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NIvolumab COmbination With Standard First-line Chemotherapy and Radiotherapy in Locally Advanced Stage IIIA/B Non-Small Cell Lung Carcinoma (NICOLAS)

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ClinicalTrials.gov Identifier: NCT02434081
Recruitment Status : Completed
First Posted : May 5, 2015
Results First Posted : October 25, 2021
Last Update Posted : August 24, 2022
Bristol-Myers Squibb
Frontier Science Foundation, Hellas
Information provided by (Responsible Party):
ETOP IBCSG Partners Foundation

Brief Summary:
The aim of the study is to investigate the tolerability (how severe the side effects are) and the efficacy (how well the treatment works) when nivolumab is added to the current standard treatment (chemotherapy and radiotherapy) given to patients with advanced NSCLC.

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Stage III Drug: Nivolumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 94 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial Evaluating the Safety and Efficacy of the Addition of Concurrent Anti-PD 1 Nivolumab to Standard First-line Chemotherapy and Radiotherapy in Locally Advanced Stage IIIA/B Non-Small Cell Lung Carcinoma
Actual Study Start Date : November 25, 2015
Actual Primary Completion Date : February 29, 2020
Actual Study Completion Date : March 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Chemo-radiotherapy with concurrent nivolumab
4 doses of nivolumab 360mg concurrently with standard chemo-radiotherapy, followed by 480mg for up to 1 year from start of nivolumab treatment.
Drug: Nivolumab
Nivolumab is a fully human monoclonal antibody that targets the programmed death-1 (PD-1) cell surface membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and B lymphocytes.Binding of PD-1 to its ligands, 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte activation. Nivolumab inhibits the interaction of programmed cell death Protein 1 (PD-1)with its ligands, PD-L1 and PD-L2, resulting in enhanced T-cell proliferation.
Other Name: BMS-936558

Primary Outcome Measures :
  1. Grade ≥3 Pneumonitis (CTCAE v4.0) up to 6 Months Post-radiotherapy [ Time Frame: Time from enrolment until 6 months post-radiotherapy ]
    It is defined as the number of patients reaching up to 6 months post-radiotherapy without any episode of CTCAE v4.0 grade ≥3 pneumonitis. It will be used as the primary endpoint for all patients followed for at least 6 months beyond radiotherapy.

Secondary Outcome Measures :
  1. Progression-free Survival by RECIST v1.1 (PFS) [ Time Frame: From the date of enrolment of the first patient up to 3 years, which is also 1 year after the enrolment of the last patient (i.e., from September 2016 to September 2019) ]

    PFS, κey secondary endpoint, is defined as the time from the date of enrolment until first documented progression or death, if progression is not documented. For patients without a PFS event, censoring occurs at the last tumour assessment.

    Database cutoff: 18 September 2019

  2. (Grade ≥3) Pneumonitis-free Rate [ Time Frame: From the date of enrolment of the first patient up to 3 years, which is also 1 year after the enrolment of the last patient (i.e., from September 2016 to September 2019) ]
    Rate of TFP3, evaluated at 1-year based on Kaplan-Meier method, where TFP3 is defined as the time from the date of enrolment until first documented pneumonitis of grade ≥3.

  3. Objective Response Rate (ORR) [ Time Frame: From the date of enrolment of the first patient up to 3 years, which is also 1 year after the enrolment of the last patient (i.e., from September 2016 to September 2019) ]

    Objective response rate (ORR) is defined as the percentage of patients with objective response (OR).

    OR was determined using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). OR is defined as the best overall response (Complete Response (disappearance of all target and non-target lesions; no new lesions) or Partial Response (≥decrease in the sum of the largest diameters of target lesions; no new lesions)) across all assessment points from enrollment to termination of trial treatment. Radiological tumour assessment was performed using CT scans.

  4. Time to Treatment Failure (TTF). [ Time Frame: From the date of enrolment of the first patient up to 3 years, which is also 1 year after the enrolment of the last patient (i.e., from September 2016 to September 2019) ]
    Time to treatment failure (TTF) is defined as time from enrolment to discontinuation of trial treatment for any reason. Disease progression, treatment toxicity, death, withdrawal and lost to follow-up which occurred after treatment completion are viewed as events.

  5. Overall Survival (OS) [ Time Frame: From the date of enrolment of the first patient up to 4 years (i.e., from September 2016 to September 2020). ]
    OS is defined as the time from the date of enrolment until death from any cause. The patients without OS event (death) were censored at their last follow-up date

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically or cytologically confirmed non small cell lung carcinoma
  • Locally advanced stage IIIA or III B (T0-3 N2-3 or T4N0-3 M0) NSCLC, according to 7th TNM classification.

