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

NCT03972488 | Active Not Recruiting Phase 3 Results FDA Drug

• 2 other identifiers: CAAA601A223012023-507443-10-00
• Study Type: interventional
• Target: 226
• Locations: 9 countries
• Sites: 40

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.

Conditions

Gastro-enteropancreatic Neuroendocrine Tumor

Keywords

Lutathera; GEP-NET; NETTER-2; 177Lu-DOTA0-TATE; Lutetium oxodotreotide; Lutetium dotatate; AAA601

Outcome Measures

Primary Outcomes (1)

• 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.

  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)

  Up to approx. 42 months

• Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary)

  Up to approx. 42 months

• Disease Control Rate (DCR) Per Central Assessment

  Up to approx. 42 months

• Duration of Response (DOR) Per Central Assessment

  Up to approx. 42 months

• Rate of Adverse Events

  from FPFV until end of study (about 94 months)

Study Arms (5)

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.

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.

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)

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).

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).

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

Interventions

Lutathera 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.

Also known as: AAA601

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

2.5% Lys-Arg sterile amino acid solution 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.

Lutathera® plus Octreotide LAR 30 mg (Investigational arm)

High dose 60 mg octreotide long-acting repeatable 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.

Octreotide LAR 60 mg (Control arm); Optional post-progression re-treatment with Lutathera after cross-over

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

Also known as: SOM230

Lutathera® plus Octreotide LAR 30 mg (Investigational arm)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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%

Sponsors & Collaborators

• Advanced Accelerator Applications: lead

Study Sites (40)

Yale Cancer Center

New Haven, Connecticut, 06520, United States

Location

USF - H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

University of Iowa Hospitals and Clinics - Oncology

Iowa City, Iowa, 52242, United States

Location

University of Kentucky UK Markey Cancer Center

Lexington, Kentucky, 40536, United States

Location

Mayo Clinic - Oncology

Rochester, Minnesota, 55905, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

London Health Sciences Centre, University of Western Ontario - Oncology

London, Canada

Location

Centre Hospitalier Universitaire de Quebec

Québec, Canada

Location

Sunnybrook Health Sciences Centre

Toronto, Canada

Location

BC Cancer Agency

Vancouver, Canada

Location

CHU Paris Nord-Val de Seine

Clichy, France

Location

Hospices Civils de Lyon (HCL) - Hopital Edouard Herriot

Lyon, France

Location

Institut du Cancer de Montpellier - Oncology

Montpellier, France

Location

CHU-Hôtel Dieu Service de Médecine Nucléaire

Nantes, France

Location

Institut Gustave Roussy

Villejuif, France

Location

Universitätsklinikum Erlangen

Erlangen, Germany

Location

Universitätsklinikum Essen - Klinik für Nuklearmedizin

Essen, Germany

Location

A.O.di Bologna Policl.S.Orsola

Bologna, Italy

Location

University of Genova - Oncology

Genova, Italy

Location

Istituto Oncologico Romagnolo

Meldola, Italy

Location

Fondazione Irccs Istituto Nazionale Tumori

Milan, Italy

Location

Ieo, Irccs

Milan, Italy

Location

IRCCS fondazione Pascale - Oncology

Naples, Italy

Location

Arcispedale Santa Maria Nuova, Reggio Emilia - Oncology

Reggio Emilia, Italy

Location

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

Roma, Italy

Location

Erasmus Medisch Centrum

Rotterdam, Netherlands

Location

UMC Utrecht - Oncology

Utrecht, Netherlands

Location

Seoul National University Bundang Hospital

Seongnam-si, South Korea

Location

Asan Medical Center - Oncology

Seoul, South Korea

Location

Seoul National University Hospital - Department of Internal Medicine

Seoul, South Korea

Location

Severance Hospital, Yonsei University Health System - Medical Oncology

Seoul, South Korea

Location

Hospital Universitario Vall d'Hebrón

Barcelona, Spain

Location

Hospital General Universitario Gregorio Marañón

Madrid, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, Spain

Location

Hospital Universitari i Politecnic La Fe

Valencia, Spain

Location

Bristol Haematology and Oncology Centre

Bristol, United Kingdom

Location

Guys And St Thomas Hospital

London, United Kingdom

Location

Kings College Hospital - Oncology

London, United Kingdom

Location

Royal Free Hospital, London

London, United Kingdom

Location

Weston Park Hospital

Sheffield, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 38851203 RESULT

• 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.

  PMID: 39570708 DERIVED

• 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.

  PMID: 33973550 DERIVED

MeSH Terms

Conditions

Gastro-enteropancreatic neuroendocrine tumor

Interventions

lutetium Lu 177 dotatate; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Octreotide; pasireotide

Intervention Hierarchy (Ancestors)

Receptor-Like Protein Tyrosine Phosphatases; Protein Tyrosine Phosphatases; Phosphoric Monoester Hydrolases; Esterases; Hydrolases; Enzymes; Enzymes and Coenzymes; Intracellular Signaling Peptides and Proteins; Proteins; Amino Acids, Peptides, and Proteins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides

Results Point of Contact

• Title: Clinical Disclosure Office
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-3000

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2019
• First Posted: June 3, 2019
• Study Start: January 8, 2020
• Primary Completion: July 20, 2023
• Study Completion (Estimated): October 29, 2027
• Last Updated: January 21, 2026
• Results First Posted: October 10, 2024

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share

Locations

US (6); DE (2); FR (5); IT (8); GB (5); CA (4); ES (4); NL (2); KR (4)