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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT03774732
Other study ID # UC-0107/1718
Secondary ID
Status Recruiting
Phase Phase 3
First received
Last updated
Start date March 21, 2019
Est. completion date September 21, 2026

Study information

Verified date December 2023
Source UNICANCER
Contact Saliha GHANEM, PhD
Phone 01 80 50 12 98
Email s-ghanem@unicancer.fr
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

Overall survival (OS) of patients with advanced (stage IIIB/IV) non-small-cell lung cancer (NSCLC) remains short after the first line of treatment with a median OS of 12.2 months in non squamous NSCLC and 9.2 months in squamous NSCLC . In this setting the programmed death 1/ligand 1 (PD-1/-L1) were targeted with nivolumab (IgG4) in advanced squamous and nonsquamous NSCLC leading to an increase of the 1-year OS rate of approximately 10-15% in both histologies. Nivolumab, pembrolizumab and atezolizumab are now considered a standard of care in 2nd line advanced NSCLC and in 1st line for pembrolizumab but but prognosis still remains poor in advanced NSCLC. Overall survival (OS) of patients with advanced (stage III/IV) NSCLC remains limited with a median OS of 12.2 months in non-squamous NSCLC and 9.2 months in squamous NSCLC if anti-PD1 alone. It is of around 16 months if pembrolizumab is combined with chemotherapy. Preclinical data indicates that anti-tumor efficacy is increased when anti-PD-1/-L1 are combined with irradiation (IR). Radiotherapy alone can elicit tumor cell death which can increase tumor antigen in the blood stream, favoring recognition by the immune system and its activation against tumor cells outside of the radiation field (="abscopal effect"). IR may also reverse acquired resistance to PD-1 blockade immunotherapy by limiting T-cell exhaustion. Because of these preclinical and clinical data several studies analysing the combination of IR and anti-PD1 in NSCLC are ongoing. Among them, two studies are testing the administration of IR and nivolumab in stage III NSCLC: the NCT02768558 phase III trial (RTOG), and the NCT02434081 phase II trial (ETOP). Antonia et al [2017] tested the use of anti-PD-L1 after chemoradiotherapy in unresectable stage III NSCLC. Median time to distant metastasis was increased (23.2 months vs. 14.6 months, p<0.001). An increase of OS is consequently expected. However, no study involving concurrent RT and pembrolizumab combined with chemotherapy in advanced NSCLC is ongoing, which is the purpose of the present study, NIRVANA-Lung.


