Randomized Interval Assessment Trial of Lu177-Dotatate in Slowly Progressive G1-2 Advanced Midgut Neuroendocrine Tumors

NCT06878664 | Recruiting Phase 3 DMC

• 2 other identifiers: RLTTio2023 / GETNE T24212024-517921-14-00
• Study Type: interventional
• Target: 166
• Locations: 2 countries
• Sites: 21

Brief Summary

This is a randomized Phase II/late phase I de-escalation clinical trial with approved investigational medicinal products in new use condition, low intervention. Disease under study Patients with unresectable or metastatic, slowly progressive, well-differentiated (Grade1 and Grade2), somatostatin receptor-positive midgut neuroendocrine tumors (GEP-NETs). It is planned to randomize 166 patients with a histologically confirmed diagnosis of slowly progressive grade 1 or grade 2 advanced midgut neuroendocrine tumors (NETs) candidates to receive 177Lu-Dotatate targeted radioligand therapy (RLT). Patients are required to have SSTR+ disease, as evidenced on somatostatin receptor imaging. Patients will be randomized into two arms:

1. 1.control arm: regimen 177Lu-Dotatate every 8 weeks (q8w)
2. 2.experimental arm: regimen 177Lu-Dotatate every 16 weeks (q16w)

Conditions

Grade1-2 Advanced Midgut Neuroendocrine Tumors (NETs)

Keywords

midgut; Neuroendocrine Tumors; Lu177-Dotatate

Outcome Measures

Primary Outcomes (1)

• Rate of Grade 2-5 hematological toxicity

  The primary endpoint for the RIALTO trial is the frequency of Grade 2-5 hematological toxicity (worst per patient) from initiation of treatment with RLT up to 24 months thereafter according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5)

  Throughout the study period, from initiation of treatment with RLT up to 24 months

Secondary Outcomes (31)

• Best hormonal response

  24 months

• Best radiological response

  24 months

• Duration of response (DoR)

  Throughout the study period, from initiation of treatment with RLT up to 24 months

• Objective response rate (ORR)

  Throughout the study period, from initiation of treatment with RLT up to 24 months

• Disease control rate (DCR)

  Throughout the study period, from initiation of treatment with RLT up to 24 months

Study Arms (2)

177Lu-Dotatate every 16 weeks

EXPERIMENTAL

Experimental arm: 1. Treatment with 177Lu-Dotatate (7.4 Gigabecquerel/cycle) during 30 min intravenous infusion every 16 weeks (q16w) x 4 cycles 2. Renal protection starting 30 minutes before targeted radioligand therapy (RLT) lasting 4 hours (iv amino acid solution of 14.4-20g of lysine and 14.9-20.7g of arginine in 1 to 2 liters of solution) 3. Long-acting standard doses of SSA (Lanreotide autogel 120 mg subcutaneous or Octreotide LAR 30 mg intramuscular, starting 24h after RLT every 4 weeks during RLT (q16w interval SSA administration should be adjusted to RLT administrations so that SSA is always given 24h after each RLT dose and at least 4 weeks prior to next RLT administration cycle) and q4w following last RLT administration until disease progression.

Drug: 177Lu-Dotatate (7.4 Gigabecquerel/cycle) during 30 min intravenous infusion every 16 weeks (q8w) x 4 cycles; 2) and 3) as in the experimental arm.; Drug: Amino acid solution; Drug: Lanreotide (Autogel formulation) or Octreotide LAR

177Lu-Dotatate every 8 weeks

ACTIVE COMPARATOR

1. Treatment with 177Lu-Dotatate (7.4 Gigabecquerel/cycle) during 30 min intravenous infusion every 8 weeks (q8w) x 4 cycles 2. Renal protection starting 30 minutes before targeted radioligand therapy (RLT) lasting 4 hours (iv amino acid solution of 14.4-20g of lysine and 14.9-20.7g of arginine in 1 to 2 liters of solution); 3. Long-acting standard doses of SSA (Lanreotide autogel 120 mg subcutaneous or Octreotide LAR 30 mg intramuscular, starting 24h after RLT every 4 weeks during RLT (q8w interval SSA administration should be adjusted to RLT administrations so that SSA is always given 24h after each RLT dose and at least 4 weeks prior to next RLT administration cycle) and q4w following last RLT administration until disease progression

