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

NCT ID: NCT03972488

Last Updated: 2026-01-21

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 226 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-08
• Study Completion Date: 2027-10-29

Brief Summary

The aim of NETTER-2 was to determine if Lutathera in combination with long-acting octreotide prolongs progression free survival (PFS) in gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients with high proliferation rate tumors (G2 and G3), when given as a first line treatment compared to treatment with high dose (60 mg) long-acting octreotide. Somatostatin analog (SSA) naive patients were eligible, as well as patients previously treated with SSAs in the absence of progression.

Detailed Description

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).

Conditions

Gastro-enteropancreatic Neuroendocrine Tumor

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Lutathera

Intervention Type: DRUG

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.

30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot)

Intervention Type: DRUG

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.

2.5% Lys-Arg sterile amino acid solution

Intervention Type: DRUG

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.

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.

Group Type: ACTIVE_COMPARATOR

High dose 60 mg octreotide long-acting repeatable

Intervention Type: DRUG

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.

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)

Group Type: EXPERIMENTAL

Lutathera

Intervention Type: DRUG

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.

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).

Group Type: ACTIVE_COMPARATOR

Lutathera

Intervention Type: DRUG

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.

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).

Group Type: ACTIVE_COMPARATOR

Lutathera

Intervention Type: DRUG

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.

High dose 60 mg octreotide long-acting repeatable

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

AAA601; SOM230

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Advanced Accelerator Applications

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Yale Cancer Center

New Haven, Connecticut, United States

USF - H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

University of Iowa Hospitals and Clinics - Oncology

Iowa City, Iowa, United States

University of Kentucky UK Markey Cancer Center

Lexington, Kentucky, United States

Mayo Clinic - Oncology

Rochester, Minnesota, United States

MD Anderson Cancer Center

Houston, Texas, United States

London Health Sciences Centre, University of Western Ontario - Oncology

London, , Canada

Centre Hospitalier Universitaire de Quebec

Québec, , Canada

Sunnybrook Health Sciences Centre

Toronto, , Canada

BC Cancer Agency

Vancouver, , Canada

CHU Paris Nord-Val de Seine

Clichy, , France

Hospices Civils de Lyon (HCL) - Hopital Edouard Herriot

Lyon, , France

Institut du Cancer de Montpellier - Oncology

Montpellier, , France

CHU-Hôtel Dieu Service de Médecine Nucléaire

Nantes, , France

Institut Gustave Roussy

Villejuif, , France

Universitätsklinikum Erlangen

Erlangen, , Germany

Universitätsklinikum Essen - Klinik für Nuklearmedizin

Essen, , Germany

A.O.di Bologna Policl.S.Orsola

Bologna, , Italy

University of Genova - Oncology

Genova, , Italy

Istituto Oncologico Romagnolo

Meldola, , Italy

Fondazione Irccs Istituto Nazionale Tumori

Milan, , Italy

Ieo, Irccs

Milan, , Italy

IRCCS fondazione Pascale - Oncology

Napoli, , Italy

Arcispedale Santa Maria Nuova, Reggio Emilia - Oncology

Reggio Emilia, , Italy

Azienda Ospedaliera Sant'Andrea - Università La Sapienza U.O.C. Mal App. Digerente e - Oncology

Roma, , Italy

Erasmus Medisch Centrum

Rotterdam, , Netherlands

UMC Utrecht - Oncology

Utrecht, , Netherlands

Seoul National University Bundang Hospital

Seongnam-si, , South Korea

Asan Medical Center - Oncology

Seoul, , South Korea

Seoul National University Hospital - Department of Internal Medicine

Seoul, , South Korea

Severance Hospital, Yonsei University Health System - Medical Oncology

Seoul, , South Korea

Hospital Universitario Vall d'Hebrón

Barcelona, , Spain

Hospital General Universitario Gregorio Marañón

Madrid, , Spain

Hospital Universitario Ramón y Cajal

Madrid, , Spain

Hospital Universitari i Politecnic La Fe

Valencia, , Spain

Bristol Haematology and Oncology Centre

Bristol, , United Kingdom

Guys And St Thomas Hospital

London, , United Kingdom

Kings College Hospital - Oncology

London, , United Kingdom

Royal Free Hospital, London

London, , United Kingdom

Weston Park Hospital

Sheffield, , United Kingdom

Countries

United States; Canada; France; Germany; Italy; Netherlands; South Korea; Spain; United Kingdom

References

Singh S, Halperin D, Myrehaug S, Herrmann K, Pavel M, Kunz PL, Chasen B, Tafuto S, Lastoria S, Capdevila J, Garcia-Burillo A, Oh DY, Yoo C, Halfdanarson TR, Falk S, Folitar I, Zhang Y, Aimone P, de Herder WW, Ferone D; all the NETTER-2 Trial Investigators. [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high-dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. 2024 Jun 29;403(10446):2807-2817. doi: 10.1016/S0140-6736(24)00701-3. Epub 2024 Jun 5.

Reference Type: RESULT

PMID: 38851203 (View on PubMed)

Bahri N, Crook C, Daneng Li. Casting a Wide NET: When Is the Optimal Time for 177Lu-Dotatate Treatment? Oncology (Williston Park). 2024 Nov 5;38(11):442-443. doi: 10.46883/2024.25921029.

Reference Type: DERIVED

PMID: 39570708 (View on PubMed)

Jungels C, Deleporte A. State of the art and future directions in the systemic treatment of neuroendocrine neoplasms. Curr Opin Oncol. 2021 Jul 1;33(4):378-385. doi: 10.1097/CCO.0000000000000740.

Reference Type: DERIVED

PMID: 33973550 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2023-507443-10-00

Identifier Type: OTHER

Identifier Source: secondary_id

CAAA601A22301

Identifier Type: -

Identifier Source: org_study_id