PD-1 Inhibitor and Chemotherapy With Concurrent Irradiation at Varied Tumour Sites in Advanced Non-small Cell Lung Cancer

Non Small Cell Lung Cancer Clinical Trial

— NIRVANA-LUNG  

Official title:

PD-1 Inhibitor and Chemotherapy With Concurrent Irradiation at Varied Tumour Sites in Advanced Non-small Cell Lung Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03774732
• Other study ID #: UC-0107/1718
• Status: Recruiting
• Phase: Phase 3
• 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
• 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

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non Small Cell Lung Cancer
• Non Small Cell Lung Cancer Metastatic
• Non-Small Cell Carcinoma of Lung, TNM Stage 4

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