MEDI4736 Or MEDI4736 + Tremelimumab In Surgically Resectable Malignant Pleural Mesothelioma

Subjects with MPM will undergo surgical mediastinal lymph node biopsy (cervical
mediastinoscopy) and simultaneous surgical biopsy of the pleural tumor by thoracoscopy, at
which time tumor tissue (at least 2 g) and peripheral blood will be collected for the study.
These procedures are performed as standard of care in the treatment of these subjects. The
subject will be randomized. Three days to three weeks after the biopsy, subjects will be
randomly treated with either MEDI-4736 (15 mg/kg once intravenously) or MEDI-4736 (1500 mg
once intravenously) plus tremelimumab (75 mg once intravenously) or a control group in a
randomized controlled study design. There will be two treatment arms (MEDI4736 only and
combination MEDI4736+tremelimumab) and one untreated arm (control). Randomization, stratified
by receiving previous chemotherapy or not, will be performed and will help to minimize
patient selection biases between three arms. Subjects under 30 kg will be treated with
weight-based dosing for both MEDI4736 and Tremelimumab combination therapy. These patients
are excluded from fixed based dosing to limit endotoxin exposure from the drug preparations.
One to six weeks after the infusion, subjects will undergo resectional surgery, including
extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D), at which time the tumor
will be removed (typically 200-1000 g) and obtained for study. Four patients that do not
undergo treatment with MEDI-4736 or tremelimumab will be included as controls. Blood will be
obtained after the induction of general anesthesia for both the thoracoscopy procedure and
the EPP or P/D resectional procedure, as is routinely done in these procedures. The sixth rib
will be obtained at the time of the resection. After the removal of the tumor, standard
protocol includes intraoperative heated chemotherapy using a lavage of intracavitary
cisplatin in the presence of conserved renal function (Sugarbaker et al., 2013, 2014;
Richards et al., 2006).

Inclusion Criteria:

1. Written informed consent obtained from the subject prior to performing any
protocol-related procedures, including screening evaluations

2. Age >/= 18 years at time of study entry

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

4. Adequate normal organ and marrow function as defined below:

Hemoglobin ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (> 1500 per mm3)
Platelet count ≥ 100 × 109/L (>100,000 per mm3) Serum bilirubin ≤ 1.5× institutional
upper limit of normal (ULN)AST<3.0 Creatinine clearance >50mL/miN Aspartate
transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN if documented
liver metastasis are present); Serum creatinine ≤ 2.0 mg/dL or calculated creatinine
clearance ≥ 50 mL/min as determined by the Cockcroft-Gault equation;

Males:

Creatinine CL (mL/min) = Weight (kg) × (140 - Age) 72 × serum creatinine (mg/dL)

Females:

Creatinine CL (mL/min) = Weight (kg) × (140 - Age) × 0.85 72 × serum creatinine
(mg/dL)

5. 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.

6. 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.

7. Surgically resectable MPM with no disease extension beyond the ipsilateral hemithorax

8. Planned resectional surgery for MPM [extrapleural pneumonectomy (EPP) or pleurectomy
and decortication (P/D)]

9. Any MPM histology (epithelial, mixed, sarcomatoid)

10. N0 or N1 nodal disease as present on perioperative chest CT and/or PET CT.

11. N2 nodal disease if no progression after 2 cycles of standard chemotherapy.
Progression will be considered if additional N1 or N2 disease develop during
chemotherapy

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site) or previous enrollment or randomization in the
present study

2. Participation in another clinical study with an investigational product during the
last 3 months

3. Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736

4. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies, other investigational agent) 30 days prior to the first dose of study
drug, and 30 days prior to the first dose of study drug for subjects who have received
prior TKIs [e.g., erlotinib, gefitinib and crizotinib] and within 6 weeks for
nitrosourea or mitomycin C).

5. Current or prior use of immunosuppressive medication within 28 days before the
infusion with MEDI4736 or MEDI4736 + tremelimumab and through 90 days post infusion,
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.

6. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy.

7. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE >Grade 1

8. Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects
with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
the past 2 years) are not excluded.

9. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis)

10. History of primary immunodeficiency

11. History of allogeneic organ transplant

12. History of hypersensitivity to MEDI4736 or any excipient

13. History of hypersensitivity to tremelimumab or the combination of MEDI4736 +
tremelimumab

14. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
bleeding diatheses including any subject known to have evidence of acute or chronic
hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
illness/social situations that would limit compliance with study requirements or
compromise the ability of the subject to give written informed consent

15. Known history of previous clinical diagnosis of tuberculosis

16. History of leptomeningeal carcinomatosis

17. Receipt of live attenuated vaccination within 30 days prior to study entry or within 6
months of receiving MEDI4736 or MEDI + tremelimumab

18. Receipt of drugs with laxative properties and herbal or natural remedies for
constipation within 90 days of receiving MEDI4736 or MEDI + tremelimumab

19. Receipt of sunitinib within 3 months of receiving tremelimumab

20. Female subjects who are pregnant, breastfeeding, or male or female subjects of
reproductive potential who are not employing an effective method of birth control

21. 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

22. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive
of but not limited to surgery, radiation, and/or corticosteroids.

23. Subjects with uncontrolled seizures

24. N3 nodal disease

25. History of interstitial lung disease/pneumonitis

26. No tissue is obtainable at the time of thoracoscopy.