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

Randomized Interval Assessment Trial of Lu177-Dotatate Every 8 Versus Every 16 Weeks in Slowly Progressive G1-2 Advanced Midgut Neuroendocrine Tumors (NETs) to Lower TOxicity

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

Research hypothesis: Less intensive somatostatin-receptor (SST) targeted radioligand therapy (RLT) (7.4 GBq/cycle 177Lu-Dotatate every 16 weeks x 4 cycles) is associated with less severe hematological toxicities and may mitigate the risk to develop therapy-related myeloid neoplasms (t-MN) with similar antitumor efficacy in slowly growing gastrointestinal grade 1-2 NETs.

Study Overview

• Status: Recruiting
• Conditions: Grade1-2 Advanced Midgut Neuroendocrine Tumors (NETs)
• Intervention / Treatment: 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; 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.

Detailed Description

1. Rationale The main hypothesis is less intensive somatostatin-receptor (SST) targeted radioligand therapy (RLT) (7.4 GBq/cycle 177Lu-Dotatate every 16 weeks x 4 cycles) is associated with less severe hematological toxicities and may mitigate the risk to develop therapy-related myeloid neoplasms (t-MN) with similar antitumor efficacy in slowly growing gastrointestinal grade 1-2 NETs.

2. Objectives Primary Objectives

   -To demonstrate decreased serious hematological toxicity with a less intensive RLT regimen in slowly progressive advanced Grade 1-2 midgut NETs.

   Secondary Objectives

   • To show comparable efficacy (clinical, hormonal and radiological response, progression-free survival and overall survival) of the less intensive RLT regimen (cycles q16w) versus the conventional one (cycles q8w). To compare the rate of clonal hematopoiesis among study arms (baseline and post-treatment) and assess its potential value to predict the risk of therapy-related myeloid neoplasms (t-MN).
   • To compare the duration of ≥ Grade 2 hematological toxicity (median and percentage rate of > 6 month duration)
   • To show decreased overall toxicity of the less intensive RLT regimen (cycles q16w) versus the conventional one (cycles q8w) Exploratory Objectives
   • To explore other predictive factors for toxicity and efficacy
   • To explore the tolerance of the subsequent systemic line of treatment Pattern of progression and modality of diagnosis
3. Main Trial Endpoints The primary endpoint for the RIALTO trial is the rate 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)

4. Secondary Trial Endpoints

   • Best hormonal response
   • Best radiological response
   • Duration of response (DoR)
   • Objective response rate (ORR)
   • Disease control rate (DCR)
   • Progression-free survival (PFS) (investigator assessed)
   • Overall survival (date of randomization to death from any cause)
   • Worst grade non-hematological toxicity per patient
   • Rate of clonal hematopoiesis by Next-Generation Sequencing (NGS) of ctDNA
   • Number of RLT cycles and cumulative dose received
   • Treatment compliance analyzing treatment delays and interruptions due to toxicity, rate of patients completing planned schedule, time from first to last RLT dose
   • Rate of Grade 2-5 hematological toxicity (worst per patient) from initiation of treatment with RLT up to 3, 6 or 12 months after the last PRRT
   • PFS will also be centrally assessed based only on morphological imaging (CT/MRI scans), regardless of SRI-PET scan results.
   • PFS will also be centrally assessed based on both morphological (CT/MRI scans) and functional imaging.
   • PFS will also be assessed based only on morphological imaging (CT/MRI scans), functional imaging and clinically progression of the functional syndrome, defined as unequivocal worsening of the functioning syndrome at the investigator criteria Secondary Safety endpoints
   • Adverse events (AE) and serious adverse events (SAE).
   • Treatment-related AEs (TRAEs).
   • Patients reported outcomes through the EORTC QLQ-C30 and GINET21 questionnaires.
   • Rate of myeloid neoplasms
   • Incidence of severe infection/sepsis (antibiotics prescription, hospitalization)
   • Duration of adverse events ≥ Grade 2
   • Rate of adverse events ≥ Grade 2 under subsequent next line of systemic treatment Exploratory endpoints
   • Correlation between clinical factors, radiomics and molecular determinants and toxicity/efficacy of 177Lu-Dotatate using mathematical models including artificial intelligence algorithms.
   • Tolerance of the subsequent systemic line of treatment
   • Pattern of progression (mesenteric, peritoneum, bone vs others) and modality of diagnosis
5. Trial Design 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)
6. Trial Population 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 with a large SRI+ mesenteric mass with abdominal-dominant disease judged by the investigator to be a midgut NET will also be eligible. Patients will be randomized into two arms: control (regimen 177Lu-Dotatate every 8 weeks) and experimental (regimen 177Lu-Dotatate every 16 weeks).
7. Study Treatments

