177Lu-edotreotide compared to everolimus in neuroendocrine tumors of the lung and thymus

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grupo Espanol De Tumores Neuroendocrinos

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Oct 2023 → ongoing

Decision date (initial)

2024-10-23

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Therapy, Safety

To demonstrate the efficacy of PRRT with 177Lu-edotreotide in comparison with everolimus assessing the progression-free Survival (PFS), defined as the time from randomization until adequately documented disease progression (PD) according to RECIST v1.1 or death, whichever occurs first.

Conditions and MedDRA coding

Patients with well to moderately differentiated neuroendocrine tumors of the lung and thymus who require systemic therapy.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

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 candidates to receive everolimus or PRRT.
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 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.
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 (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.
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: 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
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 7 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 7 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 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.
16. Subject agrees not to participate in another interventional study while on treatment in the present study.

Exclusion criteria 16

1. Patients who are not able to swallow tablets.
2. 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.
3. 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.
4. 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.
5. 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).
6. Current spontaneous urinary incontinence preventing safe administration of the IMP, in the investigator’s opinion.
7. 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.
8. 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.
9. Patients with brain mets unless stable on treatment for > 12 weeks and with no evidence of raised intracranial pressure or mass effect.
10. 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).
11. 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.
12. 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).
13. 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.
14. 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.
15. 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).
16. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint for the LEVEL Trial is the progression-free survival (PFS) defined as the time from the date of randomization to the date of first documentation of disease progression according to RECIST 1.1 by investigator-assessment or death due to any cause, whichever occurs first

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grupo Espanol De Tumores Neuroendocrinos

Sponsor organisation

Grupo Espanol De Tumores Neuroendocrinos

Address

Calle Paris 162 Principal 1ª

City

Barcelona

Postcode

08036

Country

Spain

Scientific contact point

Organisation

Grupo Espanol De Tumores Neuroendocrinos

Contact name

Federico Nepote

Public contact point

Organisation

Grupo Espanol De Tumores Neuroendocrinos

Contact name

Federico Nepote

Locations

4 EU/EEA countries · 28 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 36 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications