PembROlizuMab Immunotherapy Versus Standard Chemotherapy for Advanced prE-treated Malignant Pleural Mesothelioma
Condition: Pleural Mesothelioma Malignant Advanced
MeSH terms: Mesothelioma; Mesothelioma, Malignant
Intervention: Pembrolizumab; Gemcitabine; Vinorelbine
Intervention description: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.; Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the "faulty" nucleoside, resulting in apoptosis (cellular "suicide").; Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.
Intervention MeSH terms: Gemcitabine; Pembrolizumab; Vinorelbine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 144.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: MPM

Summary:

      Trial comparing standard treatment (chemotherapy) with pembrolizumab treatment in patients
      with advanced pretreated malignant mesothelioma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed malignant pleural mesothelioma (all subtypes are eligible)

          -  Progressing after or on previous platinum based chemotherapy.

          -  Availability of tumour tissue for translational research.

          -  Female and male patients aged 18 years or over.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

          -  Life expectancy of at least 3 months.

          -  Measurable or evaluable disease according to RECIST 1.1 criteria.

          -  Adequate renal function

          -  Creatinine 1.5 × Upper Limit of Normal (ULN) OR Calculated creatinine clearance 40
             mL/min (using the Cockroft-Gault formula).

          -  Adequate haematological function

          -  Haemoglobin 90 g/L or 5.6 mmol/L

          -  White Blood Cell (WBC) 1.0 × 109/L

          -  Lymphocytes 0.5 g/L

          -  Absolute neutrophils count (ANC) 1.5 × 109/L

          -  Platelet count 100 × 109/L.

          -  Adequate liver function

          -  ALT and AST 2.5 × ULN. If the patient has liver metastases, ALT and AST must be ≤5 ×
             ULN.

          -  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 35 days
             before randomisation (the test has to be repeated 72 hours before pembrolizumab
             treatment start).

          -  Written informed consent must be signed and dated by the patient and the investigator
             prior to any trial-related intervention including the submission of mandatory
             biomaterial.

        Exclusion Criteria:

          -  Prior therapy with an anti-programmed cell death protein 1 (anti-PD-1),
             anti-programmed cell death ligand 1 (anti-PD-L1), anti-programmed cell death ligand 2
             (anti-PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)
             antibody (including ipilimumab or any other antibody or drug specifically targeting
             T-cell co-stimulation or checkpoint pathways).

          -  Prior therapy with gemcitabine or vinorelbine.

          -  Known active central nervous system metastases and/or carcinomatous meningitis.
             Patients with previously treated brain metastases may participate provided they are
             stable (without evidence of progression by imaging for at least 4 weeks prior to
             randomisation and any neurologic symptoms have returned to baseline), have no evidence
             of new or enlarging brain metastases, and are not using steroids for at least 7 days
             prior to randomisation. This exception does not include carcinomatous meningitis,
             which is excluded regardless of clinical stability.

          -  Known or suspected hypersensitivity to pembrolizumab or any of its excipients.

          -  Known unstable or unresolved surgical or chemotherapy-related toxicity that would
             compromise the patient's capacity to participate in the trial.

          -  Previous allogeneic tissue/solid organ transplant.

          -  Live vaccines within 30 days prior to first dose of pembrolizumab.

          -  Regular intake of immune-modulating drugs (such as interferon, methotrexate).

          -  History of (non-infectious) pneumonitis that required steroids, evidence of
             interstitial lung disease or active, non-infectious pneumonitis.

          -  Active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) or topical therapy
             (e.g., steroids) for psoriasis or eczema is not considered a form of systemic
             treatment.

          -  Ongoing clinically serious infections requiring systemic antibiotic or antiviral,
             antimicrobial, or antifungal therapy.

          -  Human immunodeficiency virus (HIV) infection.

          -  Known active hepatitis B or hepatitis C.

          -  Known history of active tuberculosis.

          -  Patients with diagnosed immunodeficiency or receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to randomisation.

          -  Patients with other serious diseases or clinical conditions, including but not limited
             to uncontrolled active infection and any other serious underlying medical condition
             that could affect the patient's capacity to participate in the trial.

          -  Substance abuse, medical, psychological or social conditions that may interfere with
             the patient's participation in the trial or evaluation of the trial results.

          -  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 and up to 120 days following cessation
             of trial treatment.