Gastro-enteropancreatic Neuroendocrine TumorPhase 3NETTER-2NCT03972488
Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET
A Phase 3 study testing Lutathera, 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot) and 2.5% Lys-Arg sterile amino acid solution in people with Gastro-enteropancreatic Neuroendocrine Tumor, run by Advanced Accelerator Applications at 40 sites in 9 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Gastro-enteropancreatic Neuroendocrine Tumor
- What is being tested?
- Lutathera, 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot) and 2.5% Lys-Arg sterile amino acid solution
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 226 participants
- Where
- 40 sitesin 9 countries
- Study dates
- 8 Jan 2020to 29 Oct 2027
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
40 sites in 9 countries.
40 sites in 9 countries
Italy8 sites
A.O.di Bologna Policl.S.Orsola
Bologna
University of Genova - Oncology
Genova
Istituto Oncologico Romagnolo
Meldola
Fondazione Irccs Istituto Nazionale Tumori
Milan
Ieo, Irccs
Milan
IRCCS fondazione Pascale - Oncology
Naples
Arcispedale Santa Maria Nuova, Reggio Emilia - Oncology
Reggio Emilia
Azienda Ospedaliera Sant'Andrea - Università La Sapienza U.O.C. Mal App. Digerente e - Oncology
Roma
United States6 sites
MD Anderson Cancer Center
Houston, Texas, 77030
University of Iowa Hospitals and Clinics - Oncology
Iowa City, Iowa, 52242
University of Kentucky UK Markey Cancer Center
Lexington, Kentucky, 40536
Yale Cancer Center
New Haven, Connecticut, 06520
Mayo Clinic - Oncology
Rochester, Minnesota, 55905
USF - H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, 33612
France5 sites
CHU Paris Nord-Val de Seine
Clichy
Hospices Civils de Lyon (HCL) - Hopital Edouard Herriot
Lyon
Institut du Cancer de Montpellier - Oncology
Montpellier
CHU-Hôtel Dieu Service de Médecine Nucléaire
Nantes
Institut Gustave Roussy
Villejuif
United Kingdom5 sites
Bristol Haematology and Oncology Centre
Bristol
Guys And St Thomas Hospital
London
Kings College Hospital - Oncology
London
Royal Free Hospital, London
London
Weston Park Hospital
Sheffield
Canada4 sites
London Health Sciences Centre, University of Western Ontario - Oncology
London
Centre Hospitalier Universitaire de Quebec
Québec
Sunnybrook Health Sciences Centre
Toronto
BC Cancer Agency
Vancouver
South Korea4 sites
Seoul National University Bundang Hospital
Seongnam-si
Asan Medical Center - Oncology
Seoul
Seoul National University Hospital - Department of Internal Medicine
Seoul
Severance Hospital, Yonsei University Health System - Medical Oncology
Seoul
Spain4 sites
Hospital Universitario Vall d'Hebrón
Barcelona
Hospital General Universitario Gregorio Marañón
Madrid
Hospital Universitario Ramón y Cajal
Madrid
Hospital Universitari i Politecnic La Fe
Valencia
Germany2 sites
Universitätsklinikum Erlangen
Erlangen
Universitätsklinikum Essen - Klinik für Nuklearmedizin
Essen
Netherlands2 sites
Erasmus Medisch Centrum
Rotterdam
UMC Utrecht - Oncology
Utrecht
About this study
Official title: A Phase III Multi-center, Randomized, Open-label Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET
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.
Read the 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).
- Being tested
- Lutathera, 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot), 2.5% Lys-Arg sterile amino acid solution, High dose 60 mg octreotide long-acting repeatable
- Keywords
- Lutathera, GEP-NET, NETTER-2, 177Lu-DOTA0-TATE, Lutetium oxodotreotide, Lutetium dotatate, AAA601
- Medical subject headings
- Gastro-enteropancreatic neuroendocrine tumor
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LutatheraDrug
Also called AAA601
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)Drug
Also called SOM230
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 solutionDrug
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.
High dose 60 mg octreotide long-acting repeatableDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Lutathera® plus Octreotide LAR 30 mg (Investigational arm) | Experimental | 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. Receives: Drug: Lutathera; Drug: 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot); Drug: 2.5% Lys-Arg sterile amino acid solution |
| Octreotide LAR 60 mg (Control arm) | Active comparator | Participants were administered with octreotide LAR 60 mg (Sandostatin LAR Depot) at 4-week intervals until the completion of the Treatment Phase. Receives: Drug: High dose 60 mg octreotide long-acting repeatable |
| Optional post-progression re-treatment with Lutathera | Experimental | 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) Receives: Drug: Lutathera |
| Optional post-progression cross-over to Lutathera | Active comparator | 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). Receives: Drug: Lutathera |
| Optional post-progression re-treatment with Lutathera after cross-over | Active comparator | 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). Receives: Drug: Lutathera; Drug: High dose 60 mg octreotide long-acting repeatable |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression Free Survival (PFS) Per Central Assessment
PFS is the time from randomization to the first line progression (centrally assessed according to RECIST 1.1) or death due to any cause. Progression is defined using Response Evaluation Criteria in Solid Tumor Criteria (RECIST 1.1) as a 20% increase in the sum of diameters of all measured target lesions or unequivocal progression of non-target lesions or appearance of a new lesion.