Recruitment information / eligibility

Status Recruiting
Enrollment 327
Est. completion date September 21, 2026
Est. primary completion date September 21, 2026
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility INCLUSION CRITERIA: 1. Patient must have signed a written informed consent form prior to any study specific procedures 2. Histologically or cytologically confirmed advanced (stage IIIB/IIIC/IV), squamous or non-squamous NSCLC 3. NSCLC patients eligible for treatment with pembrolizumab and chemotherapy according to the European Marketing Authorization: 1. squamous: in combination with carboplatin and either paclitaxel or nab-paclitaxel 2. non squamous with no EGFR or ALK positive mutations: in combination with pemetrexed and a platinum based chemotherapy 4. Patient =18 of age 5. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1 6. Life expectancy >3 months 7. Measurable lesion as assessed by RECIST version 1.1 8. Metastases and/or primary tumour eligible for 3 dimensional conventional radiotherapy (3D-CRT) or stereotactic ablative radiotherapy (SABR) in terms of dose constraints at organ at risk (according to QUANTEC review) 9. Patients must have adequate organ function defined by the following laboratory results obtained within 14 days prior to the first study treatment: 1. absolute neutrophil count of =1 500 /mm³ 2. platelets = 100 000/mm³ 3. haemoglobin >9 g/dL (transfusions allowed) 4. creatinine clearance >60 mL/min 5. bilirubin =1.5 X upper limit of normal (ULN) (unless Gilbert's syndrome where 3 X ULN is permitted) 6. serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =2.5 X ULN (unless documented liver metastasis where =5 X ULN is permitted) 7. Alkaline phosphatase (ALP) =2.5 X ULN (unless documented bone or liver metastasis where =5 X ULN is permitted) 8. International normalized ratio (INR), prothrombin (PT), and prothrombin time (PTT) =1.5 X ULN (unless the subject is receiving anticoagulant therapy) 10. Woman of childbearing potential and male patients must agree to use adequate contraception for the duration of study participation and up to 6 months after completing treatment/therapy 11. Patients affiliated to the social security system (or equivalent) 12. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits, and examinations including follow-up NON-INCLUSION CRITERIA: 1. Non-squamous NSCLC with targetable tumor mutations, activating EGFR mutations or ALK translocation Note: documentation of these mutation for non-squamous histology is mandatory as standard of care 2. Stage IIIB/IIIC NSCLC patient eligible to curative (thoracic radiotherapy or surgery) treatments in first line treatment 3. Prior therapy with T-cell costimulation or checkpoint-targeted agents Note: Stage I-III NSCLC who previously received single-agent anti-PD(L)1 immunotherapy and ultimately develop metastases remain eligible (minimal immunotherapy washout period of 3 months) 4. Clinical need of radiotherapy (e.g.: whole brain irradiation, painful metastasis, bleeding, compressive metastases) 5. Irradiation within 2 months before inclusion 6. Leptomeningeal carcinomatosis, or metastases with indistinct borders making targeting not feasible 7. Patient with evidence of active (presence of symptoms or requiring steroid treatment) central nervous system (CNS) metastases and/or carcinomatous meningitis. Patient with brain metastasis can be included if asymptomatic and not requiring steroids 8. Metastases located within 3 cm of the previously irradiated structures (EQD2doses): 1. Spinal cord previously irradiated to >40 Gy; 2. Brachial plexus previously irradiated to >50 Gy; 3. Small intestine, large intestine, or stomach previously irradiated to >45 Gy; 4. Brainstem previously irradiated to >50 Gy; 5. Lung previously irradiated with prior V20Gy >30% 9. Active autoimmune disease except vitiligo, type-1 diabetes, hypothyroid stabilized with hormonal substitution, psoriasis 10. Symptomatic interstitial lung disease 11. Systemic immunosuppression or systemic immunosuppressive medicinal products within 2 weeks prior to study entry 12. Concomitant treatment with steroids > 10 mg Note1: higher dose of steroids can be prescribed in case of occurrence of toxicities during radiotherapy; prophylactic dose of maximum 1 mg per kg during 2 weeks are authorized during the delivery of more than 6 Gy per fraction Note2: temporary use of steroid (less than 4 weeks) at a dose of 1 mg/kg is accepted 13. Prior invasive malignancy within the past 2 years (except non-melanomatous skin cancer non-invasive carcinoma in-situ of the breast, oral cavity, bladder or cervix) 14. Known Acquired Immune Deficiency Syndrome (AIDS) or severe uncontrolled co-morbidity 15. Known currently active infection including hepatitis B and hepatitis C 16. Patient who was administered a live, attenuated vaccine within 28 days prior to enrolment 17. Patient with any other disease or illness that requires hospitalisation or is incompatible with the study treatment are not eligible. Patient unable to comply with study obligations for geographic, social, or physical reasons, or who is unable to understand the purpose and procedures of the study 18. Patient who have taken any investigational medicinal product or have used an investigational device within 30 days of inclusion 19. Pregnant or breast feeding woman 20. Person deprived of their liberty or under protective custody or guardianship 21. If pemetrexed: patient is unable or unwilling to take folic acid or vitamin B12 supplementation 22. Pre-existing peripheral neuropathy of a severity of grade = 2 by NCI CTCAE v5.0 23. Known hypersensitivity to one of the compounds or substances used in this protocol 24. Major surgery within the 28 days before initiating study treatment

Study Design


Related Conditions & MeSH terms


Intervention

Radiation:
Radiotherapy
Irradiation technique (3D-CRT or SABR) will be at physician discretion.
Drug:
Pembrolizumab
pembrolizumab will be administered as per standard of care every 3 weeks until progression or toxicity
Chemotherapy
for squamous NSCLC carboplatin AUC6, paclitaxel 200 mg/m² every 3 weeks for 4 cycles; for non-squamous NSCLC carboplatin AUC5 or cisplatin 75 mg/m² every 3 weeks for 4 cycles, and pemetrexed 500 mg/m² every 3 weeks until progression or toxicity

