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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

146 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-10-18

Study Completion Date

2031-10-31

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Neuroendocrine Tumors Intestinal Well Differentiated Endocrine Tumor Progressive Disease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

It's a prospective, national, multicenter, open-label, randomized, phase II study, to compare 2 additional cycles of Lutathera® versus active surveillance in patients who already received two cycles of "Second PRRT" (already retreated with two cycles).

Written informed consent will be collected before any study related procedures take place.

Patients previously treated with 4 cycles of Lutathera® will be registered after a first progression (clinic, biologic and/or radiologic) of their neuroendocrine tumor.

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Experimental arm

2 additional infusions of Lutathera® according to the marketing authorization schema

Group Type EXPERIMENTAL

Lutathera

Intervention Type DRUG

2 additional infusions of Lutathera®

Control arm

No treatment with active monitoring (clinical, biological and radiological follow-up) every 2 months.

Group Type NO_INTERVENTION

No interventions assigned to this group

Interventions

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Lutathera

2 additional infusions of Lutathera®

Intervention Type DRUG

Eligibility Criteria

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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.

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Deshayes Emmanuel, PHD

Role: STUDY_CHAIR

ICM Co. Ltd.

Reach out to these primary contacts for questions about participation or study logistics.

Moussion Aurore, MD

Role: CONTACT

[email protected]

+33467612446 ext. +33

Texier Emmanuelle

Role: CONTACT

[email protected]

0467613102

Role: primary

[email protected]

Reference Type DERIVED

PMID: 36550428 (View on PubMed)

Other Identifiers

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PROICM 2021-04 REL

Identifier Type: -

Identifier Source: org_study_id

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

Study Results

Basic Information

Brief Summary

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Detailed Description

Conditions

Study Design

Study Groups

Experimental arm

Lutathera

Control arm

Interventions

Lutathera

Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

Sponsors

Institut du Cancer de Montpellier - Val d'Aurelle

Responsible Party

Principal Investigators

Deshayes Emmanuel, PHD

Locations

Institut de Cancérologie de l'Ouest Site d'Angers

Institut Bergonié

CHRU Morvan

Hospices civils de LYON - GHE

Centre François Baclesse

CH Métropole de Savoie

Centre Jean Perrin

Hopital Beaujon

CHU de DIJON

CHU Grenoble Alpes (CHUGA)

CHRU Lille

Centre léon bérard

Institut Paoli Calmettes

Hôpital de la Timone

ICM Val d'Aurelle

CHU Nantes

Centre Antoine Lacassagne

Hôpital Pitié Salpétrière

Hôpital Cochin

Hôpital Haut-Lévêque

Centre Henri Becquerel

CHU de Rouen

CHU ST Etienne

Institut de Cancérologie de l'Ouest

Institut de cancérologie Strasbourg

IUCT Oncopole

CHRU Nancy Brabois

Institut Gustave Roussy

Countries

Central Contacts

Moussion Aurore, MD

Texier Emmanuelle

Facility Contacts

Sylvie GIRAUD, MD

Paul SCHWARTZ, MD

Jean-Phillipe METGES, MD

Solène CASTELLNOU, MD

Elisabeth QAUK, MD

Jean-Cyril BOURRE, MD

Anthony KELLY, MD

Louis DE MESTIER, MD

Côme LEPAGE, MD

Julie ROUX, MD

Amandine BERON, PR

Anne-Laure GIRAUDET, MD

Nathalie CHARRIER, MD

David TAIEB, PR

Emmanuel DESHAYES, MD

Catherine ANSQUER, MD

Danielle BENISVY, MD

Charlotte LUSSEY, MD

Florence TENENBAUM, MD