Assessment of Retreatment With Lutathera® in Patients With New Progression of Intestinal Well-differenciated NET (ReLUTH)

June 2, 2026 updated by: Institut du Cancer de Montpellier - Val d'Aurelle

A Prospective Randomized Phase II Study Assess the Schema of Retreatment With Lutathera® ([177LU]LU-DOTA-TATE) in Patients With New Progression of Intestinal Well-differenciated Neuroendocrine Tumor

In France, since the reimbursement of Lutathera®, this treatment is allowed for retreatment if patients still fulfill the criteria of its indication and 4 news cycles could be proposed. However, clinical practices are heterogeneous regarding the number of new cycles and most teams perform only two additional cycles (every 8 weeks). Therefore, the coordinator propose to evaluate the efficacy of two additional cycle of Lutathera® versus active surveillance in patients already retreated with two cycles Lutathera® for a new progression of intestinal neuroendocrine tumor and who previously received the 4 cycles of treatment with a clinical benefit.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The NETTER-1 clinical trial compared peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-TATE (Lutathera®) every eight weeks (4 doses) plus 30 mg octreotide LAR every 4 weeks with high dose (60 mg) of octreotide LAR every 4 weeks in patients with progressive and unresectable midgut neuroendocrine well differentiated (G1, G2) tumors (NETs) with somatostatin-receptor positive imaging (SSTRi+). Lutathera® improves both median progression free survival (PFS) (28.4 months vs 8.5 months) and median overall survival (OS) ("not reached" vs 27.4 months) with a follow-up of 42 months. Lutathera® also has an impact on quality of life. Therefore, this treatment was approved by the European Medicines Agency and is now reimbursed in France in that specific indication. Despite these promising results, progression will occur in most of patients within a variable time with limited treatment options left. Retreatment with additional cycles of Lutathera® may be an option. Van der Zwan et al. showed in a large retrospective cohort (the "ROTTERDAM cohort") a median PFS of 14.6 months after retreatment with two additional cycles of PRRT with [177Lu]Lu-DOTA-TATE and a significant longer OS than in the non-randomized control group. Interestingly, the safety was similar in salvage group than in initial PRRT: no grade (G) 3/4 renal toxicity occurred and hematological toxicities were similar to the group of patients who received the initial treatment (4 cycles). In a smaller cohort of 15 patients, Yordanova et al. showed that 8 or more cycles of [177Lu]Lu-DOTA-TATE were well tolerated and led to a survival improvement. In this study, each salvage therapy consisted of 2 or 3 cycles. No severe (G3, G4) renal toxicity or G4 adverse event occurred. In France, since the reimbursement of Lutathera®, this treatment is allowed for retreatment if patients still fulfill the criteria of its indication and 4 news cycles could be proposed. However, clinical practices are heterogeneous regarding the number of new cycles and most teams perform only two additional cycles (every 8 weeks). Therefore, the coordinator propose to evaluate the efficacy of two additional cycle of Lutathera® versus active surveillance in patients already retreated with two cycles Lutathera® for a new progression of intestinal neuroendocrine tumor and who previously received the 4 cycles of treatment with a clinical benefit.

Study Type

Interventional

Enrollment (Estimated)

146

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age ≥ 18 years,
  • Histologically proven intestinal G1 or G2 neuroendocrine tumors (NET),
  • Patient previously treated with 4 cycles of Lutathera® (defined as "First PRRT"),
  • Disease control after "First PRRT" ≥ 12 months,
  • Patient presenting a progression of disease (clinic, biologic and/or radiologic) after a first PRRT,
  • Decision of retreatment with Lutathera® (defined as "Second PRRT") validated by RENATEN and/or multidisciplinary tumor board and in the scope of the French reimbursement process,
  • ECOG performance status 0-2,
  • Life expectancy ≥ 6 months as prognosticated by the physician,
  • Somatostatin receptor imaging positive imaging (SSTRi+) disease within 4 months prior to inclusion : (may be PET imaging (68Ga-based SSTR analogues) or scintigraphy imaging: 111In-pentetreotide or 99mTc-octreotide. At least 90% of lesions must be positive for SSTRi with a significant uptake (>= liver of surrounding tissue),
  • Measurable disease per RECIST 1.1 (Appendix 1), on CT/MRI scans, defined as at least 1 lesion with ≥ 1 cm in longest diameter, and ≥ 2 radiological tumors lesions in total,
  • Adequate bone marrow reserve (Hb > 8 g/dl, neutrophils ≥ 1500/mm³ and platelets ≥ 80 000/mm³),
  • Negative pregnancy test in women of childbearing potential (the β-HCG dosage must be ≤ 4 days before inclusion). Women who have no reproductive potential are postmenopausal women or women who have had permanent sterilization, eg. tubal occlusion, hysterectomy, bilateral salpingectomy),
  • Effective contraception in men or women of childbearing or pre-menopausal age and up to a minimum of 6 months following the end of treatment,
  • Patient´s signed written informed consent,
  • Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures,
  • Affiliation to the French Social Security System

Exclusion Criteria:

