Phase II Randomized Trial of Lutetium (177Lu) Oxodotreotide Dosing Intervals in Grade 1-2 Advanced Midgut Neuroendocrine Tumors to Assess Hematological Toxicity

Trial ID: 2024-517921-14-00
Protocol: RLTTio2023
Sponsor: Grupo Espanol De Tumores Neuroendocrinos

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Diseases & Conditions

Small intestine neuroendocrine tumour

Objectives

The primary objective of this study is to demonstrate decreased serious **hematological toxicity** with a less intensive regimen of Lutetium (177Lu) oxodotreotide in patients with slowly progressive advanced Grade 1-2 midgut **neuroendocrine tumors** (NETs). This is clinically relevant as reducing hematological toxicity can improve patient safety and treatment tolerability, potentially enhancing the quality of life and adherence to therapy.

Secondary objectives include:

To show comparable efficacy, including clinical, hormonal, and radiological response, progression-free survival, and overall survival, of the less intensive regimen (cycles every 16 weeks) versus the conventional regimen (cycles every 8 weeks).
To compare the rate of clonal hematopoiesis among study arms (baseline and post-treatment) and assess its potential value in predicting the risk of therapy-related myeloid neoplasms (t-MN).
To compare the duration of ≥ Grade 2 hematological toxicity, focusing on the median and percentage rate of toxicity lasting more than 6 months.
To show decreased overall toxicity of the less intensive regimen compared to the conventional regimen.

These secondary objectives aim to evaluate the broader impact of the treatment regimen on efficacy and safety, providing insights into optimizing therapeutic strategies for midgut NETs.

Participants

The clinical trial involves participants diagnosed with **neuroendocrine tumors** of midgut origin, specifically those with unresectable, advanced, or metastatic conditions. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a life expectancy of at least 12 months and must demonstrate adequate organ function, as well as recovery from any prior treatment-related adverse events to a Grade 1 or lower. The trial includes individuals with a Karnofsky performance status of 70% or higher, indicating a relatively stable general health status. Participants must have health coverage that includes clinical trial treatments and procedures. The trial population was selected based on specific inclusion criteria, such as the presence of somatostatin receptor-positive lesions and measurable disease according to RECIST v1.1 criteria. Lifestyle considerations include the requirement for female participants to use highly effective birth control methods and for sexually active men to use condoms during and after the study. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **lutetium (177Lu) oxodotreotide** in patients with advanced midgut **neuroendocrine tumors**. This is a randomized, double-blind, controlled trial aimed at comparing the administration of the radioligand therapy every 8 weeks versus every 16 weeks. The primary objective is to demonstrate a reduction in serious hematological toxicity with a less intensive treatment regimen. The trial is expected to run until January 31, 2029, with recruitment starting on January 31, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis, age, and adequate organ function. The inclusion visit will also involve obtaining informed consent. Following the screening, participants will be randomized into one of the two treatment arms. Regular follow-up visits will be scheduled to monitor treatment efficacy, safety, and any adverse events, with assessments aligned with standard clinical practice for managing advanced or metastatic neuroendocrine tumors. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement is up to 24 months, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5 to evaluate the primary endpoint, which is the rate of Grade 2-5 hematological toxicity. The study is categorized as a low-intervention trial, with trial-specific assessments integrated into routine clinical procedures to minimize additional burden on participants.

Treatment

The clinical trial involves the administration of **Lutathera 370 MBq/mL solution for infusion**, which contains the active substance **lutetium (177Lu) oxodotreotide**. This experimental medication is provided in the form of a solution for infusion and is administered via the **intravenous route**. The dosing regimen for this trial specifies a maximum daily dose of 7.4 GBq, with a total maximum dose of 29.6 GBq over the course of the treatment period. The treatment is scheduled to be administered every 8 or 16 weeks, depending on the trial arm, with a maximum treatment period of 64 weeks. The active substance, lutetium (177Lu) oxodotreotide, is a chemically synthesized compound, and the product is manufactured by Advanced Accelerator Applications. The trial aims to assess the efficacy and safety of this regimen in patients with slowly progressive advanced Grade 1-2 midgut neuroendocrine tumors (NETs).

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of the experimental medication, Lutathera. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The primary objective is to evaluate the potential reduction in serious hematological toxicity associated with a less intensive regimen of radioligand therapy (RLT) in the specified patient population.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the evaluation of the rate of Grade 2-5 **hematological toxicity**. This will be measured from the initiation of treatment with radioligand therapy (RLT) up to 24 months thereafter. The assessment will adhere to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5). The trial aims to demonstrate decreased serious hematological toxicity with a less intensive RLT regimen in patients with slowly progressive advanced Grade 1-2 midgut neuroendocrine tumors (NETs). The trial is designed as a low-intervention, de-escalation clinical trial, aligning with standard clinical practices for managing advanced or metastatic NETs of the gastrointestinal tract. The trial-specific assessments are integrated with standard clinical procedures, ensuring that patients do not need to make additional visits specifically for trial determinations. Efficacy assessments will include monitoring for thrombocytopenia, anemia, neutropenia, renal toxicity, and hepatotoxicity, with additional blood drawn to assess clonal hematopoiesis at baseline, 3, 12, and 24 months after the first dose of RLT.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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 RECIST v1.1 lesions should also be somatostatin receptor positive in SSTR imaging
Measurable disease according to RECIST v1.1 criteria
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%.
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.
Patients ≥ 18 years of age.
Recovery to Grade ≤ 1 from any adverse event (AE) from prior treatment (excluding alopecia and/or asthenia).
Life expectancy ≥ 12 months.
Patients with health coverage (public or private), that includes coverage for patients enrolled in clinical trials, to both study treatments and determinations/procedures.
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%) 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 final administration of study treatment. Additionally, it is recommended that your female partner of childbearing age use a highly effective method of contraception.
Subject agrees not to participate in another interventional study while on treatment in the present study.

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Exclusion Criteria

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 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%) 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.