Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET

Inclusion Criteria:

• Presence of metastasized or locally advanced, inoperable (curative intent)histologically proven, well differentiated Grade 2 or Grade 3 gastroenteropancreaticneuroendocrine (GEP-NET) tumor diagnosed within 6 months prior to screening.

• Ki67 index ≥10 and ≤ 55%

• Patients ≥ 15 years of age and a body weight of > 40 kg at screening

• Expression of somatostatin receptors on all target lesions documented by CT/MRIscans, assessed by any of the following somatostatin receptor imaging (SRI)modalities within 3 months prior to randomization: [68Ga]-DOTA-TOC (e.g.Somakit-TOC®) PET/CT (or MRI when applicable based on target lesions) imaging, [68Ga]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging (e.g. NETSPOT®), Somatostatin Receptor scintigraphy (SRS) with [111In]-pentetreotide (Octreoscan® SPECT/CT), SRS with [99mTc]-Tektrotyd, [64Cu]-DOTA-TATE PET/CT (or MRIwhen applicable based on target lesions) imaging.

• The tumor uptake observed in the target lesions must be > normal liver uptake.

• Karnofsky Performance Score (KPS) ≥ 60

• Presence of at least 1 measurable site of disease

• Patients who have provided a signed informed consent form to participate in thestudy, obtained prior to the start of any protocol related activities

Exclusion Criteria:

• Creatinine clearance < 40 mL/min calculated by the Cockroft Gault method

• Hb concentration < 5.0 mmol/L (<8.0 g/dL); WBC < 2x10E9/L (2000/mm3); platelets < 75x10E9/L (75x10E3/mm3)

• Total bilirubin > 3 x ULN

• Serum albumin < 3.0 g/dL unless prothrombin time is within the normal range

• Pregnancy or lactation

• Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, are not allowed to participate in this study UNLESS they areusing highly effective methods of contraception throughout the study treatmentperiod (including cross-over and re-treatment, if applicable) and for 7 months afterstudy drug discontinuation

• Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization inthe study.

• Documented RECIST progression to previous treatments for the current GEP-NET at anytime prior to randomization

• Patients for whom in the opinion of the investigator other therapeutic options (egchemo-, targeted therapy) are considered more appropriate than therapy offered inthe study, based on patient and disease characteristics

• Any previous therapy with Interferons, Everolimus (mTOR-inhibitors), chemotherapy orother systemic therapies for GEP-NET administered for more than 1 month or within 12weeks prior to randomization in the study.

• Any previous radioembolization, chemoembolization and radiofrequency ablation forGEP-NET

• Any surgery within 12 weeks prior to randomization in the study

• Known brain metastases, unless these metastases have been treated and stabilized forat least 24 weeks, prior to screening in the study. Patients with a history of brainmetastases must have a head CT or MRI with contrast to document stable disease priorto randomization in the study.

• Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with history ofcongestive heart failure who do not violate this exclusion criterion will undergo anevaluation of their cardiac ejection fraction prior to randomization viaechocardiography. The results from an earlier assessment (not exceeding 30 daysprior to randomization) may substitute the evaluation at the discretion of theInvestigator, if no clinical worsening is noted. The patient's measured cardiacejection fraction in these patients must be ≥40% before randomization.

• QTcF > 470 msec for females and QTcF > 450 msec for males or congenital long QTsyndrome

• Uncontrolled diabetes mellitus as defined by hemoglobin A1c value > 7.5%

• Hyperkaleamia > 6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to studyenrolment

• Any patient receiving treatment with short-acting octreotide, which cannot beinterrupted for 24 h before and 24 h after the administration of Lutathera, or anypatient receiving treatment with SSAs (e.g. octreotide long-acting), which cannot beinterrupted for at least 6 weeks before the administration of Lutathera.

• Patients with any other significant medical, psychiatric, or surgical condition,currently uncontrolled by treatment, which may interfere with the completion of thestudy.

• Prior external beam radiation therapy to more than 25% of the bone marrow.

• Current spontaneous urinary incontinence

• Other known co-existing malignancies except non-melanoma skin cancer and carcinomain situ of the uterine cervix, unless definitively treated and proven no evidence ofrecurrence for 5 years

• Patient with known incompatibility to CT Scans with IV contrast due to allergicreaction or renal insufficiency. If such a patient can be imaged with MRI, then thepatient would not be excluded.

• Hypersensitivity to any somatostatin analogues, the IMPs active substance or to anyof the excipients.

• Patients who have participated in any therapeutic clinical study/received anyinvestigational agent within the last 30 days