Locations

Country Name City State
France Institut de Cancérologie de l'Ouest - Site Paul Papin Angers
France Centre Marie Curie Arras
France Hôpital Privé Arras Les Bonnettes Arras
France Institut Sainte Catherine Avignon
France Centre Pierre Curie Beuvry
France Clinique Ambroise Pare Beuvry
France Hôpital Simone Veil Blois Blois
France Institut Bergonie Bordeaux
France CHRU de Brest Brest
France Centre François Baclesse Caen
France Centre Hospitalier Universitaire De Caen - Hôpital Cote De Nacre Caen
France Centre Hospitalier Dr Jean-Eric TECHER Calais
France Centre hospitalier de Cannes Simone Veil Cannes
France Centre Hospitalier William Morey Chalon Sur Saone
France Institut de Cancérologie de Bourgogne Chalon-sur-Saône
France Pôle départemental de Cancérologie Libérale 37 Chambray-lès-Tours
France Centre Jean Perrin Clermont-Ferrand
France Centre Hospitalier Intercommunal De Creteil Créteil
France Centre Georges Francois Leclerc Dijon
France Institut de Cancérologie de Bourgogne Dijon
France Polyclinique du Parc Drevon Dijon
France Centre André DUTREIX Dunkerque
France Centre Hospitalier de Dunkerque Dunkerque
France Centre de radiothérapie et de cancérologie de Blois La Chaussée-Saint-Victor
France CHU Sud de la Réunion La Réunion
France Hôpital de Bicêtre Le Kremlin-Bicêtre
France Centre Oscar Lambret Lille
France Clinique Chenieux Limoges
France Hôpital Européen Marseille Marseille
France Hôpital Privé Clairval Marseille
France Centre Hospitalier de Montelimar Montélimar
France Centre de cancérologie du grand Montpellier-Clinique Clementville Montpellier
France Centre Hospitalier des Pays de Morlaix Morlaix
France Centre Azuréen De Cancérologie Mougins
France Hôpital Privé Arnault Tzanck Mougins
France Centre Antoine Lacassagne Nice
France CHU de Nîmes Nîmes
France Fondation Hôpital Saint-Joseph Paris
France Hopital Pitie Salpetriere Paris
France Hopital Tenon Paris
France Centre Catalan d'Oncologie Perpignan
France Institut Jean Godinot Reims
France Centre Frédéric JOLIOT Rouen
France Centre Henri Becquerel Rouen
France Clinique Saint-Hilaire Rouen
France Hopital Charles Nicolle Rouen
France Institut Curie - Hôpital René Huguenin Saint-Cloud
France CHU St Etienne Saint-Étienne
France Centre Joliot Curie Saint-Martin-Boulogne
France Centre Paul Strauss Strasbourg
France Polyclinique de l'Ormeau Tarbes
France CHU de Toulouse Hôpital Larrey Toulouse
France Institut Claudius Regaud Toulouse
France Centre Marie Curie Valence
France Hôpital Privé Drôme Ardèche Valence
France Institut De Cancerologie De Lorraine Vandœuvre-lès-Nancy
France Gustave Roussy Villejuif
Monaco Centre Hospitalier Princesse Grace Monaco

Sponsors (2)

Lead Sponsor Collaborator
UNICANCER National Cancer Institute, France

Countries where clinical trial is conducted

France,  Monaco, 

Outcome

Type Measure Description Time frame Safety issue
Primary 1-year Overall Survival The primary endpoint of this trial is overall survival (OS) defined as the time from randomization to the date of documented death from any cause or last follow-up. 1 year
Secondary Tumour response Tumour response is defined as the percentage of patients with a complete response (CR) or partial response (PR), according to RECIST 1.1 and iRECIST (centralized response evaluation). 1 year
Secondary Progression-free survival Progression-free survival (PFS) is defined as the time from randomization until documented disease progression (PD) according to RECIST 1.1 and iRECIST (centralized response evaluation for both arms), or death, whichever occurs first. 1 year
Secondary Local and distant controls in irradiated patients Local and distant controls in irradiated patients are defined as the time from randomization to the first documented local event or distant event. 6 months and 1 year
Secondary Quality of life of the patients using EORTC-QLQ-C 30 Quality of life will be assessed using QLQ-C 30 questionnaire from the European Organization for Research and Treatment of Cancer (EORTC). It is a 30-item self-reporting questionnaire developed to assess the quality of life of cancer patients. It is grouped into five functional subscales (role, physical, cognitive, emotional and social functioning). In addition, there are three multi-item symptom scales (fatigue, pain, and nausea and vomiting), individual questions concerning common symptoms in cancer patients,and two questions assessing overall Quality of Life up to 2 years
Secondary Acute/Late toxicities Acute/ late toxicity will be assessed according to the flowchart and graded by CTCAE v5 1 year
Secondary Non-small lung cancer specific survival To evaluate, compared to standard of care, whether the addition of radiotherapy improves survival of patients until death from non-small lung cancer 1 year
Secondary 2-year Overall survival Overall survival (OS) is defined as the time from randomization to the date of documented death from any cause or last follow-up. 2 years
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