Efficacy, safety and patient-reported outcomes of peptide receptor radionuclide therapy with 177Lu-edotreotide compared to everolimus in somatostatin receptor positive neuroendocrine tumors of the lung and thymus. The LEVEL trial
- Trial ID
- 2022-502154-13-00
- Protocol
- GETNE-T2217
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the **efficacy** of peptide receptor radionuclide therapy (PRRT) with **177Lu-edotreotide** in comparison with **everolimus** by assessing progression-free survival (PFS) in patients with well to moderately differentiated **neuroendocrine tumors** of the lung and thymus. PFS is defined as the time from randomization until adequately documented disease progression according to RECIST v1.1 or death, whichever occurs first. This objective is clinically relevant as it aims to establish a more effective treatment option for patients requiring systemic therapy, potentially improving their survival outcomes and quality of life.
Participants
The clinical trial involves **patients** with well to moderately differentiated **neuroendocrine tumors** of the lung and thymus who require systemic therapy. The study population includes both male and female subjects, aged 18 years and older. Participants are required to have a histologically confirmed metastatic or locally advanced unresectable neuroendocrine tumor of lung or thymus origin, either functioning or non-functioning. The trial population was selected based on specific inclusion criteria, including an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ and bone marrow function. Participants must have radiographically documented and measurable metastatic or locally advanced disease at baseline according to RECIST v1.1. The trial does not provide information on the total number of participants, as the sponsor has not disclosed this data. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The trial includes a vulnerable population, and both male and female subjects are required to adhere to specific reproductive health guidelines during and after the study period.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and safety of peptide receptor radionuclide therapy with 177Lu-edotreotide compared to everolimus in patients with well to moderately differentiated neuroendocrine tumors of the lung and thymus. This is a Phase III, randomized, double-blind, controlled trial. The primary endpoint is progression-free survival, defined as the time from randomization until disease progression or death, whichever occurs first. The trial is expected to run until December 31, 2028, with recruitment starting on September 1, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and organ function. Following randomization, participants will receive either 177Lu-edotreotide or everolimus, with the treatment administered intravenously or orally, respectively. The maximum treatment period for 177Lu-edotreotide is 44 weeks, while everolimus is administered for up to 12 weeks. Study visits will include regular follow-up assessments to monitor disease progression and treatment safety. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participant involvement is expected to last for the duration of the treatment period, with additional follow-up as necessary. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants are required to adhere to specific contraceptive measures and agree not to participate in other interventional studies during the trial period. The trial aims to provide valuable insights into the comparative effectiveness of these treatments in managing neuroendocrine tumors.
Treatment
The clinical trial involves the administration of **Arginine-Lysine solution for infusion**, which is a **solution for infusion** containing the active substances **L-lysine hydrochloride** and **L-arginine hydrochloride**. This pharmaceutical product is manufactured by ITM Solucin GmbH. The solution is administered intravenously, with a maximum daily dose of 25 grams and a total maximum dose of 150 grams over a treatment period of up to 44 days. The solution is of chemical origin and is not formulated for pediatric use.
Another experimental treatment in the trial is **177Lu-Edotreotide**, a **solution for injection/infusion** also produced by ITM Solucin GmbH. The active substance in this formulation is **lutetium (177Lu) edotreotide**. This treatment is administered intravenously, with a maximum daily dose of 8.2 gigabecquerels and a total maximum dose of 45 gigabecquerels over a treatment period of up to 44 days. The substance is of chemical origin and is not intended for pediatric use.
The trial also includes the use of **Afinitor 10 mg tablets**, which contain the active substance **everolimus**. These tablets are manufactured by Novartis Europharm Limited and are administered orally. The maximum daily dose is 10 milligrams, with a total maximum dose of 10 milligrams over a treatment period of up to 12 weeks. The tablets are of chemical origin and are not formulated for pediatric use.
Efficacy
The efficacy of the clinical trial titled "Efficacy, safety and patient-reported outcomes of peptide receptor radionuclide therapy with 177Lu-edotreotide compared to everolimus in somatostatin receptor positive neuroendocrine tumors of the lung and thymus" will be assessed primarily through the measurement of **progression-free survival (PFS)**. PFS is defined as the time from randomization until the first documentation of disease progression according to RECIST v1.1 criteria or death from any cause, whichever occurs first. This endpoint will be evaluated by investigator assessment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent.
- Patients ≥ 18 years of age.
- Patients who have histologically confirmed metastatic or locally advanced unresectable well/moderately differentiated (World Health Organization [WHO] 2015 criteria) neuroendocrine tumor of lung (typical and atypical carcinoids) or thymus origin either functioning or non-functioning candidates to receive everolimus or PRRT.
- Patients must have the appropriate pathological features based on WHO classification, and description of proliferation activity as indicated by mitotic count per 10 high-power fields (HPF) and presence of necrosis, or Ki67 index.
