Induction Chemo+Immunotherapy in Resectable Epithelioid and Biphasic Pleural Mesothelioma (CHIMERA Study)

Inclusion Criteria:

• Male/female participants who are at least 18 years of age on the day of signinginformed consent with histologically confirmed diagnosis of surgical resectablestage I-IIIA treatment-naïve epithelioid/biphasic pleural mesothelioma will beenrolled in this study.

• Diagnosis of epithelioid/biphasic pleural mesothelioma must be histologicallyconfirmed, preferably by video-assisted thoracoscopic surgery (VATS).

• At screening, complete surgical resection of the mesothelioma must be deemedachievable, as assessed by a multidisciplinary evaluation.

• The participant (or legally acceptable representative if applicable) provideswritten informed consent for the trial.

• Measurable disease, defined as at least 1 lesion measured in two positions at threeseparate levels on transverse cuts of CT scan that is suitable for repeatedassessment using modified Response Evaluation Criteria in Solid Tumours [m-RECIST 1.1] for pleural mesothelioma is preferred; however, inclusion of specific caseswithout measurable disease could be discussed with the medical monitor and duringthe multidisciplinary team discussion of the surgical centers.

• Histologically proved diagnosis of treatment-naive epithelioid/biphasic pleuralmesothelioma.

• Surgical resectable disease [stage I - II - IIIA (T1-3 - N0/1-M0) according to ninthTNM edition].

• No previous surgical resection of mesothelioma.

• Archival tumor tissue sample or newly obtained [core, incisional or excisional]biopsy of a tumor lesion not previously irradiated has been provided.Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.Newly obtained biopsies are preferred to archived tissue.

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

• Has adequate PFT defined as an FEV1 >50% (of predicted normal volume) or ≥ 1.2 L/Secand a DLCO >40% of predicted normal value. Participants for whom DLCO measurementsare not available will be deemed to have adequate oxygen transfer if pulse oximetry (O2 saturation) ≥90% room air.

• Have adequate organ function as defined in the following table (Table 3). Specimensmust be collected within 10 days prior to the start of study intervention.

Exclusion Criteria:

• Subject incapacitated to understand and voluntarily sign an ICF prior to anystudy-related assessments/procedures being conducted

• Primitive peritoneal, pericardial and tunica vaginalis testis mesotheliomas.

• Cytological diagnosis of pleural mesothelioma not histologically confirmed.

• Prior treatment with systemic anti-cancer therapy for pleural mesothelioma, priorintraoperative intracavitary chemotherapy for pleural mesothelioma, prior treatmentwith an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any otherantibody or drug specifically targeting T-cell co-stimulation or checkpointpathways.

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of study drug.

• Subjects with interstitial lung disease that is symptomatic or may interfere withthe detection or management of suspected drug-related pulmonary toxicity.

• Has uncontrolled, potentially reversible cardiac conditions, as Investigator'sjudgment (eg. Unstable ischemia, uncontrolled symptomatic arrhythmia, congestiveheart failure, QTcF prolongation > 500 millisecond) or participants with congenitallong QT syndrome.

• Has received prior radiotherapy within 2 weeks of start of study intervention orradiation-related toxicities requiring corticosteroids. Note: Two weeks or fewer ofpalliative radiotherapy for non-CNS disease is permitted. The last radiotherapytreatment must have been performed at least 7 days before the first dose of studyintervention.

• Has received an investigational agent or has used an investigational device within 4weeks prior to study intervention administration.

• Known additional malignancy that is progressing or has required active treatmentwithin the past 5 years. Note: Participants with basal cell carcinoma of the skin,squamous cell carcinoma of the skin or adequately treated carcinoma in-situ withoutevidence of disease are not excluded. Participants with low-risk early-stageprostate cancer (T1-T2a, Gleason score ≤6, and PSA <10 ng/mL) either treated withdefinitive intent or untreated in active surveillance with stable disease are notexcluded.

• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of itsexcipients.

• Has active autoimmune disease that has required systemic treatment in the past 2years except replacement therapy (eg., thyroxine, insulin, or physiologiccorticosteroid).

• History of Hepatitis B (defined as HbsAg reactive) or known active Hepatitis C virus (defined as detectable HCV RNA [qualitative]) infection.

• Has not adequately recovered from major surgery or has ongoing surgicalcomplications.

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality or other circumstance that might confound the results of the study,interfere with the participant's participation for the full duration of the study,such that it is not in the best interest of the participant to participate, in theopinion of the treating investigator.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

• Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of trial treatment.

• Has had an allogenic tissue/solid organ transplant.

• History of HIV infection. HIV testing is not required unless mandated by localhealth authority.