Measured: from randomization to the first line progression or death due to any cause, up to approx. 42 months
Secondary outcomes (7)
Overall Response Rate (ORR) Per Central Assessment (Key Secondary)
ORR is defined as the percentage of patients with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Measured: Up to approx. 42 months
Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary)
TTD is defined as the first deterioration of at least 10 points from baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30): global health status, diarrhea, fatigue, and pain.
The Quality of Life Questionnaire C30 (QLQ-C30) was developed by the European Organization for Research and Treatment of Cancer (EORTC) to assess quality of life in cancer patients. It includes five function domains (physical, emotional, social, role, cognitive), eight symptoms (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, and appetite loss), as well as global health/quality-of-life and financial impact. Subjects respond on a four-point scale from "not at all" to "very much" for most items. Raw scores are linearly transformed so each score ranged a 0-100, where higher scores indicate worse symptoms (e.g., more severe/worsened) and lower scores indicate less symptoms (e.g., less severe/improvement).
Measured: Up to approx. 42 months
Disease Control Rate (DCR) Per Central Assessment
Disease Control Rate is the percentage of participants with a best overall response of complete response (CR), partial response (PR) or stable disease (SD) (centrally assessed according to RECIST 1.1). CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD).
Measured: Up to approx. 42 months
Duration of Response (DOR) Per Central Assessment
Duration of Response defined as time from first complete or partial response to progression or death due to underlying cancer according to RECIST 1.1.
Measured: Up to approx. 42 months
Rate of Adverse Events
Rate of adverse events scored according to CTCAE grade
Measured: from FPFV until end of study (about 94 months)
Rate of Laboratory Toxicities
Rate of laboratory toxicities scored according to CTCAE grade
Measured: from FPFV until end of study (about 94 months)
Overall Survival (OS)
OS is the time from randomization date until day of death due to any cause.
Measured: from FPFV until end of study (about 94 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Jun 2019
- Study start8 Jan 2020
- Primary completion20 Jul 2023
- Study completion29 Oct 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Gastro-enteropancreatic Neuroendocrine TumorStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 226 participants (actual)
Sponsor and investigators
- Lead sponsor
- Advanced Accelerator Applications
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03972488
- Sponsor's protocol ID
- CAAA601A22301
- Other IDs
- 2023-507443-10-00, 2023
- Acronym
- NETTER-2
- Status last verified
- Jan 2026
- First submitted
- 24 May 2019
- Last updated
- 21 Jan 2026
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.
Publications
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.
PubMed 38851203Ferone D, Pavel M, Herrmann K, Kunz PL, Myrehaug S, Halperin D, Chasen B, Capdevila J, Garcia-Burillo A, Tafuto S, Lastoria S, Oh DY, Yoo C, Falk S, Halfdanarson TR, Sansovini M, Gerard L, Deshayes E, Filice A, Folitar I, Zhang Y, de Herder WW, Singh S. [177Lu]Lu-DOTA-TATE plus long-acting octreotide in patients with newly diagnosed, advanced, grade 2-3, gastroenteropancreatic neuroendocrine tumours: preplanned and post-hoc efficacy analyses from the randomised, phase 3 NETTER-2 trial. EClinicalMedicine. 2026 Aug 7;98:104109. doi: 10.1016/j.eclinm.2026.104109. eCollection 2026 Aug.
PubMed 42604001Holzgreve A, Unterrainer LM, Tiling M, Mansour N, Spitzweg C, Brendel M, Ricke J, Unterrainer M, Kunz WG, Mehrens D. Cost-Effectiveness of [177Lu]Lu-DOTATATE for the Treatment of Newly Diagnosed Advanced Gastroenteropancreatic Neuroendocrine Tumors: An Analysis Based on Results of the NETTER-2 Trial. J Nucl Med. 2025 Jul 1;66(7):1075-1081. doi: 10.2967/jnumed.124.269416.
PubMed 40473457Bahri 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.
PubMed 39570708Jungels 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.
