Evaluation of Retreatment Protocols with Lutetium (177Lu) Oxodotreotide in Patients with Progressive Intestinal Well-Differentiated Neuroendocrine Tumors
- Trial ID
- 2024-511001-28-00
- Protocol
- PROICM 2021-04 REL
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of two additional cycles of Lutathera® (one injection every two months) compared to active surveillance over a period of six months in patients with new progression of intestinal well-differentiated **neuroendocrine tumors** who have already been retreated with two cycles. This is clinically relevant as it aims to determine the potential benefits of extended treatment with Lutathera® in managing disease progression, which could inform treatment protocols and improve patient outcomes.
Secondary objectives include evaluating the impact of the additional Lutathera® cycles on:
- **Safety**, to assess any adverse effects associated with the extended treatment.
- **Progression-free survival (PFS)**, to determine the duration patients remain free from disease progression.
- **Overall survival (OS)**, to evaluate the potential extension of life expectancy.
- **Health quality of life (QoL)**, to assess the impact on patients' well-being during and after treatment in both study arms.
Participants
The clinical trial involves participants diagnosed with **neuroendocrine tumors**, specifically histologically proven intestinal G1 or G2 types. The study population includes both male and female subjects aged 18 years and older, with no vulnerable populations selected. Participants are required to have a measurable disease per RECIST 1.1 criteria, adequate bone marrow reserve, and a life expectancy of at least 6 months. They must have previously undergone four cycles of Lutathera® treatment, with disease control for at least 12 months post-treatment, and present disease progression after the initial treatment. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants must be affiliated with the French Social Security System and demonstrate willingness and ability to comply with study procedures. Key lifestyle considerations include effective contraception for participants of childbearing potential and adherence to scheduled visits and treatment plans. The trial does not focus on any specific dietary or physical activity requirements.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of two additional cycles of Lutathera® in patients with new progression of intestinal well-differentiated **neuroendocrine tumor**. The trial aims to compare the treatment regimen of Lutathera® with active surveillance over a period of six months. The study is structured to include an initial screening visit, followed by regular follow-up visits every two months, and concludes with an end-of-study visit. The total duration of the trial is estimated to end by September 2031, with recruitment having commenced in September 2021.
Participants will be involved in the study for a maximum treatment period of 32 weeks, during which they will receive Lutathera® via **intravenous** infusion. The inclusion criteria require participants to be 18 years or older, with measurable disease as per RECIST 1.1, adequate bone marrow reserve, and a life expectancy of at least six months. Participants must have previously undergone four cycles of Lutathera® and demonstrated disease control for at least 12 months post-treatment. The trial will assess primary endpoints such as Disease Control Rate (DCR) at six months, with secondary endpoints including safety, progression-free survival (PFS), and overall survival (OS).
Study visits are scheduled to monitor the participants' health status, treatment efficacy, and any adverse events. The inclusion visit will confirm eligibility based on the outlined criteria, while follow-up visits will evaluate disease progression and treatment response. The end-of-study visit will summarize the participant's overall health outcomes and any long-term effects of the treatment. Participants may be withdrawn from the study if they experience significant adverse effects, fail to comply with the study protocol, or if the investigator deems it necessary for their safety.
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 intravenously. The dosage is set at a maximum of 7.4 MBq per day, with a total maximum dose of 4 MBq over the treatment period. The treatment is scheduled to be administered every two months, with a maximum treatment period of 32 weeks. The administration of Lutathera is intended to evaluate its efficacy in patients with new progression of intestinal well-differentiated neuroendocrine tumors.
In addition to the experimental medication, the trial also includes the use of **LysaKare** 25 g/25 g solution for infusion, which contains the active substances **L-lysine hydrochloride** and **L-arginine hydrochloride**. This solution is also administered intravenously and serves as an auxiliary treatment. The maximum daily dose is 1 mL, with a total maximum dose of 4 mL over the treatment period. The administration of LysaKare is intended to support the primary treatment with Lutathera, ensuring patient safety and enhancing the therapeutic effect.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the **Disease Control Rate (DCR)** at 6 months from randomization, which is defined as the proportion of patients achieving Complete Response, Partial Response, or Stable Disease according to RECIST v1.1 criteria, with evaluations conducted every 2 months. Secondary endpoints include safety assessments according to NCI-CTCAE v5.0, radiographic progression-free survival (rPFS), progression-free survival (PFS), overall survival (OS), and quality of life (QoL) as measured by the EORTC QLQ-C30 and EORTC GI.NET21 questionnaires.