Drug: 177Lu-Dotatate (7.4 Gigabecquerel/cycle) during 30 min intravenous infusion every 8 weeks (q8w) x 4 cycles; 2) and 3) as in the experimental arm.; Drug: Amino acid solution; Drug: Lanreotide (Autogel formulation) or Octreotide LAR

Interventions

177Lu-Dotatate (7.4 Gigabecquerel/cycle) during 30 min intravenous infusion every 16 weeks (q8w) x 4 cycles; 2) and 3) as in the experimental arm. DRUG

Treatment with 177Lu-Dotatate (7.4 Gigabecquerel/cycle) during 30 min intravenous infusion every 16 weeks 177Lu-Dotatate, a radiopharmaceutical medicine which is an somatostatin analogue derived from octreotide that complexes via DOTA with non-carrier added (n.c.a) 177Lu radioconjugate. 177Lu-Dotatate will be supplied as a 370 MBq/mL solution for infusion. One mL of solution contains 370 MBq The total amount of radioactivity per single-dose vial is 7 400 MBq at the date and time of infusion. Given the fixed volumetric activity of 370 MBq/mL at the date and time of calibration, the volume of the solution in the vial ranges between 20.5 and 25.0 mL in order to provide the required amount of radioactivity at the date and time of infusion of lutetium (177Lu) oxodotreotide at the date and time of calibration.

Also known as: 177Lu-DOTA0-Tyr 3-Octreotate, 177Lu-DOTATE, LUTATHERA, lutetium (177Lu) oxodotreotide

177Lu-Dotatate every 16 weeks

177Lu-Dotatate (7.4 Gigabecquerel/cycle) during 30 min intravenous infusion every 8 weeks (q8w) x 4 cycles; 2) and 3) as in the experimental arm. DRUG

Treatment with 177Lu-Dotatate (7.4 Gigabecquerel/cycle) during 30 min intravenous infusion every 8 weeks (q8w) x 4 cycles 177Lu-Dotatate, a radiopharmaceutical medicine which is an somatostatin analogue derived from octreotide that complexes via DOTA with non-carrier added (n.c.a) 177Lu radioconjugate. Synonyms are: 177Lu-DOTA0-Tyr 3-Octreotate, 177Lu-DOTATE LUTATHERA, lutetium (177Lu) oxodotreotide 177Lu-Dotatate will be supplied as a 370 MBq/mL solution for infusion One mL of solution contains 370 MBq The total amount of radioactivity per single-dose vial is 7 400 MBq at the date and time of infusion. Given the fixed volumetric activity of 370 MBq/mL at the date and time of calibration, the volume of the solution in the vial ranges between 20.5 and 25.0 mL in order to provide the required amount of radioactivity at the date and time of infusion of lutetium (177Lu) oxodotreotide at the date and time of calibration.

177Lu-Dotatate every 8 weeks

Amino acid solution DRUG

Renal protection starting 30 minutes before RLT and lasting 4 hours (iv) amino acid solution of 14.4-20 g of lysine and 14.9-20.7 g of arginine in 1 to 2 liters of solution)

177Lu-Dotatate every 16 weeks; 177Lu-Dotatate every 8 weeks

Lanreotide (Autogel formulation) or Octreotide LAR DRUG

Long-acting standard doses of SSA (Lanreotide autogel 120 mg subcutaneous (sc) or Octreotide LAR 30 mg im, starting 24h after RLT and every 4 weeks during RLT (q16w interval SSA administration should be adjusted to RLT administrations so that SSA is always given 24h after each RLT dose and at least 4 weeks prior to next RLT administration cycle) and q4w following last RLT administration until disease progression.