Within 35 days before beginning of first platinum-based chemotherapy cycle:

  • Nodal status N2 or N3 must to be proven (by biopsy, EBUS, mediastinoscopy or thoracoscopy) except for overt cT4 disease.
  • Whole body FDG-PET, plus contrast enhanced CT of thorax / upper Abdomen (from top of thorax until adrenal glands, and full liver and kidney included) in addition to or in combination with PET.
  • Brain MRI (preferred) or high-quality brain CT with intravenous contrast at the time of staging mandatory.
  • Measurable disease (according to RECIST v1.1 criteria)
  • Age ≥ 18 years
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
  • Life expectancy > 3 months
  • Previous delivery of a maximum of one 3-weekly cycle of platinum-based chemotherapy
  • All AEs from previous therapies (including the first chemotherapy cycle in the context of this trial) resolved to grade <2 (except fatigue, alopecia, nausea, lack of appetite and peripheral neuropathy).
  • Adequate haematological function:
  • WBC ≥ 2000/μL
  • haemoglobin ≥ 9 g/dL
  • neutrophil count ≥ 1×109/L
  • platelet count ≥ 100 × 109/L
  • Adequate liver function:
  • Total bilirubin ≤ 1.5 x ULN (except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dl)
  • ALT ≤3 × ULN
  • alkaline phosphatase ≤ 5 x ULN.
  • Adequate renal function: Calculated creatinine clearance ≥ 30 ml/min (according to Cockroft-Gault):
  • ≥60ml/min for patient receiving cisplatin
  • ≥30ml/min for patient receiving carboplatin.
  • Pulmonary function FEV1 of 1.0 l or > 40% predicted value and DLCO > 30% predicted value
  • Patient capable of proper therapeutic compliance, and accessible to correct follow-up.
  • Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before trial enrolment. The test must be repeated within 24 hours before beginning nivolumab treatment and then before every 2nd nivolumab administration. Pregnancy tests should be repeated at approximately 30 days and approximately 70 days after nivolumab treatment stops.
  • Written Informed Consent (IC) for trial treatment must be signed and dated by the patient and the investigator prior to any trial-related evaluation and/or intervention.

Exclusion Criteria:

  • Patient with mixed small-cell and non-small-cell histologic features
  • Patient with pleural or pericardial effusions proven to be malignant
  • Prior chemotherapy, radiotherapy or molecular targeted therapy for NSCLC (with the exception of one cycle of chemotherapy given prior to enrolment into this trial)
  • Patients with an active, known or suspected autoimmune disease. Patients are permitted to enrol if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
  • Patient who has had in the past 3 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast.
  • Patient with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical processes that could affect the patient's capacity to participate in the trial.
  • Ongoing clinically serious infections requiring systemic antibiotic or antiviral, antimicrobial, antifungal therapy.
  • Known or suspected hypersensitivity to nivolumab or any of its excipients
  • History of severe hypersensitivity reaction to any monoclonal antibody
  • Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the trial or evaluation of the trial results.
  • Established pathological diagnosis of underlying interstitial lung disease or pulmonary fibrosis
  • Women who are pregnant or in the period of lactation
  • Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the trial treatment and for a period of at least 7 months (male participants) and 5 months (female participants) following the last administration of nivolumab.
  • Patients receiving any concurrent anticancer systemic therapy
  • HIV, active Hepatitis B or Hepatitis C infection
  • Previous radiotherapy to the thorax (prior to inclusion), including radiotherapy for breast cancer
  • Planned radiotherapy to lung of mean dose > 20 Gy or V20 > 35 %
  • Patient who received treatment with an investigational drug agent during the 3 weeks before enrolment in the trial
  • Metastatic disease (mandatory assessment of the brain either by MRI or high-quality CT with intravenous contrast at the time of staging as well as systemic PET and CT scan)
  • Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways

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): NCT02434081

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University Hospital Leuven
Leuven, Belgium
Thoracic Oncology Centre Munich
Munich, Germany
Amsterdam, Netherlands
Maastricht, Netherlands, 6229 ET
Vall d'Hebron University Hospital
Barcelona, Spain, 08035
Catalan Institute of Oncology
Barcelona, Spain, 08907
Hospital Virgen de la Salud
Toledo, Spain, 45071
HFR Fribourg- Hôpital cantonal
Fribourg, Switzerland, 1708
Kantonsspital Winterthur
Winterthur, Switzerland, 8401
Hirslanden Klinik Zürich
Zurich, Switzerland, 8032
University Hospital Zürich
Zürich, Switzerland
Sponsors and Collaborators
ETOP IBCSG Partners Foundation
Bristol-Myers Squibb
Frontier Science Foundation, Hellas
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Study Chair: Solange Peters, MD PhD University of Lausanne Hospitals
Study Chair: Dirk De Ruysscher, MD PhD Maastro Clinic, Maastricht, The Netherlands
  Study Documents (Full-Text)

Documents provided by ETOP IBCSG Partners Foundation:
Study Protocol  [PDF] July 4, 2017
Statistical Analysis Plan  [PDF] June 10, 2019

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Responsible Party: ETOP IBCSG Partners Foundation
ClinicalTrials.gov Identifier: NCT02434081    
Other Study ID Numbers: ETOP 6-14 NICOLAS
2014-005097-11 ( EudraCT Number )
SNCTP000001672 ( Registry Identifier: Swiss National Clinical Trials Portal (SNCTP) )
First Posted: May 5, 2015    Key Record Dates
Results First Posted: October 25, 2021
Last Update Posted: August 24, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by ETOP IBCSG Partners Foundation:
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action