Study to Evaluate the Efficacy and Safety of [177Lu]Lu-DOTA-TATE in Patients With Grade 1 and Grade 2 Advanced GEP-NET

A Phase III Multi-center, Randomized, Open-label Study to Evaluate the Efficacy and Safety of [177Lu]Lu-DOTA-TATE in Patients Newly Diagnosed With Grade 1 and Grade 2 (Ki-67 <10%) Advanced GEP-NET With High Disease Burden (NETTER-3)

The purpose of the current study is to evaluate the efficacy and safety of [177Lu]Lu-DOTA-TATE plus octreotide long-acting release (LAR) versus octreotide LAR alone in newly diagnosed patients with somatostatin receptor positive (SSTR+), well differentiated Grade1 and Grade 2 (G1 and G2) (Ki-67 <10%) advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with high disease burden

The study consists of a screening phase, a treatment phase and a follow-up phase. This study compares treatment with [177Lu]Lu-DOTA-TATE plus octreotide LAR and octreotide LAR only.

Inclusion Criteria:

• Presence of metastasized or locally advanced, unresectable (curative intent), histologically proven, well differentiated Grade 1 or Grade 2 (Ki-67 <10%) gastroenteropancreatic neuroendocrine tumor (GEP-NET) diagnosed within 6 months prior to screening.

• Participants with high disease burden in the Investigator's opinion. Following criteria should be used as the guiding principle for determining high disease burden:

  • Primary tumor or a metastatic lesion > 4 cm
  • More than one tumor or metastatic lesions measuring > 2 cm
  • Elevated alkaline phosphatase > 2.5 X upper limit of normal (ULN)
  • Presence of bone metastasis
  • Presence of peritoneal metastasis
  • Symptoms due to tumor volume such as pain, fatigue, weight loss, anorexia etc.
  • Symptoms due to hormone excess requiring active management
  • Additionally, participants who, in the Investigator's opinion, have high disease burden due to their disease characteristics not specified above could also be considered eligible.

• Participants ≥ 12 years of age.

• RLI somatostatin receptor (SSTR) uptake on all target lesions (defined by RECIST v1.1 criteria) at least as high as normal liver uptake assessed within 3 months prior to randomization. Any of the RLI modalities as available (some examples are listed below) can be used as per local practice:

  • [68Ga]Ga-DOTA-TOC PET/CT or PET/MRI
  • [68Ga]Ga-DOTA-TATE PET/CT or PET/MRI
  • [64Cu]Cu-DOTA-TATE PET/CT or PET/MRI
  • Somatostatin receptor scintigraphy (SRS) (planar and/or SPECT/CT) with [111In]In-pentetreotide
  • SRS (planar and/or SPECT/CT) with [99mTc]Tc-octreotide.

• Adequate bone marrow and organ function as defined by the following laboratory values prior to receiving the first study treatment:

  • White blood cell (WBC) count ≥ 2 x 109/L
  • Platelet count ≥ 75 x 109/L
  • Hemoglobin (Hb) ≥ 8 g/dL
  • Creatinine clearance > 40 mL/min calculated by the Cockcroft Gault method
  • Total bilirubin ≤ 3 x ULN
  • Potassium within normal limits. Potassium level of up to 6.0 millimoles per liter (mmol/L) is acceptable at study entry if associated with creatinine clearance within normal limits calculated using Cockcroft-Gault formula. Mild decrease (grade 1) below lower limit of normal (LLN) is acceptable at study entry if considered not clinically significant by Investigator.

• ECOG performance status 0-1.

• Presence of at least 1 measurable site of disease.

Exclusion Criteria:

• Prior administration of a therapeutic radiopharmaceutical for GEP-NET at any time prior to randomization in the study.
• Any previous therapy with interferons, mTOR-inhibitors, chemotherapy or other systemic therapies except somatostatin analogues (SSAs) of GEP-NET. If as per Investigator's opinion a participant is candidate for such therapies, such participant must not be enrolled.
• Participant who received more than 4 cycles of prior SSAs (e.g., octreotide long-acting release) are not eligible. In addition, any participant receiving treatment with short-acting octreotide, which cannot be interrupted for 24 h before the administration of [177Lu]Lu-DOTA-TATE, or any participant receiving treatment with SSAs, which cannot be interrupted for at least 4 weeks before the administration of [177Lu]Lu-DOTA-TATE.
• Documented RECIST v1.1 progression during previous SSA treatments for the current GEP-NET at any time prior to randomization.
• Any previous radioembolization, chemoembolization and radiofrequency ablation for GEP-NET.
• Any major surgery within 12 weeks prior to randomization in the study.
• Known brain metastases.
• Participant with known intolerance to CT scans with intravenous (i.v.) contrast due to allergic reaction or renal insufficiency. If such a participant can be imaged with MRI, then the participant would not be excluded.
• Hypersensitivity to any somatostatin analogues, to the Investigational Medicinal Products (IMPs) active substance or to any of the excipients.
• Active severe urinary incontinence, severe voiding dysfunction, or urinary obstruction requiring an indwelling/condom catheter that, in the judgment of the Investigator, could prevent adhering to radiation safety instructions.

Other protocol-defined Inclusion/Exclusion criteria may apply.