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PD-(L)1 Inhibitors With Concurrent Irradiation at Varied Tumour Sites in Advanced Non-small Cell Lung Cancer (NIRVANA-LUNG)

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ClinicalTrials.gov Identifier: NCT03774732
Recruitment Status : Suspended (Temporary suspension since March 13 due to COVID-19 pandemic)
First Posted : December 13, 2018
Last Update Posted : April 20, 2020
Sponsor:
Collaborator:
National Cancer Institute, France
Information provided by (Responsible Party):
UNICANCER

Brief 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 new strategies are required to improve survival of these patients.

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 analyzing the combination of IR and anti-PD1 in NSCLC are on-going. Among them, 2 studies are testing the administration of IR and nivolumab in stage III NSCLC.

The feasibility and efficacy of the combination of anti-PD(L)1 therapy and radiotherapy to Advanced NSCLC, which is the purpose of this proposed study (NIRVANA-Lung), has not yet been evaluated in France. This phase 3 study will evaluate the addition of IR to anti-PD1 inhibition with nivolumab, pembrolizumab or atezolizumab in advanced NSCLC patients (IIIB/IIIC/IV).


Condition or disease Intervention/treatment Phase
Non Small Cell Lung Cancer Non Small Cell Lung Cancer Metastatic Non-Small Cell Carcinoma of Lung, TNM Stage 4 Radiation: Radiotherapy Drug: Anti-PD(L)-1 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 510 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PD-(L)1 Inhibitors With Concurrent Irradiation at Varied Tumour Sites in Advanced Non-small Cell Lung Cancer
Actual Study Start Date : March 21, 2019
Estimated Primary Completion Date : May 15, 2022
Estimated Study Completion Date : May 15, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Anti-PD(L) 1 + Radiotherapy

In the experimental arm, patient will receive the same treatment as the control arm in addition with conformal 3D radiotherapy (3D-CRT) or stereotactic ablative radiotherapy (SABR) that will be delivered 15 days after the beginning of immunotherapy using photons/electrons with standard field encompassing tumour.

Irradiation technique (3D-CRT or SABR) will be at physician discretion. Ideally, oligometastatic patient (defined by the presence of less than 6 metastases) should be treated with SABR and non-oligometastatic patient should be treated with 3D-CRT.

Radiotherapy will be delivered at least a dose of 18 Gy in 3 X 6 Gy for 3D-CRT. Irradiated tumor size will be ≤5 cm (GTV < 65 mL sphere); partial tumor irradiation should be delivered if larger tumor size while respecting dose constraints.

Radiation: Radiotherapy
Irradiation technique (3D-CRT or SABR) will be at physician discretion.
Other Name: 3D-CRT or SABR

Drug: Anti-PD(L)-1
Anti-PD-(L)1: Nivolumab, atezolizumab or pembrolizumab will be administered as per standard of care
Other Name: Nivolumab, atezolizumab or pembrolizumab

Active Comparator: Anti-PD(L) 1

Anti-PD-(L)1 will be administered as per standard of care:

The anti-PD-1 antibody nivolumab will be administered at a dose of 3 mg/kg every 2 weeks.

The anti-PD-1 antibody pembrolizumab will be administered at a dose of 200 mg (1st line) or 2 mg/kg (2nd line) every 3 weeks.

The anti-PD-L1 antibody atezolizumab will be administered at a dose of 1 200 mg every 3 weeks.

Immunotherapy treatment may be continued as long as patient is experiencing clinical benefit, as assessed by an investigator, in the absence of unacceptable toxicity or symptomatic deterioration attributed to disease progression after an integrated assessment of radiographic data, biopsy results (if available) and clinical status.