PubMed 33973550
Study at a glance
From the registry record, last updated by the sponsor on 21 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase III Multi-center, Randomized, Open-label Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET
- ClinicalTrials.gov ID
- NCT03972488
- Acronym / sponsor ID
- NETTER-2 / CAAA601A22301
- Keywords
- Lutathera, GEP-NET, NETTER-2, 177Lu-DOTA0-TATE, Lutetium oxodotreotide, Lutetium dotatate, AAA601
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 226 participants (actual)
- Lead sponsor
- Advanced Accelerator ApplicationsIndustry (pharma, biotech, devices)
- Study start
- 8 Jan 2020 (actual)
- Primary completion
- 20 Jul 2023 (actual)
- Study completion
- 29 Oct 2027 (estimated)
- First posted
- 3 Jun 2019 (actual)
- Results
- Posted 10 Oct 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Lutathera® plus Octreotide LAR 30 mg (Investigational arm) | Experimental | Drug: Lutathera, Drug: 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot), Drug: 2.5% Lys-Arg sterile amino acid solutionLutathera 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. |
| Octreotide LAR 60 mg (Control arm) | Active comparator | Drug: High dose 60 mg octreotide long-acting repeatableParticipants were administered with octreotide LAR 60 mg (Sandostatin LAR Depot) at 4-week intervals until the completion of the Treatment Phase. |
| Optional post-progression re-treatment with Lutathera | Experimental | Drug: LutatheraParticipants 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) |
| Optional post-progression cross-over to Lutathera | Active comparator | Drug: LutatheraParticipants 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). |
| Optional post-progression re-treatment with Lutathera after cross-over | Active comparator | Drug: Lutathera, Drug: High dose 60 mg octreotide long-acting repeatableParticipants 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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (25 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LutatheraAlso: AAA601Lutathera 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 | Lutathera® plus Octreotide LAR 30 mg (Investigational arm), Optional post-progression cross-over to Lutathera, Optional post-progression re-treatment with Lutathera, Optional post-progression re-treatment with Lutathera after cross-over |
| 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot)Also: SOM230Sandostatin® 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 | Lutathera® plus Octreotide LAR 30 mg (Investigational arm) |
| 2.5% Lys-Arg sterile amino acid solutionParticipants 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 | Lutathera® plus Octreotide LAR 30 mg (Investigational arm) |
| High dose 60 mg octreotide long-acting repeatableSandostatin® 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 | Octreotide LAR 60 mg (Control arm), Optional post-progression re-treatment with Lutathera after cross-over |
Primary outcome
Progression Free Survival (PFS) Per Central Assessment
Time frame: from randomization to the first line progression or death due to any cause, up to approx. 42 months
PFS is the time from randomization to the first line progression (centrally assessed according to RECIST 1.1) or death due to any cause. Progression is defined using Response Evaluation Criteria in Solid Tumor Criteria (RECIST 1.1) as a 20% increase in the sum of diameters of all measured target lesions or unequivocal progression of non-target lesions or appearance of a new lesion.
7 secondary outcomes
Overall Response Rate (ORR) Per Central Assessment (Key Secondary)
Time frame: Up to approx. 42 months
Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary)
Time frame: Up to approx. 42 months
Disease Control Rate (DCR) Per Central Assessment
Time frame: Up to approx. 42 months
Duration of Response (DOR) Per Central Assessment
Time frame: Up to approx. 42 months
Rate of Adverse Events
Time frame: from FPFV until end of study (about 94 months)
Rate of Laboratory Toxicities
Time frame: from FPFV until end of study (about 94 months)
Overall Survival (OS)
Time frame: from FPFV until end of study (about 94 months)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Jan 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 38851203Singh 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.
- Derived from this study: PubMed 42604001Ferone D, Pavel M, Herrmann K, Kunz PL, Myrehaug S, Halperin D, Chasen B, Capdevila J, Garcia-Burillo A, Tafuto S, Lastoria S, Oh DY, Yoo C, Falk S, Halfdanarson TR, Sansovini M, Gerard L, Deshayes E, Filice A, Folitar I, Zhang Y, de Herder WW, Singh S. [177Lu]Lu-DOTA-TATE plus long-acting octreotide in patients with newly diagnosed, advanced, grade 2-3, gastroenteropancreatic neuroendocrine tumours: preplanned and post-hoc efficacy analyses from the randomised, phase 3 NETTER-2 trial. EClinicalMedicine. 2026 Aug 7;98:104109. doi: 10.1016/j.eclinm.2026.104109. eCollection 2026 Aug.
- Derived from this study: PubMed 40473457Holzgreve A, Unterrainer LM, Tiling M, Mansour N, Spitzweg C, Brendel M, Ricke J, Unterrainer M, Kunz WG, Mehrens D. Cost-Effectiveness of [177Lu]Lu-DOTATATE for the Treatment of Newly Diagnosed Advanced Gastroenteropancreatic Neuroendocrine Tumors: An Analysis Based on Results of the NETTER-2 Trial. J Nucl Med. 2025 Jul 1;66(7):1075-1081. doi: 10.2967/jnumed.124.269416.
- Derived from this study: PubMed 39570708Bahri 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.
- Derived from this study: PubMed 33973550Jungels 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.
- Individual participant dataSharing planned: Yes. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
40 sites in 9 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Lutathera, 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot) and 2.5% Lys-Arg sterile amino acid solution in people with Gastro-enteropancreatic Neuroendocrine Tumor, run by Advanced Accelerator Applications at 40 sites in 9 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 21 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 40 sites in Italy, United States, France, United Kingdom, Canada and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression Free Survival (PFS) Per Central Assessment (time frame: from randomization to the first line progression or death due to any cause, up to approx. 42 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03972488, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jan 2026.