177Lu-Dotatate every 16 weeks; 177Lu-Dotatate every 8 weeks

Eligibility Criteria

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

You may qualify if:

• Patients who have histologically confirmed diagnosis of unresectable, advanced or metastatic midgut NETs (originated in the jejunum-ileum or right colon) who are candidates to receive 177Lu-Dotatate targeted radioligand therapy (RLT) and SSA. Patients with a large SRI+ mesenteric mass with abdominal-dominant disease judged by the investigator to be a midgut NET will also be eligible.
• Ki-67 index ≤ 20%.
• Disease progression per RECIST v1.1 within 36 months prior to study entry,
• Patients may be treatment naïve (first-line) or have received prior systemic therapy except for any type of prior RLT (not restricted to 177Lu-Dotatate).
• In somatostatin receptor (SSTR) imaging all RECIST v1.1 evaluable target lesions and non-target lesions need to be SSTR positive (SSTR+) as defined by equal or above the liver uptake (this includes lesions of at least 10 mm in diameter in CT or MRI). If an FDG PET is performed (not mandatory), all FDG PET positive lesions should also be somatostatin receptor positive in SSRT imaging (see guidance Appendix 10).
• Measurable disease according to RECIST v1.1 criteria (Appendix 3)
• Adequate organ function (hematological, renal and liver) based upon meeting all of the following laboratory criteria:
• Neutrophil count (ANC) ≥ 2.000/mm3
• Platelet count ≥ 75 × 109/L
• Hemoglobin ≥ 8 g/dL
• Serum bilirubin ≤ 3.0 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease
• Serum albumin \<3.0 g/dL unless prothrombin time is within the normal range.
• Creatinine clearance (CrCl) ≥ 50 mL/min as estimated by the Cockroft-Gault formula or as measured by 24-hour urine collection (GFR can also be used instead of CrCl). Note: renal tract obstruction is not allowed.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 xULN for subjects with liver metastases
• Karnofsky performance status (KPS) scale ≥ 70%

You may not qualify if:

• Patients who have known hypersensitivity to lutetium-177 (177Lu), oxodotreotide, DOTA, somatostatin analogues, lysine, arginine, or any excipient/derivative of these agents
• Prior external beam radiation therapy (EBRT) to more than 25% of the bone marrow
• Prior whole liver internal radiation therapy (SIRT)
• Prior radioligand therapy (RLT) (not restricted to 177Lu-Dotatate).
• Prior major surgery, systemic therapy, embolization or other locoregional treatments within 4 weeks of study entry
• Patients who have a known active Hepatitis B (e.g., HBsAg reactive) or active hepatitis C (e.g., HCV RNA \[qualitative\] is detected). Patients who have a known active history of human immunodeficiency virus (HIV) infection (HIV 1 or 2).
• Other known malignancies unless cured or definitively treated with no evidence of recurrence for 3 years
• Serious non-malignant disease (e.g. psychiatric, infectious, autoimmune, cardiovascular or dementia), that may interfere with the objectives of the trial or with the safety or compliance of the patient, as judged by the investigator.
• Female patients must agree not to breastfeed or donate ovules starting at screening and throughout the study period, and for at least 7 months after the final study drug administration.
• Male patients must agree not to donate sperm starting at screening and throughout the study period, and for at least 4 months after the final study drug administration.
• Pregnancy or lactation. Men and women should not procreate during study treatment and until seven months after the final study drug administration.
• For female patients of childbearing potential (defined as \< 2 years after last menstruation and not surgically sterile) and male patients who are not surgically sterile and have female partners of childbearing potential that do not agree to use a medically accepted and highly effective birth control method (i.e. those with a failure rate less than 1%; refer to Appendix 4) for the duration of the study treatment and for 7 months after the final dose of study treatment
• Patient under guardianship or curatorship or deprived of liberty by a judicial or administrative decision or patient unable to give consent.