Drug: Anti-PD(L)-1
Anti-PD-(L)1: Nivolumab, atezolizumab or pembrolizumab will be administered as per standard of care
Other Name: Nivolumab, atezolizumab or pembrolizumab




Primary Outcome Measures :
  1. Overall Survival [ Time Frame: 2 years ]
    Overall Survival (OS) rate is defined as the time from randomization to the date of documented death from any cause or last follow-up.OS rate will be reported at 2 years


Secondary Outcome Measures :
  1. Tumour response [ Time Frame: 1 and 2 years ]
    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).

  2. Progression-free survival [ Time Frame: 1 and 2 years ]
    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.

  3. Local and distant controls in irradiated patients [ Time Frame: 6 months and 1 years ]
    Local and distant controls in irradiated patients are defined as the time from randomization to the first documented local event or distant event.

  4. Quality of life of the patients using EORTC-QLQ-C 30 [ Time Frame: up to 2 years ]
    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

  5. Acute/Late toxicities [ Time Frame: up to 2 years ]
    Acute/ late toxicity will be assessed according to the flowchart and graded by CTCAE v5



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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. Availability of tumoral PD-L1 status if pembrolizumab used (for the other drugs if possible tumoral PD-L1 status or tumor sample to assess it).
  4. First-line treatment only: NSCLC patients eligible for treatment with pembrolizumab according to the European Marketing Authorisation as a first line:

    1. no EGFR, ALK, or ROS-1 positive tumour mutations,
    2. Tumoral expression of PD-L1 ≥50%.
  5. Second (third)-line treatment: NSCLC patients eligible for treatment with a PD-1 or PD-L1 antagonist according to the European Marketing Authorisation as a second line:

    1. Previous treatment with chemotherapy and/or targeted treatment,
    2. Patients with EGFR, ALK, or ROS-1 positive tumour mutations should also have received targeted therapy before receiving nivolumab, pembrolizumab or atezolizumab,
    3. PD-L1 >1% for patients receiving pembrolizumab; any tumoral PD-L1 status for those receiving nivolumab or atezolizumab.
  6. Second line treatment: non-radically treatable stage IIIB/C or IV disease that has progressed on or after platinum-based chemotherapy and/or targeted therapy (targeting EGFR mutation or ALK translocation or ROS-1 translocation)
  7. Patient ≥18 and ≤80 years of age.
  8. ECOG performance status 0 - 1.
  9. Life expectancy >3 months.
  10. Measurable lesion as assessed by RECIST version 1.1.
  11. Metastases 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).
  12. 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 >30 mL/min,
    5. bilirubin ≤1.5 X upper limit of normal (ULN) (unless Gilbert 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. INR , PT, PTT ≤1.5 x ULN (unless the subject is receiving anticoagulant therapy).
  13. 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.
  14. Patients affiliated to the social security system.
  15. 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. Patient with targetable tumor mutations, activating EGFR mutations, ROS-1 translocation 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.
  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 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 (equivalent dose of prednisone >10 mg/kg) treatment: otherwise it has to be stopped 7 days before inclusion.
  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. Active hepatitis B or C.
  16. Patient who was administered a live, attenuated vaccine within 28 days prior to enrolment.
  17. Patient with any other disease or illness which 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03774732


Locations
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France
Centre Antoine Lacassagne
Nice, France
Gustave Roussy
Villejuif, France
Sponsors and Collaborators
UNICANCER
National Cancer Institute, France
Investigators
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Principal Investigator: Jérôme DOYEN, MD Centre Antoine Lacassagne
Principal Investigator: Antonin LEVY, MD Gustave Roussy, Cancer Campus, Grand Paris
Principal Investigator: Benjamin BESSE, MD Gustave Roussy, Cancer Campus, Grand Paris
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Responsible Party: UNICANCER
ClinicalTrials.gov Identifier: NCT03774732    
Other Study ID Numbers: UC-0107/1718
First Posted: December 13, 2018    Key Record Dates
Last Update Posted: April 20, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by UNICANCER:
NSCLC
radiotherapy
immunotherapy
PD(L)-1blockage
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Pembrolizumab
Nivolumab
Atezolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents