This is a non-randomized phase II , open label, comparative study. Patients with advanced non-resectable and/or progressive gastro-entero-pancreatic Neuroendocrine Tumours - GEP-NET, (G1, G2 and G3), Broncho-pulmonary Carcinoids (BPCs Atypical-AC or Typical-TC), pheochromocytoma/paraganglioma (PPGLs) and neuroendocrine tumours of unknown primary (NET-CUP) with overexpression of somatostatin receptor (SSTR positive) will be enrolled in the study and will be treated using Peptide Receptor Radionuclide Therapy (PRRT) initially with Yttrium-90 (90Y) DOTATATE (DOTA-0-Tyr3-Octreotate), and then compare to Lutecium-177 (177Lu) DOTATATE or mix of both Yttrium-90 (90Y) and Lutecium-177 (177Lu) DOTATATE. Total maximum activity for Yttrium-90 up to 4x3,7GBq, for Lutecium-177 up to 4x5,55GBq (Lu-177) and for both (mix) 4x3,7GBq (90Y and 177Lu 50% each).

This is a non-randomized phase II, open-label, comparative study. Patients with advanced, unresectable and/or progressive Gastro-Entero-Pancreatic Neuroendocrine Tumors - GEP-NET, (histological grade G1, G2 and G3), Broncho-Pulmonary Carcinoids (BPCs), including typical carcinoid (AC) and typical carcinoid (TC), pheochromocytoma/paragangliomas (PPGLs) and neuroendocrine tumors (cancers) of unknown primary (NET-CUP). All with overexpression of somatostatin receptor (SSTR positive) based on somatostatin receptor imaging (scintigraphy or PET), will be enrolled in this study.

Initially patients will be assigned to single arm of PRRT using yttrium-90 (90Y) DOTATATE (DOTA-0-Tyr3-Octreotate) and then patients will be non-randomly assigned to one of the two groups lutecium-177 (177Lu) DOTATATE or mix yttrium (90Y) DOTATATE and lutecium-177 (177Lu) DOTATATE (50% each). The dosages (total activity used in each group of treated patients will be as follows:

1. Total activity of 90Y DOTATATE 4x3,7GBq (14,8 GBq) for 4 cycles at 8 ± 2 weeks (400mCi)
2. Total activity of 177Lu DOTATATE 4x5,55GBq (22,2 GBq for 4 cycles at 8 ± 2 weeks (600 mCi)
3. Total activity of mix both 90Y DOTATATE and 177Lu DOTATATE (50 each) 4x3,7 GBq for 4 cycles at 8 ± 2 weeks (400mCi).

The non-randomized, phase II study design, allows for proposed initial active treatment arm using standard dose of 90Y DOTATATE and experimental treatment arm which composed of two options of PRRT with lutecium-177 DOTATATE or mix 90Y and 177Lu DOTATATE. The experimental therapy arm will be consisting of randomly allocated patients.

Subjects including in this study will be evaluated in the mixed patients' population, including GEP-NET, bronchopulmonary carcinoid (BPCs), paraganglioma/pheochromocytomas (PPGLs) and NET of unknown origin (NET-CUP).

Estimates of the original goals of the study can be assessed for each scheme separately using a two-step design using an external standard for comparison (the investigator's previous published results include standard PRRT using 90Y DOTATATE in subjects with GEP-NET).

Although the sample size in this study is not based on any specific statistical hypothesis to compare separate groups of patients those with PRRT using 90Y DOTATATE, next those with 177Lu DOTATATE and those who will receive mix 90Y and 177Lu DOTATATE.

This study design allows an objective set of clinical efficacy results in terms of PRRT responses and safety in these three treatment regimens in the same patient population, even different groups of tumors, which may be useful when planning next generation of the clinical trial using PRRT.

