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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03774732
Recruitment Status : Recruiting
First Posted : December 13, 2018
Last Update Posted : July 28, 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 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.


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: Pembrolizumab Drug: Chemotherapy Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 460 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PD-1 Inhibitors and Chemotherapy 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: Pembrolizumab+ Chemotherapy + Radiotherapy

In the experimental arm, patients will receive the same treatment as the control arm (chemotherapy plus pembrolizumab) in addition with conformal 3D radiotherapy (3D-CRT) or stereotactic ablative radiotherapy (SABR) that will be delivered at C2D1, 21 days after the beginning of pembrolizumab 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 those with non-oligometastatic disease should be treated with 3D-CRT.

Radiotherapy will be delivered a dose of at least 18 Gy in 3 X 6 Gy for 3D-CRT (cf. protocol for possible schemes and volumes restriction).

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: Pembrolizumab
pembrolizumab will be administered as per standard of care every 3 weeks until progression or toxicity

Drug: 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
Other Name: Carboplatin, paclitaxel, nab-paclitaxel, cisplatin, pemetrexed

Active Comparator: Pembrolizumab+ Chemotherapy

Squamous-cell lung carcinoma:

Pembrolizumab every 3 weeks and carboplatin + paclitaxel or nab paclitaxel every 3 weeks for 4 cycles then pembrolizumab every 3 or 6 weeks (according to the current version of the SmPC )

Non squamous-cell lung carcinoma:

Pembrolizumab every 3 weeks and carboplatin or cisplatin + pemetrexed every 3 weeks for 4 cycles, and then pemetrexed plus pembrolizumab every 3 weeks (according to the current version of the SmPC)

Pembrolizumab 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: Pembrolizumab
pembrolizumab will be administered as per standard of care every 3 weeks until progression or toxicity

Drug: 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
Other Name: Carboplatin, paclitaxel, nab-paclitaxel, cisplatin, pemetrexed




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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 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. 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 and <75 years 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
  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
  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

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


Contacts
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Contact: Naïma BONNET, PhD +33 1 85 34 33 74 n-bonnet@unicancer.fr
Contact: Assia LAMRANI-GHAOUTI a-lamrani-ghaouti@unicancer.fr

Locations
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France
Institut Sainte Catherine Recruiting
Avignon, France
Contact: Nicolas POUREL, MD         
Institut Bergonie Recruiting
Bordeaux, France
Contact: Sophie COUSIN, MD         
Centre François Baclesse Recruiting
Caen, France
Contact: Radj GERVAIS, MD         
Centre Jean Perrin Recruiting
Clermont-Ferrand, France
Contact: Pascale DUBRAY LONGERAS         
Clinique Chenieux Recruiting
Limoges, France, 87039
Contact: Xavier ZASADNY, MD         
Centre de cancérologie du grand Montpellier-Clinique Clementville Recruiting
Montpellier, France
Contact: Emmanuel BEGUIER, MD         
Centre Antoine Lacassagne Recruiting
Nice, France
Contact: Jérôme DOYEN, MD         
Centre Paul Strauss Recruiting
Strasbourg, France
Contact: Roland SCHOTT, MD         
Institut Claudius Regaud Recruiting
Toulouse, France
Contact: Jonathan KHALIFA, M.D         
Gustave Roussy Recruiting
Villejuif, France
Contact: Antonin LEVY, MD, PhD         
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: July 28, 2020
Last Verified: July 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)-1 blockage
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
Paclitaxel
Cisplatin
Carboplatin
Pembrolizumab
Pemetrexed
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Enzyme Inhibitors
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors