Durvalumab and Tremelimumab with or without Chemotherapy for the Treatment of Potentially Resectable Pleural Mesothelioma

Inclusion Criteria

• Potentially Surgically resectable suspected or confirmed MPM * Computed tomography (CT) and positron emission tomography (PET) without disease beyond ipsilateral hemithorax * CT and PET scan without obvious invasion through the chest wall and mediastinum * Surgical evaluation for resectability by experienced mesothelioma surgeons to assess whether tumor appears resectable on CT and PET. (Final resectability determination is based on intra-operative exploratory thoracotomy to assess chest wall and/or mediastinal invasion that is not apparent based on pre-operative radiological assessment. Given this assessment after enrollment, this determination will be utilized for the safety phase) * Based on the above criteria, patients will undergo planned resectional (cytoreductive) surgery for MPM [extrapleural pneumonectomy (EPP) or pleurectomy and decortication (P/D)]
• Any MPM histology (epithelial, mixed, sarcomatoid): * N0 or N1 nodal disease, as present on preoperative chest CT and/or PET/CT * N2 nodal disease * Histology and subtype may be confirmed after enrollment based on thorascopic biopsy if the pathological diagnosis is not confirmed prior to referral
• Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
• Age ≥ 18 years at time of study entry
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L ( ≥ 1500 per mm^3)
• Platelet count ≥ 100 x 10^9/L ( ≥ 100,000 per mm^3)
• Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) < 3.0
• Creatinine clearance > 50mL/min
• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN if documented liver metastases are present)
• Serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance ≥ 50 mL/min as determined by the Cockcroft-Gault equation
• Female subjects must either be of non-reproductive potential (i.e., post-menopausal by history: ≥ 60 years old and no menses for > 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry
• The subject 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
• Weight > 30 Kg

Exclusion Criteria

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study sites) or previous enrollment or randomization in the present study
• Participation in another clinical study with an investigational product during the last 3 months
• Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab
• Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) < 28 days
• Clinically significant electrocardiogram (ECG) at the investigators discretion
• Current or prior use of immunosuppressive medication within 28 days before the infusion with durvalumab or durvalumab + tremelimumab with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
• Any unresolved toxicity (> Common Terminology Criteria for Adverse Events [CTCAE] grade 2) from previous anti-cancer therapy from diseases other than MPM
• Any prior grade ≥ 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > grade 1 for disease other than MPM. Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids
• Known auto-immune conditions requiring systemic immune suppression therapy other than prednisone < 10 mg daily (or equivalent)
• History of interstitial pneumonitis of autoimmune etiology (including immune checkpoint pneumonitis) which has been symptomatic and/or treatment in the past
• History of primary immunodeficiency
• History of allogeneic organ transplant
• Intolerance of anti- PD-1/PD-L1 or CTLA-4 axis drug(s), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines or other immune-stimulatory anti-tumor agents
• Concurrent severe and/or uncontrolled medical conditions which may compromise participation in the study, including impaired heart function or clinically significant heart disease
• A concurrent diagnosis of a separate malignancy is allowed if clinically stable and does not require tumor-directed therapy
• Known history of HIV seropositivity or known acquired immunodeficiency syndrome (AIDS), hepatitis C virus (allowed if received curative therapy), acute or chronic active hepatitis B infection, or other serious chronic infection requiring ongoing treatment
• Current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment on day 1 of study drug. Patients receiving prophylactic antibiotics (e.g., for prevention of urinary tract infection or chronic obstructive pulmonary disease) are eligible
• History of leptomeningeal carcinomatosis
• Receipt of live attenuated vaccination within 30 days prior to receiving durvalumab + tremelimumab
• Female subjects who are pregnant, breastfeeding, or male or female subjects of reproductive potential who are not employing an effective method of birth control
• Any condition that, in the opinion of the investigator, would interfere with the evaluation of the study treatment or interpretation of subject safety or study results
• Presence of brain metastases regardless of whether controlled or not
• Subjects with uncontrolled seizures
• No tissue is obtainable at the time of thoracoscopy