A randomized, open-label phase II multicenter study evaluating the efficacy of oral Everolimus alone or in combination with Pasireotide LAR i.m. in advanced progressive pancreatic neuroendocrine tumors (PNET) * The COOPERATE-II study

1. Advanced (unresectable or metastatic), histologically confirmed well differentiated (low to intermediate grade) pancreatic neuroendocrine tumor (PNET).
2. Radiological documentation of progressive disease within the last 12 months prior to randomization.
3. WHO performance status * 2
4. Adequate bone marrow function:
* WBC * 2.5 x 109/L,
* ANC * 1.5 x 109/L,
* Platelets * 100 x 109/L,
* Hb * 9 g/dL
5. No evidence of significant liver/pancreas disease:
* Serum total bilirubin * 1.5 x ULN,
* INR < 1.3,
* ALT or AST * 3 x ULN
* Serum lipase * 2 x ULN
6. Serum creatinine * 2.0 mg/dl and estimated glomerular filtration rate (eGFR) > 30 ml/min/m2 (calculated with MDRD formula).

1. Patients currently requiring SSA treatment.
2. Patients who received prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, everolimus), or pasireotide.
3. Patients who received any cytotoxic chemotherapy, targeted therapy, SSAs, or biotherapy within the last 4 weeks.
4. Patients with more than 2 prior systemic treatment regimens
7. Prior treatment with radiolabeled SSAs within the last 12 months.
8. Patients with hepatic artery embolization, cryoablation or radiofrequency ablation of hepatic metastasis within the last 3 months prior to randomization.
9. Patients who have received radiotherapy of target lesions. Patients who have received local radiotherapy of non-target lesions for local symptom control within the last 4 weeks must have recovered from any adverse effects of radiotherapy prior to randomization.
10. Patients who have undergone major surgery/surgical therapy for any cause within 1 month or surgical therapy of loco-regional metastases within the last 3 months prior to randomization. Patients should have recovered from the treatment and have a good clinical condition before entering this study.
11. Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent.
12. Patients with symptomatic cholelithiasis.
13. Patients who are not clinically euthyroid. Patients with history hypothyroidism are eligible if they are on adequate and stable replacement thyroid hormone therapy for at least 3 months.
14. Patients with abnormal coagulation (PT [INR] or aPTT elevated by 30% above normal limits).
15. QT-related exclusion criteria:
* Patients with a QTcF > 470 ms,
* History of syncope or family history of idiopathic sudden death, Long QT syndrome,
* Sustained or clinically significant cardiac arrhythmias,
* Patients with risk factors for torsades de pointes: Potassium < 3.0 mmol/L, magnesium < 0.4 mmol/L or, calcium < 1.75 mmol/L at baseline. If the electrolyte abnormalities are corrected prior to start of study drug, the patient may become eligible for the trial. Cardiac failure, clinically significant/symptomatic bradycardia or high-grade AV block,
* Concomitant medications known to prolong the QT interval (see Appendix 2).
* Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes mellitus or Parkinson*s disease), HIV, liver cirrhosis, uncontrolled hypothyroidism or cardiac failure.
16. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
* Uncontrolled diabetes as defined by HbA1c * 8% despite adequate therapy,
* Fasting serum cholesterol > 300 mg/dL (7.75 mmol/L) OR fasting triglycerides > 2.5 x ULN despite appropriate lipid lowering medication.
* Severely impaired lung function defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air. DLCO should be adjusted to hemoglobin value and patient lung volumes.
* Patients with the presence of active or suspected acute or chronic uncontrolled infection or with a history of immunodeficiency, including a positive HIV test result (ELISA and Western blot). A HIV test will not be required; however, previous medical history will be reviewed.
* Non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with this study treatment.
* History or active liver disease such as cirrhosis, decompensated liver disease, chronic active hepatitis or chronic persistent hepatitis.
* Quantifiable HBV-DNA or positive hepatitis B surface antigen (HbsAg).
* Quantifiable HCV-RNA.
* History of, or current alcohol misuse/abuse within the past 12 months.
* Known gallbladder or bile duct disease, acute or chronic pancreatitis.
* Life-threatening autoimmune and ischemic disorders.
* Patients who have a history of another primary malignancy within the last 3 years, with the exception of locally excised non-melanoma skin cancer and carcinoma in situ of uterine cervix.
* Symptomatic CNS metastases requiring corticosteroid therapy.
* Patients who have any current or prior medical condition that may interfere with the conduct of the study or the evaluation of its results in the opinion of the Investigator or the Sponsor*s Medical Monitor.