Patients will be randomized in a 1:1 ratio to experimental or control arms respectively:

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.

Control arm:

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

8. Ethical Considerations

The study will be conducted in accordance with the principles of the Helsinki Declaration Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964 updated to its latest version Fortaleza, Brazil, October 2013. With the Good Clinical Practice (GCP) standards issued by the Working Party on Medicinal Product Efficacy of the European Economic Community (1990) (CPMP / ICH / 135/95).

• Study Type: Interventional
• Enrollment (Estimated): 166
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Responsible person designated by the sponsor; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
• Study Contact Backup: Name: A responsible person designated by the sponsor; Phone Number: +34 93 434 44 12; Email: investigacio@mfar.net

Study Locations

• France
  • Caen
    • Caen, Caen, France, 14000
      • Not yet recruiting
      • Centre Francois Baclesse
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
  • Dijon
    • Dijon, Dijon, France, 21000
      • Not yet recruiting
      • CHU Dijon
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
  • Lille
    • Lille, Lille, France, 59000
      • Not yet recruiting
      • Hospital Center University De Lille
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
  • Lyon
    • Lyon, Lyon, France, 69002
      • Not yet recruiting
      • Hospices Civiles de Lyon
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
  • Marseille
    • Marseille, Marseille, France, 13009
      • Not yet recruiting
      • Institut Paoli Calmette
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
  • Paris
    • Clichy, Paris, France, 92110
      • Not yet recruiting
      • Hôpital Beaujon
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
    • Paris, Paris, France, 75014
      • Not yet recruiting
      • Hopital Cochin
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
  • Rennes
    • Rennes, Rennes, France, 35000
      • Not yet recruiting
      • Centre Eugène Marquis
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12
• Spain
  • Balearic Islands
    • Burgos, Balearic Islands, Spain, 09006
      • Recruiting
      • Hospital Universitario de Burgos
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
  • Barcelona
    • Barcelona, Barcelona, Spain, 08035
      • Recruiting
      • Hospital Universitari Vall d'Hebron
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08908
      • Recruiting
      • Instituto Catalan de Oncologia - Hospital Duran i Reynals
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
  • Granada
    • Granada, Granada, Spain, 18014
      • Recruiting
      • Hospital Virgen De Las Nieves De Granada
      • Principal Investigator: Principal investigator Selected by Sponsor
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
  • La Coruña
    • Santiago de Compostela, La Coruña, Spain, 15706
      • Not yet recruiting
      • Complexo Hospitalario Universitario De Santiago
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
  • Madrid
    • Madrid, Madrid, Spain, 28034
      • Recruiting
      • Hospital Universitario Ramon y Cajal
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
    • Madrid, Madrid, Spain, 28046
      • Not yet recruiting
      • Hospital Universitario La Paz
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
    • Madrid, Madrid, Spain, 28007
      • Not yet recruiting
      • Hospital General Universitario Gregorio Marañon
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
    • Madrid, Madrid, Spain, 28041
      • Recruiting
      • Hospital 12 de Octubre
      • Contact: Investigator Selected Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
      • Principal Investigator: Principal investigator Selected by Sponsor Selected by Sponsor, M.D., Ph.D.
  • Principality of Asturias
    • Oviedo, Principality of Asturias, Spain, 33011
      • Not yet recruiting
      • Hospital Universitario Central de Asturias
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
  • Sevilla
    • Seville, Sevilla, Spain, 41013
      • Not yet recruiting
      • Hospital Universitario Virgen del Rocio
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
  • Valencia
    • Valencia, Valencia, Spain, 46010
      • Recruiting
      • Hospital Clinico de Valencia
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net
    • Valencia, Valencia, Spain, 46026
      • Recruiting
      • Hospital Universitario y Politécnico La Fe
      • Principal Investigator: Principal investigator Selected by Sponsor, M.D., Ph.D.
      • Contact: A responsible person Selected by Sponsor,, M.D., Ph.D.; Phone Number: +34 93 434 44 12; Email: investigacion@mfar.net