Inclusion Criteria:

• Adults ≥18 years old, male or female, with histologically proven, well-differentiated G1/2 GEP-NET, BPCs, PPGLs or NET (cancer with unknown primary - CUP), with Ki-67 <20%, in selected cases patients with NETG3 will be included if there will be reported well/moderate morphological appearance but Ki-67>20% but less then Ki<30%; and there will be high expression of somatostatin receptor seen in functional imaging utilized functional imaging 99mTc HYNICTOC or 68Ga DOTATATE or 68Ga DOTATOC.
• The presence of high expression of somatostatin receptors demonstrated on Somatostatin Receptor Imaging using 99mTc HYNICTOC (SPECT) or 68Ga DOTATATE or 68Ga DOTATOC (PET) scans, et least as uptake in not involved liver, Krenning >2
• Non-resectable, advanced determined by an appropriately specialized surgeon or deemed not suitable for liver directed therapies where liver is the only site of disease;
• Performance status (PS) based on ECOG 0-2;
• Unresectable, advanced/metastatic progressive disease evaluated as clinical, biochemical, bad control symptoms of tumour hypersecretion or disease progression seen in imaging structural or functional.
• Adequate renal function (measured creatinine clearance > 30 ml/min by DTPA or eGFR),
• Adequate bone marrow function (Hb>8 g/d/L, WBC>2.0 x109L, ACN>1.5 x109L and PLT>80 x 103/L);
• Adequate liver function (serum total bilirubin ≤ 1.5 x ULN, and Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASPAT), Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver metastases)). INR ≤ 1.5 (or on a stable dose of LMW heparin for >2 weeks at time of enrollment);
• Life expectancy of at least 6 months;
• The tumor parameters that can be measured objectively as the size to be assessed in radiological studies on the basis of the RECIST 1.0;
• In the absence of the ability to measure tumor size based on RECIST criteria, they have tumor parameters that can be measured objectively as tumor markers determined in the blood or urine CgA, 5HIAA.
• Study treatment both planned and able to start within 28 days of inclusion;
• Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments;
• Signed, written informed consent.

Exclusion Criteria:

• • Primary non-NETs;

  • Cytotoxic chemotherapy e.g. CAPTEM, or any other type of chemotherapy recorded 6 weeks before enrollment into the study;
  • Any type of biotherapy using somatostatin analogues or any targeted therapy within the last four weeks;
  • Pre-existing locoregional treatment such as radiomebolization (SIR-spheres) or HDR brachytherapy under CT control, performed in the last 6 months;
  • Major surgery/surgical therapy for any cause within two months before start of PRRT;
  • Surgical therapy of loco-regional metastases within the last three months prior to inclusion;
  • Uncontrolled metastases to the central nervous system, in the case of surgical and / or radiotherapeutic treatment, patients should remain on a stable dose of steroids for at least 2 weeks before enrollment, without deterioration of the general state associated with the presence of metastatic disease in the CNS;
  • Poorly controlled concurrent medical illness. E.g. unstable diabetes with glycosylated hemoglobin (HbA1c> 9.0), the optimal glycaemic control should be achieved before starting trial therapy);
  • Symptomatic heart failure NYHA class III or IV, congestive cardiac failure, myocardial infarction in the last 6 months, serious uncontrolled cardiac arrhythmia, unstable angina, or other serious cardiac problems;
  • Active uncontrolled infection, including Hepatitis and Hepatitis, HIV, in the case of HCV and HBV infection, the patient can be included in the study confirming the suppression of viral replication and the patient remains on the correct therapeutic dose of antiviral drugs;
  • Pregnant patients (a negative pregnancy test is required);
  • Women of childbearing age must present a negative pregnancy test at the beginning of the study and must use double barrier to contraception. Women of childbearing age are defined as menopausal if they remain menstrual for at least 1 year, or surgical sterilization or removal of the uterus before the start of the study;
  • Breast-feeding female patients;
  • Patients in a mental state who can't understand the nature, extent and possible consequences of participating in the study associated with radioisotope treatment, or there is evidence of a lack of cooperation by the patient;
  • Exclusive clinical and laboratory findings that may compromise the patient's safety or reduce the chances of obtaining satisfactory data to achieve the goal (s) of the study;
  • Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse;
  • The patient may be included in the maintenance treatment if the patient's clinical condition is stable.