Data collection and analysis will involve independent central review by radiologists who are blinded to treatment assignments, ensuring objective evaluation of disease progression. The trial will utilize validated scales and questionnaires to measure patient-reported outcomes and quality of life. The schedule for efficacy assessments includes regular intervals, specifically every 2 months, to monitor disease progression and response to treatment. This structured approach ensures comprehensive evaluation of the treatment's impact on patients with intestinal well-differentiated neuroendocrine tumors.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years
- Histologically proven intestinal G1 or G2 neuroendocrine tumors (NET),
- Patient previously treated with 4 cycles of Lutathera® (defined as “First PRRT”),
- Disease control after “First PRRT” ≥ 12 months
- Patient presenting a progression of disease (clinic, biologic and/or radiologic) after a first PRRT
- Decision of retreatment with Lutathera® (defined as “Second PRRT”) validated by RENATEN and/or multidisciplinary tumor board and in the scope of the French reimbursement process
- ECOG performance status 0-2
- Life expectancy ≥ 6 months as prognosticated by the physician
- Somatostatin receptor imaging positive imaging (SSTRi+) disease within 4 months prior to inclusion: (may be PET imaging (68Ga-based SSTR analogues) or scintigraphy imaging: 111In-pentetreotide or 99mTc-octreotide. At least 90% of lesions must be positive for SSTRi with a significant uptake (>= liver or surrounding tissue),
- Measurable disease per RECIST 1.1 (Appendix 1), on CT/MRI scans, defined as at least 1 lesion with ≥ 1 cm in longest diameter, and ≥ 2 radiological tumors lesions in total
- Adequate bone marrow reserve (Hb > 8 g/dl, neutrophils ≥ 1500/mm³ and platelets ≥ 80 000/mm³),
- Negative pregnancy test in women of childbearing potential (the β-HCG dosage must be ≤ 4 days before inclusion). Women who have no reproductive potential are postmenopausal women or women who have had permanent sterilization, eg. tubal occlusion, hysterectomy, bilateral salpingectomy),
- Effective contraception in men or women of childbearing or pre-menopausal age and up to a minimum of 7 months for female patients and 4 months for male patients following the end of treatment,
- Patient´s signed written informed consent
- Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures
- Affiliation to the French Social Security System.
Exclusion Criteria
- Patient who did not respond (no CR, PR or SD) to “first PRRT”.
- Radiological progression after two cycles of “Second PRRT” according to RECIST version 1.1
- Grade 4 hematotoxicity and/or nephrotoxicity during the initial PRRT, or unresolved AEs categorized as Grade 2 or higher (as per Common Terminology Criteria for Adverse Events (CTCAE v5.0) from previous PRRT cycles or any other therapy for NET, excluding alopecia and peripheral neuropathy,
- Pancreatic NET,
- NeuroEndocrine Carcinoma,
- Prior external beam radiation therapy to more than 25% of the bone marrow,
- Severe renal (estimated Glomerular Filtration Rate (GFR) according to Cockcroft Gault method < 40 mL/min or nephrotic syndrome) or hepatic insufficiency (Alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) > 2.5 x ULN or ALT/AST > 5 x ULN if liver function abnormalities are due to the underlying malignancy and/or total serum bilirubin > 2.5 x ULN),
- Serum albumin < 3.0 g/dL unless prothrombin time is within the normal range,
- Uncontrolled diabetes mellitus as defined by a fasting blood glucose above 2 ULN,
- Uncontrolled decompensated heart failure, myocardial infarction uncontrolled, stroke, pulmonary embolism or revascularization procedure, unstable angina pectoris, uncontrolled cardiac arrhythmia, and clinically significant bradycardia during the last 12 months,
- Hypertension that cannot be controlled despite medications (≥ 160/95 mmHg despite optimal medical therapy)
- Brain metastases (unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrolment in the study. Patients with a history of brain metastases must have a head CT scan with contrast or MRI to document stable disease prior to enrolment in the study),
- Pregnancy or breast feeding
- Substance abuse, medical, psychological, or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results,
- Known hypersensitivity to any of the study drugs, study drug classes, or any constituent of the products,
- Concomitant participation or participation within the last 30 days in another clinical trial,
- History of other solid tumor in 5 years before the inclusion excepted of cancer in situ of the cervix and skin cancer (basal or squamous cell) treated and controlled.
- Legal incapacity or physical, psychological or mental status interfering with the patient's ability to sign the informed consent or to terminate the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Sept 2021 | 209 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Lutathera 370 MBq/mL solution for infusion | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 7.4 | 32 | PRD5434501 |
LysaKare 25 g/25 g solution for infusion | Other | SOLUTION FOR INFUSION | INTRAVENOUS ADMINISTRATION | 1 | 32 | PRD7492562 |