  • Patient who did not respond (no CR, PR or SD) to "first PRRT".
  • Radiological progression after two cycles of "Second PRRT" according to RECIST version 1.1,
  • Grade 4 hematotoxicity and/or nephrotoxicity during the initial PRRT, or unresolved AEs categorized as Grade 2 or higher (as per Common Terminology Criteria for Adverse Events (CTCAE v5.0) from previous PRRT cycles or any other therapy for NET, excluding alopecia and peripheral neuropathy,
  • Pancreatic NET,
  • NeuroEndocrine Carcinoma,
  • Prior external beam radiation therapy to more than 25% of the bone marrow,
  • Severe renal (estimated Glomerular Filtration Rate (GFR) according to Modification of Diet in Renal Disease (MDRD) < 40 mL/min or nephrotic syndrome) or hepatic insufficiency (Alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) > 2.5 x ULN or ALT/AST > 5 x ULN if liver function abnormalities are due to the underlying malignancy and/or total serum bilirubin > 2.5 x ULN),
  • Serum albumin < 3.0 g/dL unless prothrombin time is within the normal range,
  • Uncontrolled diabetes mellitus as defined by a fasting blood glucose above 2 ULN,
  • Uncontrolled decompensated heart failure, myocardial infarction uncontrolled, stroke, pulmonary embolism or revascularization procedure, unstable angina pectoris, uncontrolled cardiac arrhythmia, and clinically significant bradycardia during the last 12 months,
  • Hypertension that cannot be controlled despite medications (≥ 160/95 mmHg despite optimal medical therapy)
  • Brain metastases (unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrolment in the study. Patients with a history of brain metastases must have a head CT scan with contrast or MRI to document stable disease prior to enrolment in the study),
  • Pregnancy or breast feeding,
  • Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results,
  • Known hypersensitivity to any of the study drugs, study drug classes, or any constituent of the products,
  • Concomitant participation or participation within the last 30 days in another clinical trial,
  • History of other solid tumor in 5 years before the inclusion excepted of cancer in situ of the cervix and skin cancer (basal or squamous cell) treated and controlled.
  • Legal incapacity or physical, psychological or mental status interfering with the patient's ability to sign the informed consent or to terminate the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Experimental arm
2 additional infusions of Lutathera® according to the marketing authorization schema
Drug: Lutathera
2 additional infusions of Lutathera®
No Intervention: Control arm
No treatment with active monitoring (clinical, biological and radiological follow-up) every 2 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluate the efficacy of two additional cycles of Lutathera® (one injection every two months), compared to active surveillance during 6 months in patients already retreated with two cycles.
Time Frame: assessement every cycle (every 8 weeks) 6 months from randomization
defined as a change of tumoral assessment (Complete Response, Partial Response and Stable Disease from RECIST v1.1) with an evaluation every 2 months.
assessement every cycle (every 8 weeks) 6 months from randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluate the impact of two additional cycles of Lutathera® (one injection every two months), compared to active surveillance in term of Safety
Time Frame: during 6 months in patients already retreated with two cycles (each cycle is 8 weeks)
Number and type of adverse event according to NCI-CTCAE v5.0.
during 6 months in patients already retreated with two cycles (each cycle is 8 weeks)
Evaluate the impact of two additional cycles of Lutathera® (one injection every two months), compared to active surveillance in term of Progression free survival
Time Frame: the time without progression of disease during 5 years after the treatment,
the time from randomization until documented disease progression on radiological tumor assessment (as evaluated by an independent central review by radiologists blindly of the treatment assignments according to RECIST v1.1) or death from any cause, whichever occurs first
the time without progression of disease during 5 years after the treatment,
Evaluate the impact of two additional cycles of Lutathera® (one injection every two months), compared to active surveillance in term of Overall survival
Time Frame: the time without death during 5 years after the treatment
the time from randomization until death from any cause.
the time without death during 5 years after the treatment
To assess quality of life of general patient
Time Frame: during and after treatment in both arm : every 8 wweks during the treatment, every 3 months during 1 year post treatment and every year during 4 years post treatment
Quality of life will be measured by EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer, Quality-of-life questionnaire C30, no min and max values)
during and after treatment in both arm : every 8 wweks during the treatment, every 3 months during 1 year post treatment and every year during 4 years post treatment
To assess quality of life of gastrointestinal neuroendocrine tumor
Time Frame: during and after treatment in both arm : every 8 wweks during the treatment, every 3 months during 1 year post treatment and every year during 4 years post treatment
Quality of life will be measured by EORTC GI.NET21 questionnaire (European Organisation for Research and Treatment of Cancer, gastrointestinal neuroendocrine tumor, no min and max values)
during and after treatment in both arm : every 8 wweks during the treatment, every 3 months during 1 year post treatment and every year during 4 years post treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Institut du Cancer de Montpellier - Val d'Aurelle

Investigators

  • Study Chair: Deshayes Emmanuel, PHD, ICM Co. Ltd.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 18, 2021

Primary Completion (Estimated)

October 1, 2033

Study Completion (Estimated)

October 1, 2033

Study Registration Dates

First Submitted

June 11, 2021

First Submitted That Met QC Criteria

June 28, 2021

First Posted (Actual)

July 8, 2021

Study Record Updates

Last Update Posted (Actual)

June 4, 2026

Last Update Submitted That Met QC Criteria

June 2, 2026

Last Verified

June 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PROICM 2021-04 REL

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All data will be available after publication of the results in peer-reviewed revues, and in national and international meetings. It includes all de-identified participants' data, the study protocol, the statistical analysis plan and the clinical study report. The corresponding author will provide data and datasets generated and/or analyzed during the study upon reasonable request.

IPD Sharing Time Frame

Access to study data upon written detailed request sent to ICM, from 6 months until 5 years after publication of summary data.

IPD Sharing Access Criteria

The data shared will be limit to that required for independent mandated verification of the published results, the applicant will need authorization from ICM for personal access, and data will only be transferred after signing of a data access agreement.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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