Clinical Trial Finder

Inclusion Criteria:

• - Presence of metastasized or locally advanced, inoperable (curative intent) histologically proven, well differentiated Grade 2 or Grade 3 gastroenteropancreatic neuroendocrine (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/MRI scans, 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 MRI when 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 the study, 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 of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study treatment period (including cross-over and re-treatment, if applicable) and for 7 months after study drug discontinuation.

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

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

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

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

• - Any previous radioembolization, chemoembolization and radiofrequency ablation for GEP-NET.

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

• - Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to screening in the study.

Patients with a history of brain metastases must have a head CT or MRI with contrast to document stable disease prior to randomization in the study.

• - Uncontrolled congestive heart failure (NYHA II, III, IV).

Patients with history of congestive heart failure who do not violate this exclusion criterion will undergo an evaluation of their cardiac ejection fraction prior to randomization via echocardiography. The results from an earlier assessment (not exceeding 30 days prior to randomization) may substitute the evaluation at the discretion of the Investigator, if no clinical worsening is noted. The patient's measured cardiac ejection fraction in these patients must be ≥40% before randomization.

• - QTcF > 470 msec for females and QTcF > 450 msec for males or congenital long QT syndrome.

• - 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 study enrolment.

• - Any patient receiving treatment with short-acting octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of Lutathera, or any patient receiving treatment with SSAs (e.g. octreotide long-acting), which cannot be interrupted 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 the study.

• - 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 carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.

• - Patient with known incompatibility to CT Scans with IV contrast due to allergic reaction or renal insufficiency.

If such a patient can be imaged with MRI, then the patient would not be excluded.

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

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

The study consisted of a screening phase, a treatment phase, an optional cross-over phase for subjects assigned to the control arm, optional re-treatment phase for subjects assigned to the Lutathera arm, and a follow-up phase. This study compared treatment with Lutathera (7.4 GBq/200 mCi 4 × administrations every 8 weeks ± 1 week; cumulative dose: 29.6 GBq/800mCi) plus octreotide long-acting release (LAR) (30 mg every 8 weeks during Lutathera treatment and every 4 weeks after last Lutathera treatment) and high dose octreotide LAR (60 mg every 4 weeks).

Arms

Experimental: Lutathera® plus Octreotide LAR 30 mg (Investigational arm)

Lutathera treatment consisted of a cumulative administered radioactivity of 29.6 GBq (800mCi) (7.4 GBq/200 mCi x 4 administrations every 8 +/- 1 week). Participants in the Lutathera arm were concomitantly administered with octreotide LAR 30 mg (Sandostatin LAR Depot) the day after each administration of Lutathera and no earlier than 4 hours after completion of the Lutathera infusion. Once Lutathera treatment completed, participants continued the 4-week interval administrations of 30 mg octreotide LAR until the completion of the Treatment Phase. Concomitantly with Lutathera, sterile amino acid solution was administered to minimize renal radiation exposure during Lutathera treatment.

Active Comparator: Octreotide LAR 60 mg (Control arm)

Participants were administered with octreotide LAR 60 mg (Sandostatin LAR Depot) at 4-week intervals until the completion of the Treatment Phase.

Experimental: Optional post-progression re-treatment with Lutathera

Participants who received Lutathera in experimental arm and who progressed and met re-treatment eligibility criteria received additional 2 - 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles)

Active Comparator: Optional post-progression cross-over to Lutathera

Participants who received Octreotide LAR in Active comparator arm and who progressed and met cross-over eligibility criteria received maximum 4 cycles of Lutaathera (7.4 GBq/200 mCi x 4 cycles) plus octreotide long-acting (30 mg every 8 weeks).

Active Comparator: Optional post-progression re-treatment with Lutathera after cross-over

Participants who received Octreotide LAR in Active comparator arm subsequently entered cross-over, received Lutathera in cross-over, progressed for the second time and met re-treatment eligibility criteria could receive additional 2 - 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles).

Interventions

Drug: - Lutathera

Lutathera is a sterile radiopharmaceutical supplied as a ready-to-use solution for infusion containing 177Lu-DOTA0-Tyr3-octreotate as a drug substance with a volumetric activity of 370 MBq/mL at reference date and time (calibration time). Each Lutathera infusion continued for 30 min.

Drug: - 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot)

Sandostatin® LAR Depot (octreotide LAR) is a pharmaceutical that was available in single-use kits containing a 6-mL vial of 10 mg, 20 mg, or 30 mg strength for intramuscular injection, a syringe containing 2.5 mL of diluent, two sterile 1½" 19-gauge needles, and two alcohol wipes.

Drug: - 2.5% Lys-Arg sterile amino acid solution

Participants who received Lutathera were administered a concomitant 2.5% Lys-Arg solution for kidney protection, with each Lutathera dose. The 2.5% Lys-Arg solution was administered intravenously for 4 hours (infusion rate: 250 ml/h); the infusion was to start 30 minutes prior to the start of the Lutathera infusion and continue during (30 min) and up to at least 3 hours after the Lutathera infusion.

Drug: - High dose 60 mg octreotide long-acting repeatable

Sandostatin® LAR Depot (octreotide LAR) is a pharmaceutical that was available in single-use kits containing a 6-mL vial of 10 mg, 20 mg, or 30 mg strength for intramuscular injection, a syringe containing 2.5 mL of diluent, two sterile 1½" 19-gauge needles, and two alcohol wipes.