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

Neuroendocrine Tumors Clinical Trial

— LEVEL  

Official title:

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05918302
• Other study ID #: GETNE-T2217
• Secondary ID: 2022-502154-13-0
• Status: Recruiting
• Phase: Phase 3
• Start date: October 27, 2023
• Est. completion date: July 2028

Study information

• Verified date: October 2023
• Source: Grupo Espanol de Tumores Neuroendocrinos
• Contact: Federico Nepote
• Phone: +34934344412
• Email: investigacion[@]mfar.net
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

LEVEL trial aims to demonstrate the higher efficacy of 177Lu-edotreotide over everolimus in patients with well to moderately differentiated neuroendocrine tumors of the lung and thymus who require systemic therapy. It is hypothesized that 177Lu-edotreotide may significantly increase the progression-free survival (PFS) compared to everolimus in lung and thymic carcinoids.

Description:

The LEVEL Trial is a randomized, prospective, international, open-label, phase III study comparing everolimus and 177Lu-edotreotide in advanced somatostatin receptor positive (SSTR+) lung and thymic well differentiated neuroendocrine tumors with high expression of somatostatin receptors confirmed by positron emission tomography somatostatin receptor imaging. In the investigator's opinion, patients recruited into the trial must be eligible to receive everolimus. Patients with both functional and nonfunctional lung and thymus neuroendocrine tumors (NETs) will be included in this trial. In total, 120 patients will be randomized in a 3:2 proportion to either experimental or control arms, respectively. Randomization will be stratified according to prior medical therapy (tumor treatment-naïve [patients who have not received any prior systemic anticancer therapy] versus non-treatment- naïve [patients who have received one or two prior line of systemic anticancer therapy, including somatostatin analogs (SSAs) as anti-tumor treatment]) and histological differentiation (typical versus atypical / well versus moderately differentiated). Stratification according to the functional status is not foreseen considering the poor predictive and prognostic relevance of this criteria on PRRT in the literature. Diagnosis of progression and tumor burden will be established based on radiological information from morphological imaging (magnetic resonance imaging [MRI] and/or computed tomography [CT]) according to RECIST v1.1. Tumors assessments will be scheduled every 12 ± 2 weeks from randomization (the first scan will be performed after Cycle 2 for the 177Lu-edotreotide until radiologically confirmed progression of the disease, initiation of new subsequent anticancer therapy, or death (whichever comes first). The scanning modality and protocol should be consistent with the baseline scan. Diagnosis of RECIST v1.1 progression will be made by the local investigator. The confirmatory scans should be performed preferably at the next scheduled imaging visit and no less than 4 weeks after the prior assessment of progression (PD) (in the absence of clinically significant deterioration). Additional MRI/CT scans may be performed at any other time if, in the investigator's clinical judgment, PD is suspected. For equivocal findings of progression, treatment may continue until the next scheduled assessment. In both arms, for a given patient, trial treatment dosing should be discontinued if there is evidence of RECIST v1.1 progression, in case of persistent toxicities or if the patient withdraws consent to continue with treatment. In all cases, if possible, all other protocol scheduled assessments should be continued until the end of the long-term follow-up period, unless the patient explicitly withdraws consent to all trial procedures and follow-up.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: July 2028
• Est. primary completion date: March 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Lung Neoplasms
• Lung Neuroendocrine Neoplasm
• Neoplasms
• Neuroendocrine Tumors
• Thymoma
• Thymus Neoplasms

Intervention

Drug:
• 177Lu-edotreotide
6 cycles of 7.5 ± 0.7 Giga becquerel (GBq) 177Lu-edotreotide
• Everolimus
10 mg orally once daily (QD)

Locations

Country	Name	City	State
France	Centre Hospitalier Universitaire (CHU) Bordeux	Bourdeaux
France	Lille University Hospital	Lille
France	Hôpital Edouard Herriot, Lyon	Lyon
France	Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, France	Marseille
France	Department of Digestive Oncology, CHU Saint Eloi, Montpellier, France/ ICM Cancer Institute at Montpellier	Montpellier
France	Centre Hospitalier Universitaire de Nantes	Nantes
France	I. Gustave Roussy, Paris	Paris
France	Department of Digestive Oncology - IUCT Rangueil-Larrey, CHU de Toulouse, Toulouse, France	Toulouse
Italy	Azienda Ospedaliera Spedali Civili Brescia	Brescia
Italy	IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - Irsì - Meldola	Meldola
Italy	AOU Policlinico G. Martino - Messina	Messina
Italy	Istituto Europeo di Oncologia - Milano	Milano
Italy	Istituto Nazionale Tumori IRCCS - Napoli	Napoli
Italy	Unit of Nuclear Medicine, S. Maria Nuova Hospital-IRCCS of Reggio Emilia, Reggio Emilia, Italy	Reggio Emilia
Italy	Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence Rome, Rome, Italy.	Roma
Italy	Azienda Ospedaliera Universitaria Integrata Verona	Verona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	ICO Institut Català d'Oncologia L'Hospitalet	Hospitalet de Llobregat	Barcelona
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Ramón y Cajal, Madrid	Madrid
Spain	Hospital Universitario Central de Asturias	Oviedo	Asturias
Spain	Complexo Hospitalario Universitario de Santiago de Compostela	Santiago De Compostela	Galicia
Spain	Hospital Universitario Virgen del Rocío	Sevilla	Andalucia
Spain	Hospital Universitario y Politécnico La Fe	Valencia

Sponsors (3)

Lead Sponsor	Collaborator
Grupo Espanol de Tumores Neuroendocrinos	ITM Oncologics GmbH, MFAR

Countries where clinical trial is conducted

France,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS)	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. In the primary analysis, PFS will be censored at the date of the last adequate tumor assessment if no PFS event is observed prior to the analysis cut-off date.	Throughout the study period, approximately 3 years per patient
Secondary	Objective response rate (ORR)	Assessed by the investigator through imaging follow-up (CT scan/MRI) using RECIST v1.1. This will be considered as the percentage/proportion of randomized patients with confirmed complete response (CR) or partial response (PR) as their overall best response throughout the study period.	Throughout the study period, approximately 3 years per patient
Secondary	Disease control rate (DCR)	Percentage/proportion of randomized patients with complete response (CR) or partial response (PR), according to ORR definition for the trial, or maintained stable disease (SD) as their overall best response, assessed by imaging follow-up (CT scan/MRI) and RECIST v1.1 criteria. Stable disease should be maintained for at least 4 months to be considered as a DCR event.	Throughout the study period, approximately 3 years per patient
Secondary	Duration of response (DoR)	Time from first confirmed response (CR or PR), according to ORR definition for the trial, to the date of the documented PD as determined using RECIST v1.1 criteria or death due to any cause, whichever occurs first. Those patients with response and without PD or death event will be censored on the date of their last tumor assessment.	Throughout the study period, approximately 3 years per patient
Secondary	Overall Survival (OS)	Defined as the time elapsed from randomization until death from any cause. We will assess the median OS, estimated by Kaplan-Meier. Patients alive and free of events at the date of the analysis will be censored at their last known contact.	Throughout the study period, approximately 3 years per patient, at each visit. Long-term follow-up to be performed at least every 6 months.
Secondary	Patient reported quality of life	Assessed through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) C30 (EORTC QLQ-C30), version 3 and lung cancer specific extension module LC-13. This are structural questionnaires self completed by the patient and which will give a numerical value to their own perception of quality of life. The scores obtained are standardized and a score between 0 (worst quality of life) and 100 (better quality of life).	Throughout the study period, approximately 3 years per patient. Assessed every 12 weeks from randomization to progression