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.
2. Ki-67 index ≤ 20%.
3. Disease progression per RECIST v1.1 within 36 months prior to study entry,
4. 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).
5. 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).
6. Measurable disease according to RECIST v1.1 criteria (Appendix 3)

7. 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
8. Karnofsky performance status (KPS) scale ≥ 70%
9. Patient information and signing of the consent form, Institutional Review Board(IRB)/Independent Ethics Committee (IEC) approved, before any study-specific procedure. The patient must be able and willing to cooperate in monitoring study visits and procedures.
10. Patients ≥ 18 years of age.
11. Recovery to Grade ≤ 1 from any adverse event (AE) from prior treatment (excluding alopecia and/or asthenia).
12. Life expectancy ≥ 12 months.
13. Patients with health coverage (public or private), that includes coverage for patients enrolled in clinical trials, to both study treatments and determinations/procedures.
14. Female subject must provide a negative urine pregnancy test at screening, and must 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. Sexually active men must agree to use the male condom during the study and until at least 7 months after the last administration of treatment. Additionally, it is recommended that your female partner of childbearing age use a highly effective method of contraception.
15. Subject agrees not to participate in another interventional study while on treatment in the present study.

Exclusion Criteria:

1. Patients who have known hypersensitivity to lutetium-177 (177Lu), oxodotreotide, DOTA, somatostatin analogues, lysine, arginine, or any excipient/derivative of these agents
2. Prior external beam radiation therapy (EBRT) to more than 25% of the bone marrow
3. Prior whole liver internal radiation therapy (SIRT)
4. Prior radioligand therapy (RLT) (not restricted to 177Lu-Dotatate).
5. Prior major surgery, systemic therapy, embolization or other locoregional treatments within 4 weeks of study entry
6. 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).
7. Other known malignancies unless cured or definitively treated with no evidence of recurrence for 3 years
8. 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.
9. 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.
10. 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.
11. Pregnancy or lactation. Men and women should not procreate during study treatment and until seven months after the final study drug administration.
12. 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
13. Patient under guardianship or curatorship or deprived of liberty by a judicial or administrative decision or patient unable to give consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 177Lu-Dotatate every 16 weeks; Experimental arm: Treatment with 177Lu-Dotatate (7.4 Gigabecquerel/cycle) during 30 min intravenous infusion every 16 weeks (q16w) x 4 cycles; 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); 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.; 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.; Other Names: 177Lu-DOTA0-Tyr 3-Octreotate, 177Lu-DOTATE; LUTATHERA, lutetium (177Lu) oxodotreotide; Drug: Amino acid solution; 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); Drug: Lanreotide (Autogel formulation) or Octreotide LAR; 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.
Active Comparator: 177Lu-Dotatate every 8 weeks; Treatment with 177Lu-Dotatate (7.4 Gigabecquerel/cycle) during 30 min intravenous infusion every 8 weeks (q8w) x 4 cycles; 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);; 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: Amino acid solution; 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); Drug: Lanreotide (Autogel formulation) or Octreotide LAR; 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.; 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.; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best hormonal response	Best hormonal response defined as greatest decrease, or >30% decrease, of chromogranin A and 5HIAA from baseline if baseline levels were >2x ULN or 5xULN	24 months
Best radiological response	Best radiological response according to local investigator RECIST V1.1	24 months
