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.

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).

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.