NIvolumab COmbination With Standard First-line Chemotherapy and Radiotherapy in Locally Advanced Stage IIIA/B Non-Small Cell Lung Carcinoma
Condition: Non-small Cell Lung Cancer Stage III
MeSH terms: Carcinoma, Non-Small-Cell Lung; Lung Neoplasms
Intervention: Nivolumab
Intervention description: 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.
Intervention MeSH terms: Nivolumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 94.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: NSCLC; IIIA/B

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.
    

Eligibility criteria:

        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