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

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).