Activity and Safety of Everolimus+Octreotide LAR+Metformin in Advanced Pancreatic Well-differentiated NETs

Inclusion Criteria:

1. Signature of written informed consent (approved by the Institutional Ethics Committee Independent ) obtained after a careful study of screening procedures
2. Age \>= 18 years old.
3. Patients with histological evidence of pNET well-differentiated G1 -G2
4. Configurable tumor disease (according to RECIST (Response Evaluation Criteria In Solid Tumors) ) .
5. Karnofsky Performance Status \>= 60%.
6. Life expectancy greater than 6 months.
7. Is permitted to enroll patients who have not received any treatment for advanced disease or patients pretreated with surgery , chemotherapy or somatostatin analogues .
8. Basal blood tests :

   * Counts of neutrophils in absolute value \> 1.5 x 109 / L.
   * Platelet count \> 100 x 109 / L.
   * Hemoglobin \> 9 g / dl .
   * Total Bilirubin \< 1.5 times the upper limit of normal .
   * AST( aspartate aminotransferase), ALT (alanine aminotransferase)\<2.5 times the upper limit of normal in patients without evidence of liver metastases.
   * AST, ALT \<2.5 times the upper limit of normal in patients with evidence of liver metastases.
   * Alkaline phosphatase \<2.5 times the upper limit of normal in patients with evidence of hepatic metastases
   * Values of serum creatinine \< 1.5 mg / dl. - CCr ( Creatinine Clearance rate) ≥ 60 mL / min 9 . During the study of male and female patients must use adequate contraceptive methods .

Exclusion Criteria:

1. Patients with histological evidence of malignant insulinoma ( pNET )
2. Surgeries performed within 28 days prior to the start of treatment.
3. Evidence of metastasis at the level of the central nervous system or spinal cord compression . Patients should be subjected to a recent study MRI or CT scan at least 28 days from the date of randomization.
4. Clinically significant cardiovascular disease , such as cardiovascular accidents occurred in less than 6 months, unstable angina , congestive heart failure grade greater than or equal to II according to the classification of the New York Heart Association (NYHA) series cardiac arrhythmias that require treatment.
5. Important comorbidities , metabolic disorders , clinical examination or laboratory investigations , which contraindicate the use of drugs to study, or patients at high risk of complications from the treatment.
6. Active or uncontrolled severe infections .
7. Cirrhosis , acute hepatitis or chronic active hepatitis .
8. Poor control of diabetes HbA1c \> = 8.0 % .
9. Diabetic patients who are treated with metformin are eligible if they have enabled the treatment with metformin for less than 6 months. Are excluded diabetic patients who make use of other hypoglycemic agents such as sulfonylureas, insulin , glinides as monotherapy or in combination with metformin.
10. Using anti - IL6 (Interleukin 6) or IGF1 .
11. Uncontrolled high blood pressure , atrial fibrillation .
12. History of immunosuppression included positive HIV test .
13. No previous or concomitant oncological pathology , except: basal cell skin cancer, in situ , as long as every other cancer patient diseasefree for at least 5 years.
14. They excluded patients with a condition of metabolic acidosis , acute or chronic , including ketoacidosis .
15. History of alcohol abuse , or habitual intake of alcohol (≥ 3 glasses of alcoholic drinks / day) sufficient to cause hepatotoxicity.
16. Prolonged fasting .
17. Severe states of dehydration.