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

Neuroendocrine Tumors Clinical Trial

— ReLUTH  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04954820
• Other study ID #: PROICM 2021-04 REL
• Status: Recruiting
• Phase: Phase 2
• Start date: October 18, 2021
• Est. completion date: September 2029

Study information

• Verified date: June 2023
• Source: Institut du Cancer de Montpellier - Val d'Aurelle
• Contact: Moussion Aurore, MD
• Phone: +33467612446
• Email: aurore.moussion[@]icm.unicancer.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 146
• Est. completion date: September 2029
• Est. primary completion date: March 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ß-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.

Related Conditions & MeSH terms

• Disease Progression
• Endocrine Gland Neoplasms
• Neoplasms
• Neuroendocrine Tumors
• Progressive Disease

Intervention

Drug:
• Lutathera
2 additional infusions of Lutathera®

Locations

Country	Name	City	State
France	Institut de Cancérologie de l'Ouest Site d'Angers	Angers
France	Institut Bergonié	Bordeaux
France	CHRU Morvan	Brest
France	Hospices civils de LYON - GHE	Bron
France	Centre François Baclesse	Caen
France	Centre Jean Perrin	Clermont-Ferrand
France	CHU de DIJON	Dijon
France	CHU Grenoble Alpes (CHUGA)	La Tronche
France	CHRU Lille	Lille
France	Centre léon bérard	Lyon
France	Hôpital de la Timone	Marseille
France	ICM Val d'Aurelle	Montpellier
France	CHU Nantes	Nantes
France	Centre Antoine Lacassagne	Nice
France	Hôpital Cochin	Paris
France	Hôpital Pitié Salpétrière	Paris
France	Hôpital Haut-Lévêque	Pessac
France	Centre Henri Becquerel	Rouen
France	CHU de Rouen	Rouen
France	Institut de Cancérologie de l'Ouest	Saint-Herblain
France	Institut de cancérologie Strasbourg	Strasbourg
France	IUCT Oncopole	Toulouse
France	CHRU Nancy Brabois	Vandœuvre-lès-Nancy
France	Institut Gustave Roussy	Villejuif

Sponsors (1)

Lead Sponsor	Collaborator
Institut du Cancer de Montpellier - Val d'Aurelle

Country where clinical trial is conducted

France, 

References & Publications (11)

Del Prete M, Buteau FA, Arsenault F, Saighi N, Bouchard LO, Beaulieu A, Beauregard JM. Personalized 177Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: initial results from the P-PRRT trial. Eur J Nucl Med Mol Imaging. 2019 Mar;46(3):728-742. doi: 10.1007/s00259-018-4209-7. Epub 2018 Nov 30. — View Citation

Gleisner KS, Brolin G, Sundlov A, Mjekiqi E, Ostlund K, Tennvall J, Larsson E. Long-Term Retention of 177Lu/177mLu-DOTATATE in Patients Investigated by gamma-Spectrometry and gamma-Camera Imaging. J Nucl Med. 2015 Jul;56(7):976-84. doi: 10.2967/jnumed.115.155390. Epub 2015 May 21. — View Citation

Rudisile S, Gosewisch A, Wenter V, Unterrainer M, Boning G, Gildehaus FJ, Fendler WP, Auernhammer CJ, Spitzweg C, Bartenstein P, Todica A, Ilhan H. Salvage PRRT with 177Lu-DOTA-octreotate in extensively pretreated patients with metastatic neuroendocrine tumor (NET): dosimetry, toxicity, efficacy, and survival. BMC Cancer. 2019 Aug 8;19(1):788. doi: 10.1186/s12885-019-6000-y. — View Citation

Sabet A, Haslerud T, Pape UF, Sabet A, Ahmadzadehfar H, Grunwald F, Guhlke S, Biersack HJ, Ezziddin S. Outcome and toxicity of salvage therapy with 177Lu-octreotate in patients with metastatic gastroenteropancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2014 Feb;41(2):205-10. doi: 10.1007/s00259-013-2547-z. Epub 2013 Sep 13. — View Citation

Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Oberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. doi: 10.1056/NEJMoa1607427. — View Citation

Strosberg J, Wolin E, Chasen B, Kulke M, Bushnell D, Caplin M, Baum RP, Kunz P, Hobday T, Hendifar A, Oberg K, Sierra ML, Thevenet T, Margalet I, Ruszniewski P, Krenning E; NETTER-1 Study Group. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol. 2018 Sep 1;36(25):2578-2584. doi: 10.1200/JCO.2018.78.5865. Epub 2018 Jun 7. — View Citation

Sundlov A, Sjogreen-Gleisner K, Svensson J, Ljungberg M, Olsson T, Bernhardt P, Tennvall J. Individualised 177Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry. Eur J Nucl Med Mol Imaging. 2017 Aug;44(9):1480-1489. doi: 10.1007/s00259-017-3678-4. Epub 2017 Mar 22. — View Citation

van Essen M, Krenning EP, Kam BL, de Herder WW, Feelders RA, Kwekkeboom DJ. Salvage therapy with (177)Lu-octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumors. J Nucl Med. 2010 Mar;51(3):383-90. doi: 10.2967/jnumed.109.068957. Epub 2010 Feb 11. — View Citation

Vaughan E, Machta J, Walker M, Toumpanakis C, Caplin M, Navalkissoor S. Retreatment with peptide receptor radionuclide therapy in patients with progressing neuroendocrine tumours: efficacy and prognostic factors for response. Br J Radiol. 2018 Nov;91(1091):20180041. doi: 10.1259/bjr.20180041. Epub 2018 Mar 20. — View Citation

Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008 Jun 20;26(18):3063-72. doi: 10.1200/JCO.2007.15.4377. — View Citation

Yordanova A, Mayer K, Brossart P, Gonzalez-Carmona MA, Strassburg CP, Essler M, Ahmadzadehfar H. Safety of multiple repeated cycles of 177Lu-octreotate in patients with recurrent neuroendocrine tumour. Eur J Nucl Med Mol Imaging. 2017 Jul;44(7):1207-1214. doi: 10.1007/s00259-017-3652-1. Epub 2017 Mar 1. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	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	Evaluate the impact of two additional cycles of Lutathera® (one injection every two months), compared to active surveillance in term of Safety	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)
Secondary	Evaluate the impact of two additional cycles of Lutathera® (one injection every two months), compared to active surveillance in term of Progression free survival	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,
Secondary	Evaluate the impact of two additional cycles of Lutathera® (one injection every two months), compared to active surveillance in term of Overall survival	the time from randomization until death from any cause.	the time without death during 5 years after the treatment
Secondary	To assess quality of life of general patient	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
Secondary	To assess quality of life of gastrointestinal neuroendocrine tumor	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

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