Sponsors & Collaborators

• Grupo Espanol de Tumores Neuroendocrinos: lead
• Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE): collaborator

Study Sites (21)

Centre François BACLESSE

Caen, Caen, 14000, France

NOT YET RECRUITING

Chu Dijon

Dijon, Dijon, 21000, France

NOT YET RECRUITING

Hospital Center University De Lille

Lille, Lille, 59000, France

NOT YET RECRUITING

Hospices civiles de Lyon

Lyon, Lyon, 69002, France

NOT YET RECRUITING

Institut Paoli Calmette

Marseille, Marseille, 13009, France

NOT YET RECRUITING

Hopital BEAUJON

Clichy, Paris, 92110, France

NOT YET RECRUITING

Hopital COCHIN

Paris, Paris, 75014, France

NOT YET RECRUITING

Centre Eugène MARQUIS

Rennes, Rennes, 35000, France

NOT YET RECRUITING

Hospital Universitario de Burgos

Burgos, Balearic Islands, 09006, Spain

RECRUITING

Hospital Universitari Vall d'Hebrón

Barcelona, Barcelona, 08035, Spain

RECRUITING

Instituto Catalán de Oncología - Hospital Duran i Reynals

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

RECRUITING

Hospital Virgen de las Nieves de Granada

Granada, Granada, 18014, Spain

RECRUITING

Complexo Hospitalario Universitario de Santiago

Santiago de Compostela, La Coruña, 15706, Spain

NOT YET RECRUITING

Hospital General Universitario Gregorio Marañón

Madrid, Madrid, 28007, Spain

NOT YET RECRUITING

Hospital Universitario Ramón y Cajal

Madrid, Madrid, 28034, Spain

RECRUITING

Hospital 12 de Octubre

Madrid, Madrid, 28041, Spain

RECRUITING

Hospital Universitario La Paz

Madrid, Madrid, 28046, Spain

NOT YET RECRUITING

Hospital Universitario Central de Asturias

Oviedo, Principality of Asturias, 33011, Spain

NOT YET RECRUITING

Hospital Universitario Virgen del Rocío

Seville, Sevilla, 41013, Spain

NOT YET RECRUITING

Hospital Clínico de Valencia

Valencia, Valencia, 46010, Spain

RECRUITING

Hospital Universitario y Politécnico La Fe

Valencia, Valencia, 46026, Spain

RECRUITING

MeSH Terms

Conditions

Neuroendocrine Tumors

Interventions

lutetium Lu 177 dotatate; Lutetium; Lutetium-177; copper dotatate CU-64; amino-acid, glucose, and electrolyte solution; lanreotide

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Lanthanoid Series Elements; Metals, Rare Earth; Elements; Inorganic Chemicals; Transition Elements; Metals

Study Officials

• Rocio Garcia Carbonero Garcia Carbonero, M.D., Ph.D.

  Hospital Universitario 12 de Octubre

  STUDY DIRECTOR

• Eric Baudin Baudin, M.D., Ph.D.

  Gustave Roussy, Cancer Campus, Grand Paris

  STUDY DIRECTOR

Central Study Contacts

A responsible person designated by the sponsor

CONTACT

+34 93 434 44 12; investigacio@mfar.net

Responsible person designated by the sponsor

CONTACT

+34 93 434 44 12; investigacion@mfar.net

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: RIALTO is an a randomized, prospective, international, open-label, phase III - I trial comparing a less intensive RLT regimen (4 cycles of 177Lu-Dotatate (7·4 GBq/cycle) every 16 weeks) versus the conventional one (4 cycles of 177Lu-Dotatate (7·4 GBq/cycle) every 8 weeks).

Study Record Dates

• First Submitted: February 4, 2025
• First Posted: March 17, 2025
• Study Start: June 12, 2025
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2029
• Last Updated: September 2, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

ES (13); FR (8)