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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
120
6 cycles of 7.5 ± 0.7 Giga becquerel (GBq) 177Lu-edotreotide
10 mg orally once daily (QD)
Antwerp University Hospital (UZA)
Edegem, Edegem, Belgium
RECRUITINGCHU Liège
Liège, Belgium
RECRUITINGHospital Center University Dijon Bourgogne (CHU Bourgogne)
Dijon, Dijon, France
RECRUITINGCentre Hospitalier Universitaire (CHU) Bordeux
Bourdeaux, France
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.
Time frame: Throughout the study period, approximately 3 years per patient
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.
Time frame: Throughout the study period, approximately 3 years per patient
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.
Time frame: Throughout the study period, approximately 3 years per patient
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.
Time frame: Throughout the study period, approximately 3 years per patient
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.
Time frame: Throughout the study period, approximately 3 years per patient, at each visit. Long-term follow-up to be performed at least every 6 months.
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).
Time frame: Throughout the study period, approximately 3 years per patient. Assessed every 12 weeks from randomization to progression
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Lille University Hospital
Lille, France
RECRUITINGHôpital Edouard Herriot, Lyon
Lyon, France
RECRUITINGDepartment of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, France
Marseille, France
RECRUITINGDepartment of Digestive Oncology, CHU Saint Eloi, Montpellier, France/ ICM Cancer Institute at Montpellier
Montpellier, France
RECRUITINGCentre Hospitalier Universitaire de Nantes
Nantes, France
RECRUITINGI. Gustave Roussy, Paris
Paris, France
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