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Trial · Interventional

Active, not recruitingPhase 3Results postedRegistry data

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

Short name NETTER-2

NCTNCT03972488 (opens ClinicalTrials.gov in a new tab)Other idCAAA601A22301Other id2023-507443-10-00Other id2023

Overview

Status
Active, not recruiting
Phase
Phase 3
Enrollment
226 participants (actual)
Sponsor
Advanced Accelerator Applications · Industry
Design
Randomized · Open label (no masking)
Countries
9 countries

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

Start
8 Jan 2020
Primary completion
20 Jul 2023
Completion
29 Oct 2027 (estimated)
First posted
3 Jun 2019
Last update posted
21 Jan 2026
Conditions
Gastro-enteropancreatic Neuroendocrine Tumor

Timeline

1 trial · 1 ongoing · 1 with posted results

  • Completed
  • Ongoing
  • Not yet recruiting
  • Stopped
  • Estimated dates (est.)
  • Results posted
20202022202420262028
  1. Ph 3

    NETTER-2

    NCT03972488

    8 Jan 2020 to est. 29 Oct 2027

Registry summary

Text and fields below are the sponsor's entries at ClinicalTrials.gov, shown as posted.

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.

Interventions

  • LutatheraDrug
  • 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot)Drug
  • 2.5% Lys-Arg sterile amino acid solutionDrug
  • High dose 60 mg octreotide long-acting repeatableDrug

Arms5

  • 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).

Primary outcomes1

Outcomes the sponsor listed as primary.

  1. 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

    Registry description

    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.

Secondary outcomes(7)
  1. Overall Response Rate (ORR) Per Central Assessment (Key Secondary)

    Time frame · Up to approx. 42 months

    Registry description

    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.

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

    Time frame · Up to approx. 42 months

    Registry description

    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).

  3. Disease Control Rate (DCR) Per Central Assessment

    Time frame · Up to approx. 42 months

    Registry description

    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).

  4. Duration of Response (DOR) Per Central Assessment

    Time frame · Up to approx. 42 months

    Registry description

    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.

  5. Rate of Adverse Events

    Time frame · from FPFV until end of study (about 94 months)

    Registry description

    Rate of adverse events scored according to CTCAE grade

  6. Rate of Laboratory Toxicities

    Time frame · from FPFV until end of study (about 94 months)

    Registry description

    Rate of laboratory toxicities scored according to CTCAE grade

  7. Overall Survival (OS)

    Time frame · from FPFV until end of study (about 94 months)

    Registry description

    OS is the time from randomization date until day of death due to any cause.

Posted results

Values are shown as posted at ClinicalTrials.gov, with their units. PepBank has not converted, pooled or compared them.

Primary outcome results

Primary outcomeMedian· from randomization to the first line progression or death due to any cause, up to approx. 42 months

Progression Free Survival (PFS) Per Central Assessment

GroupValue (months)
Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm)22.8
Octreotide LAR 60 mg (Control Arm)8.5
Secondary and other outcome results(7)
Secondary outcomeNumber· Up to approx. 42 months

Overall Response Rate (ORR) Per Central Assessment (Key Secondary)

GroupValue (Percentage of participants)
Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm)43.0
Octreotide LAR 60 mg (Control Arm)9.3
Secondary outcomeMedian· Up to approx. 42 months

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

GroupValue (months)
Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm)13.2
Octreotide LAR 60 mg (Control Arm)8.6
Secondary outcomeNumber· Up to approx. 42 months

Disease Control Rate (DCR) Per Central Assessment

GroupValue (Percentage of participants)
Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm)90.7
Octreotide LAR 60 mg (Control Arm)66.7
Secondary outcomeMedian· Up to approx. 42 months

Duration of Response (DOR) Per Central Assessment

GroupValue (months)
Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm)23.3
Octreotide LAR 60 mg (Control Arm)NA
Secondary outcome· from FPFV until end of study (about 94 months)

Rate of Adverse Events

GroupValue
Secondary outcome· from FPFV until end of study (about 94 months)

Rate of Laboratory Toxicities

GroupValue
Secondary outcome· from FPFV until end of study (about 94 months)

Overall Survival (OS)

GroupValue

Adverse events, as posted

Adverse events as posted: participants affected out of participants at risk, by group
GroupDeathsSerious eventsOther events
Lutathera® Plus Octreotide LAR 30 mgLutathera 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.32 / 14730 / 147129 / 147
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.14 / 7315 / 7365 / 73
Crossover LutatheraParticipants who received Octreotide LAR in Active comparator Arm and who progressed and met cross over eligibility criteria received maximum 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles) plus octreotide long-acting (30 mg every 8 weeks)3 / 292 / 2922 / 29
Re-Treatment 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)0 / 80 / 86 / 8

Each cell reads participants affected / participants at risk, as the registry posted them.

Registry data comes from ClinicalTrials.gov. Study results come from studies, not from the registry. How PepBank works

Studies2

Studies that cite this trial.

Studies with results

0 studies on this page

Indexing hint: Randomized controlled trial · 2024

[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.

Singh et al. 2024Lancet (London, England)cited by 300

PMID 38851203DOI 10.1016/s0140-6736(24)00701-3PUB-38851203

Full text at the publisher
Publisher page

More studies

1 study on this page

PubMed tag: none · 2024

Casting a Wide NET: When Is the Optimal Time for 177Lu-Dotatate Treatment?

Bahri et al. 2024Oncology (Williston Park, N.Y.)

PMID 39570708DOI 10.46883/2024.25921029PUB-39570708

Full text at the publisher
Publisher page

Other registry references

References listed at the registry that are not in PepBank. They link to PubMed.

  • DerivedFerone 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. PMID 42604001
  • DerivedHolzgreve 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. PMID 40473457
  • DerivedJungels 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

Eligibility

Who could join, as posted.

Sex
All
Age
from 18 Years
Healthy volunteers
Not accepted
Inclusion and exclusion criteria, as posted
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

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