Efficacy and Safety of Radiotherapy Compared to Everolimus in Somatostatin Receptor Positive Neuroendocrine Tumors of the Lung and Thymus.

Launched by GRUPO ESPANOL DE TUMORES NEUROENDOCRINOS · Jun 23, 2023

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ClinConnect Summary

The LEVEL trial is studying the effectiveness and safety of a new treatment called 177Lu-edotreotide compared to an existing medication known as everolimus for patients with certain types of neuroendocrine tumors in the lungs and thymus. These tumors are generally slow-growing and may require systemic therapy, which means treatments that affect the whole body rather than just one area. The goal of the trial is to see if 177Lu-edotreotide can help patients live longer without their cancer getting worse.

To be eligible for the trial, participants must be at least 18 years old and have a confirmed diagnosis of well or moderately differentiated neuroendocrine tumors that are either metastatic (spread to other parts of the body) or locally advanced and cannot be surgically removed. Patients also need to have measurable disease progression in the past year. If you join the trial, you will receive either the new treatment or everolimus, and your health will be monitored closely throughout the study. It’s important to note that certain health conditions and previous treatments may affect eligibility, so discussing your specific situation with your healthcare provider is crucial.

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Eligibility criteria

• Inclusion Criteria:
• • 1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent.
• • 2. Patients ≥ 18 years of age.
• • 3. 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.
• • 4. 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.
• • 5. In SSTR imaging all RECIST v1.1 selected target lesions and all other lesions considered dominant by the investigator should be positive. If an fluorodeoxyglucose (FDG)-positron emission tomography (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 positive in SSRT imaging.
• • 6. 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.
• • 7. 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.
• • 8. Patients have radiographically documented and measurable metastatic or locally advanced disease at baseline according to RECIST v1.1.
• • 9. An archival tumor tissue sample should be available for submission to the central laboratory prior to study treatment (36 months). If an archival tumor tissue sample is not available, a new biopsy tissue sample should be provided if feasible.
• • 10. Patients who have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• 11. Adequate organ and bone marrow function based upon meeting all of the following laboratory criteria:
• • 1. Neutrophil count (ANC) ≥ 1,500/mm\^3
• • 2. Platelet count ≥ 75 × 10\^9/L
• • 3. Hemoglobin ≥ 8 g/dL
• • 4. Serum bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease or liver metastases
• • 5. Creatinine clearance (CrCl) ≥ 40 mL/min as estimated by the Cockcroft-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.
• • 6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 x ULN for subjects with liver metastases
• • 12. 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 6 months after the final dose of study treatment.
• • 13. Female patients must agree not to breastfeed or donate ovules starting at screening and throughout the study period, and for at least 6 months after the final study drug administration.
• • 14. 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.
• • 15. Male patients with a pregnant or breastfeeding partner(s) must agree to abstinence or use a condom for the duration of the pregnancy or time the partner is breastfeeding throughout the study period and for at least 6 months after the final study drug administration.
• • 16. Subject agrees not to participate in another interventional study while on treatment in the present study.
• Exclusion Criteria:
• • 1. Patients who are not able to swallow tablets.
• • 2. 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.
• • 3. Patients with brain mets unless stable on treatment for \> 12 weeks and with no evidence of raised intracranial pressure or mass effect.
• • 4. 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).
• • 5. 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.
• • 6. Patients who have a known active Hepatitis B (e.g., HBsAg reactive) or active hepatitis C (e.g., hepatitis C virus (HCV) RNA \[qualitative\] is detected). Patients who have a known history of human immunodeficiency virus (HIV) infection (HIV 1 or 2).
• • 7. 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.
• • 8. 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.
• • 9. Prior peptide receptor radionuclide therapy (PRRT) or mammalian target of rapamycin (mTOR) inhibitors (e.g. deforolimus, everolimus, sirolimus, temsirolimus, etc.); or hepatic radio-embolization (within 6 months prior to first dose of study treatment).
• • 10. Prior radiotherapy or major surgery within 12 weeks prior to the first dose of study drug.
• • 11. 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.
• • 12. Patients who have known hypersensitivity to Everolimus or to any excipient contained in the drug formulation of Everolimus.
• • 13. 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).
• • 14. Current spontaneous urinary incontinence preventing safe administration of the investigational medicinal product (IMP), in the investigator's opinion.
• • 15. 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.