplatin and Irinotecan based chemotherapy.

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