Duration of response (DoR)	Duration of response (DoR) according to local investigator RECIST v1.1. Time from first response (CR or PR), according to ORR definition for the trial, to the date of the documented PD as determined using RECIST v1.1 criteria or death due to any cause, whichever occurs first. Those patients with response and without PD or death event will be censored on the date of their last tumor assessment.	Throughout the study period, from initiation of treatment with RLT up to 24 months
Objective response rate (ORR)	Objective response rate (ORR) according to local investigator RECIST v1.1. Assessed by the investigator through imaging follow-up (CT scan/MRI) using RECIST v1.1 (Appendix 3). This will be considered as the percentage/proportion of randomized patients with complete response (CR) or partial response (PR) as their overall best response throughout the study period. The investigator will report the change in size of tumors as compared with baseline, before the first dose of study treatment.	Throughout the study period, from initiation of treatment with RLT up to 24 months
Disease control rate (DCR)	Disease control rate (DCR) RECIST v1.1 according to local investigator RECIST v1.1. Assessed by the investigator through imaging follow-up (CT scan/MRI) using RECIST v1.1. This will be considered as the percentage/proportion of randomized patients with complete response (CR) or partial response (PR) as their overall best response throughout the study period. The investigator will report the change in size of tumors as compared with baseline, before the first dose of study treatment.	Throughout the study period, from initiation of treatment with RLT up to 24 months
Progression-free survival (PFS)	Progression-free survival (PFS) (investigator assessed) defined as the time between randomization date and disease progression according to RECIST v1.1 or death from any cause (primary analysis of PFS) .PFS will be censored at the date of the last adequate tumor assessment if no PFS event is observed prior to the analysis cut-off date.	Throughout the study period, up to 3 months from radomization
Progression-free survival (PFS)	Progression-free survival (PFS) (investigator assessed) defined as the time between randomization date and disease progression according to RECIST v1.1 or death from any cause (primary analysis of PFS). PFS will be censored at the date of the last adequate tumor assessment if no PFS event is observed prior to the analysis cut-off date.	Throughout the study period, up to 12 months from radomization
Progression-free survival (PFS)	Progression-free survival (PFS) (investigator assessed) defined as the time between randomization date and disease progression according to RECIST v1.1 or death from any cause (primary analysis of PFS) .PFS will be censored at the date of the last adequate tumor assessment if no PFS event is observed prior to the analysis cut-off date.	Throughout the study period, up to 24 months from radomization
Overall survival	Overall survival defined as the time elapsed from randomization until death from any cause. Patients alive and free of events at the date of the analysis will be censored at their last known contact.	Throughout the study period, up to 6 months from radomization
Overall survival	Overall survival defined as the time elapsed from randomization until death from any cause. Patients alive and free of events at the date of the analysis will be censored at their last known contact.	Throughout the study period, up to 12 months from radomization
Overall survival	Overall survival defined as the time elapsed from randomization until death from any cause. Patients alive and free of events at the date of the analysis will be censored at their last known contact.	Throughout the study period, up to 18 months from radomization
Overall survival	Overall survival defined as the time elapsed from randomization until death from any cause. Patients alive and free of events at the date of the analysis will be censored at their last known contact.	Throughout the study period, up to 24 months from radomitation
Worst grade non-hematological toxicity per patient	Percentage of patients with Non-hematological toxicity. Non-hematological toxicity: defined as worst grade non-hematological toxicity per patient according to NCI-CTCAE v 5.0 criteria.	Throughout the study period, up to 24 months
Rate of clonal hematopoiesis	Rate of clonal hematopoiesis by Next-Generation Sequencing (NGS) of ctDNA calculated by mutations frequency in ctDNA samples	Throughout the study period, at baseline
Rate of clonal hematopoiesis	Rate of clonal hematopoiesis by Next-Generation Sequencing (NGS) of ctDNA calculated by mutations frequency in ctDNA	Throughout the study period, up to 3 months from the start of treatment of the study
