Informations générales (source: ClinicalTrials.gov)
PD-1 Inhibitor and Chemotherapy With Concurrent Irradiation at Varied Tumour Sites in Advanced Non-small Cell Lung Cancer (NIRVANA-LUNG)
Interventional
Phase 3
UNICANCER (Voir sur ClinicalTrials)
janvier 2018
juillet 2027
21 septembre 2024
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.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CHI DE CRETEIL | Isabelle MONNET | 29/03/2024 01:28:31 | Contacter | ||
| CLCC INSTITUT CURIE | 04/06/2024 14:01:28 | Contact (sur clinicalTrials) | |||
| CLCC INSTITUT GUSTAVE ROUSSY | Antonin LEVY | 18/03/2024 11:06:01 | Contacter | ||
| CLCC RENE HUGUENIN INSTITUT CURIE | 04/09/2024 13:49:32 | Contact (sur clinicalTrials) | |||
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| AP-HP - Hôpital La Pitié-Salpêtrière | Contact (sur clinicalTrials) | ||||
| AP-HP - Hôpital Tenon | Contact (sur clinicalTrials) | ||||
| GH PARIS SITE SAINT JOSEPH | Contact (sur clinicalTrials) | ||||
| Les établissements hors Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Centre Antoine Lacassagne - Nice - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier Universitaire De Caen - Hôpital Cote De Nacre - Caen - France | Contact (sur clinicalTrials) | ||||
| Centre Jean Perrin - Clermont-Ferrand - France | Contact (sur clinicalTrials) | ||||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Centre André DUTREIX - Dunkerque - France | Contact (sur clinicalTrials) | ||||
| Centre Azuréen De Cancérologie - Mougins - France | Contact (sur clinicalTrials) | ||||
| Centre Catalan d'Oncologie - Perpignan - France | Contact (sur clinicalTrials) | ||||
| Centre de cancérologie du grand Montpellier-Clinique Clementville - Montpellier - France | Contact (sur clinicalTrials) | ||||
| Centre de radiothérapie et de cancérologie de Blois - La Chaussée-Saint-Victor - France | Contact (sur clinicalTrials) | ||||
| Centre Frédéric JOLIOT - Rouen - France | Contact (sur clinicalTrials) | ||||
| Centre Henri Becquerel - Rouen - France | Contact (sur clinicalTrials) | ||||
| Centre hospitalier de Cannes Simone Veil - Cannes - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier de Dunkerque - Dunkerque - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier de Montelimar - Montélimar - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier des Pays de Morlaix - Morlaix - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier Dr Jean-Eric TECHER - Calais - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier William Morey - Chalon Sur Saone - France | Contact (sur clinicalTrials) | ||||
| Centre Joliot Curie - Saint-Martin-Boulogne - France | Contact (sur clinicalTrials) | ||||
| Centre Marie Curie - Arras - France | Contact (sur clinicalTrials) | ||||
| Centre Marie Curie - Valence - France | Contact (sur clinicalTrials) | ||||
| Centre Oscar Lambret - Lille - France | Contact (sur clinicalTrials) | ||||
| Centre Paul Strauss - Strasbourg - France | Contact (sur clinicalTrials) | ||||
| Centre Pierre Curie - Beuvry - France | Contact (sur clinicalTrials) | ||||
| CHRU de Brest - Brest - France | Contact (sur clinicalTrials) | ||||
| CHU de Nîmes - Nîmes - France | Contact (sur clinicalTrials) | ||||
| CHU de Toulouse Hôpital Larrey - Toulouse - France | Contact (sur clinicalTrials) | ||||
| CHU St Etienne - Saint-Étienne - France | Contact (sur clinicalTrials) | ||||
| CHU Sud de la Réunion - La Réunion - France | Contact (sur clinicalTrials) | ||||
| Clinique Ambroise Pare - Beuvry - France | Contact (sur clinicalTrials) | ||||
| Clinique Chenieux - 87039 - Limoges - France | Contact (sur clinicalTrials) | ||||
| Clinique Saint-Hilaire - Rouen - France | Contact (sur clinicalTrials) | ||||
| Hopital Charles Nicolle - Rouen - France | Contact (sur clinicalTrials) | ||||
| Hôpital de Bicêtre - Le Kremlin-Bicêtre - France | Contact (sur clinicalTrials) | ||||
| Hôpital Européen Marseille - Marseille - France | Contact (sur clinicalTrials) | ||||
| Hôpital Privé Arnault Tzanck - Mougins - France | Contact (sur clinicalTrials) | ||||
| Hôpital Privé Arras Les Bonnettes - Arras - France | Contact (sur clinicalTrials) | ||||
| Hôpital Privé Clairval - Marseille - France | Contact (sur clinicalTrials) | ||||
| Hôpital Privé Drôme Ardèche - Valence - France | Contact (sur clinicalTrials) | ||||
| Hôpital Simone Veil Blois - Blois - France | Contact (sur clinicalTrials) | ||||
| Institut Bergonie - Bordeaux - France | Contact (sur clinicalTrials) | ||||
| Institut Claudius Regaud - Toulouse - France | Contact (sur clinicalTrials) | ||||
| Institut Curie - Hôpital René Huguenin - Saint-Cloud - France | Contact (sur clinicalTrials) | ||||
| Institut de Cancérologie de Bourgogne - Chalon-sur-Saône - France | Contact (sur clinicalTrials) | ||||
| Institut de Cancérologie de Bourgogne - Dijon - France | Contact (sur clinicalTrials) | ||||
| Institut De Cancerologie De Lorraine - Vandœuvre-lès-Nancy - France | Contact (sur clinicalTrials) | ||||
| Institut de Cancérologie de l'Ouest - Site Paul Papin - Angers - France | Contact (sur clinicalTrials) | ||||
| Institut Jean Godinot - Reims - France | Contact (sur clinicalTrials) | ||||
| Institut Sainte Catherine - Avignon - France | Contact (sur clinicalTrials) | ||||
| Pôle départemental de Cancérologie Libérale 37 - Chambray-lès-Tours - France | Contact (sur clinicalTrials) | ||||
| Polyclinique de l'Ormeau - Tarbes - France | Contact (sur clinicalTrials) | ||||
| Polyclinique du Parc Drevon - Dijon - France | Contact (sur clinicalTrials) | ||||
Critères
Tous
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
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