- In SSTR imaging all RECIST v1.1 selected target lesions and all other lesions considered dominant by the investigator should be somatostatin receptor positive (SSRT+). If an FDG PET is performed (not mandatory), all FDG PET positive RECIST v1.1 target lesions and all other FDG PET positive lesions considered dominant by the investigator should also be somtostatin receptor positive in SSRT imaging.
- Lesions must have shown radiological evidence of disease progression in the 12 months prior to inclusion in the study. Patients who were receiving systemic anticancer therapy, progression should be documented on therapy or after stopping therapy due to adverse events or other reasons. Patients without prior therapy, documentation of progression is also mandatory to watch and wait strategy or during the follow up after surgery.
- Patients may be included in first-line therapy (systemic treatment naïve) or may have experienced progression on somatostatin analogues or additional systemic treatments, which may include but not limited to chemotherapy, targeted agents or immunotherapy (maximum of 2 prior systemic anti-tumor treatments). NOTE: Somatostatin analogues for patients with functioning tumors are allowed.
- Patients have radiographically documented and measurable metastatic or locally advanced disease at baseline according to RECIST v1.1.
- An archival tumor tissue sample should be available for submission to the central laboratory prior to study treatment (samples obtained for up to 36 months prior to initiation of study treatment are considered valid for this purpose). If an archival tumor tissue sample is not available, a new biopsy tissue sample should be provided if feasible.
- Patients who have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Adequate organ and bone marrow function based upon meeting all of the following laboratory criteria: Neutrophil count (ANC) ≥ 1,500/mm3 Platelet count ≥ 75 × 109/L Hemoglobin ≥ 8 g/dL Serum bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert’s disease or liver metastases Creatinine clearance (CrCl) ≥ 40 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
- 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.
- 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 6 months after the final study drug administration.
- Male patients must agree to abstinence or use a condom for the duration of the study period and for at least 6 months after the final study drug administration.
- Subject agrees not to participate in another interventional study while on treatment in the present study.
Exclusion Criteria
- Patients who are not able to swallow tablets.
- Prior radiotherapy or major surgery within 12 weeks prior to the first dose of study drug. Note: In the case of palliative radiotherapies, a 4-week difference between radiotherapy and the start of treatment will be sufficient.
- Patients who have had chemotherapy, biologics, investigational agents, and/or antitumor treatment with immunotherapy that is not completed 4 weeks prior to the first dose of study drug.
- Patients who have known hypersensitivity to Everolimus or to any excipient contained in the drug formulation of Everolimus. Patients who have hypersensitivity to other rapamycin derivatives.
- Patients who have known hypersensitivity to 177Lu-edotreotide or to any excipient contained in the drug formulation of 177Lu-edotreotide or the nephroprotective amino acid solution (AAS).
- Current spontaneous urinary incontinence preventing safe administration of the IMP, in the investigator’s opinion.
- Patients who have other underlying medical conditions that, in the opinion of the investigator, would impair the ability of the subject to receive or tolerate the planned treatment and follow-up.
- Patients with poorly-differentiated or high-grade neuroendocrine carcinoma (i.e. large cell neuroendocrine carcinoma of lung, small cell lung cancer) or mixed tumors (i.e. adenocarcinoid tumor) are not eligible.
- Patients with brain mets unless stable on treatment for > 12 weeks and with no evidence of raised intracranial pressure or mass effect.
- Patients who have ongoing clinically significant toxicity (Grade 2 or higher with the exception of alopecia) associated with prior treatment (including systemic therapy, radiotherapy or surgery).
- Patients who have a recent diagnosis of another malignancy (within 12 months prior to inclusion), patients who are on active treatment for other cancer before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy.
- 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 history of human immunodeficiency virus (HIV) infection (HIV 1 or 2).
- Patients who have received a live vaccine up to 4 weeks prior to the first dose of trial treatment. Note:Live attenuated vaccines should not be administered during the trial treatment and over the next 3 months after the last treatment dose.
- Patients who have documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to the first dose of study drug.
- Prior peptide receptor radionuclide therapy (PRRT) or mammalian target of rapamycin (mTOR) inhibitors (e.g. deforolimus, everolimus, sirolimus, temsirolimus, etc.); or hepatic radioembolization (within 6 months prior to first dose of study treatment).
- Patients who have limited their capability to freely decide to participate (patients under guardianship / curatorship), or are in a situation of institutional or hierarchical dependency that could inappropriately influence their decision to participate.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 01 Sept 2023 | 20 |
 France | Recruiting | 01 Sept 2023 | 50 |
 Italy | Recruiting | 01 Sept 2023 | 50 |
 Spain | Recruiting | 01 Sept 2023 | 50 |
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 |
|---|---|---|---|---|---|---|
177Lu-Edotreotide | Test | SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS | 8.2 | 44 | PRD10948571 |
Afinitor 10 mg tablets | Test | TABLETS | ORAL | 10 | 12 | PRD400618 |
Arginine-Lysine solution for infusion | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 25 | 44 | PRD9416063 |