Rate of clonal hematopoiesis	Rate of clonal hematopoiesis by Next-Generation Sequencing (NGS) of ctDNA calculated by mutations frequency in ctDNA samples	Throughout the study period, up to 12 months from the start of treatment of the study
Rate of clonal hematopoiesis	Rate of clonal hematopoiesis by Next-Generation Sequencing (NGS) of ctDNA calculated by mutations frequency in ctDNA samples.	Throughout the study period, up to 24 months from the start of treatment of the study
Number of RLT cycles per patient	Number of RLT cycles per patient	Throughout the study period, up to 24 month
Acumulative dose received each patient	Number acumulative dose received each patient	Throughout the study period up to 24 month
Treatment compliance analyzing treatment delays and interruptions due to toxicity	Treatment compliance analyzing treatment delays and interruptions due to toxicity, rate of patients completing planned schedule, time from first to last RLT dose	Throughout the study period, time from first to last RLT dose
Rate of Grade 2-5 hematological toxicity (worst per patient)	Rate of Grade 2-5 hematological toxicity (worst per patient) from initiation of treatment with RLT up to 12 months after the last PRRT	Throughout the study period, from initiation of treatment with RLT up to12 months after the last PRRT
PFS centralized based only on morphological imaging	PFS will also be centrally assessed according to RECIST 1.1 based only on morphological imaging (CT/MRI scans), regardless of SRI-PET scan results.	Throughout the study period, up to 24 mounth from radomization
PFS will also be centralized on both morphological and functional imaging.	Progression-free survival will also be centrally assessed according to RECIST 1.1 based on both morphological (CT/MRI scans) and functional imaging.	Throughout the study period up to 24 mounth from radomization
PFS will also be assessed according to RECIST 1.1 based only on morphological imaging, functional imaging and clinically progression of the functional syndrome	PFS will also be assessed according to RECIST 1.1 based only on morphological imaging (CT/MRI scans), functional imaging and clinically progression of the functional syndrome, defined as unequivocal worsening of the functioning syndrome at the investigator criteria	Throughout the study period, up to 24 mounth from radomization
Adverse events (AE) and serious adverse events (SAE).	Number patients that suffered a Adverse event (AE) or serious adverse events (SAE) specific	Throughout the study period. 24 months
Treatment-related AEs (TRAEs).	Number Treatment-related AEs (TRAEs).	Throughout the study period, 24 month
Patients reported outcomes through the EORTC QLQ-C30 and GINET21 questionnaires.	Patients reported outcomes through the EORTC QLQ-C30 and GINET21 questionnaires.	Throughout the study period, 24 months
Rate of myeloid neoplasms	Porcentatge patients with myeloid neoplasms	Throughout the study period
Incidence of severe infection/sepsis	Incidence of severe infection/sepsis (antibiotics prescription, hospitalization)	Throughout the study period
Rate of adverse events ≥ Grade 2	Rate of adverse events ≥ Grade 2 under subsequent next line of systemic treatment	Throughout the study period
Duration of adverse events ≥ Grade 2	Duration of adverse events ≥ Grade 2 (median, %>6 months)	Throughout the study period

Collaborators and Investigators

• Sponsor: Grupo Espanol de Tumores Neuroendocrinos
• Collaborators: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)
• Investigators: Study Director: 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 record dates

Study Major Dates

• Study Start (Actual): June 12, 2025
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: February 4, 2025
• First Submitted That Met QC Criteria: March 10, 2025
• First Posted (Actual): March 17, 2025

Study Record Updates

• Last Update Posted (Estimated): September 2, 2025
• Last Update Submitted That Met QC Criteria: August 29, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Neuroendocrine Tumors; midgut; Lu177-Dotatate
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Inorganic Chemicals; Elements; Metals; Transition Elements; Lanthanoid Series Elements; Metals, Rare Earth; lutetium Lu 177 dotatate; Lutetium-177; Lutetium; copper dotatate CU-64; amino-acid, glucose, and electrolyte solution; lanreotide
• Other Study ID Numbers: RLTTio2023 / GETNE T2421; 2024-517921-14-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No