Phase II MEDI4736 in Combination With Chemotherapy for First-Line Treatment of Unresectable Mesothelioma

Mesothelioma is a malignant tumor of the mesothelial surfaces primarily arising in the
thoracic pleura and is estimated to cause 43,000 deaths worldwide each year with over 3300
cases occurring annually in the United States. Approximately 80% of cases of mesothelioma are
due to inflammation induced by prior asbestos exposure with a lead time from exposure to
development of cancer of 20-30 years.

This is a single arm, open label phase II study of the anti-PD-L1 antibody, durvalumab, in
combination with standard chemotherapy. Pemetrexed and cisplatin will be given for up to six
3-week cycles with the addition of concurrent durvalumab dosed every 3 weeks. The first 6
patients who are enrolled and commence treatment will be monitored for safety of the
combination. Use of carboplatin in place of cisplatin will be permitted for patients who are
ineligible for cisplatin due to impaired renal function at screening, however these patients
must otherwise fulfill the eligibility criteria for the study. For patients that receive
cisplatin, carboplatin may also be substituted after Cycle 1 for cisplatin related toxicity
(e.g., grade 3 ototoxicity, grade 3 nausea) at the investigator's discretion. After
completion of Cycle 6 of concurrent therapy, patients with stable or responding disease per
modified RECIST for malignant mesothelioma will continue on single agent durvalumab every 3
weeks until progression. Maximum duration of durvalumab treatment is 12 months starting from
Cycle 1 of concurrent treatment (inclusive of any treatment delays or missed treatments).

Tumor assessments will be performed approximately every 6 weeks during concurrent therapy and
every 9 weeks during the maintenance phase.

Mandatory pre-treatment tumor tissue sample (i.e., obtained during a previous procedure or
biopsy) and blood samples (prior to Cycle 1, Cycle 2 and Cycle 5) for research will also be
required.

Criteria:

- Histologically and/or cytologically confirmed malignant pleural mesothelioma.

- Unresectable disease (defined as the participant not being a candidate for curative
surgery).

- Measurable disease, defined as at least 1 lesion (measurable) that can be accurately
assessed at baseline by computed tomography (CT) or magnetic resonance imaging (MRI)
and is suitable for repeated assessment (modified RECIST for pleural mesothelioma).

- Available unstained archived tumor tissue sample in sufficient quantity to allow for
analyses. At least fifteen unstained slides or a tumor block (preferred). NOTE: A fine
needle aspiration sample is not sufficient to make the patient eligible for
enrollment. Given the complexity of mesothelioma pathological diagnosis and that these
will be newly diagnosed patients it is expected that they will have a core needle
biopsy or surgical tumor biopsy as part of their initial diagnostic work up.

- Age ≥ 18 years.

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

- Ability to understand and willingness to sign Institutional Review Board
(IRB)-approved informed consent.

- Willing to provide archived tumor tissue and blood samples for research.

- Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks
prior to registration:

- Absolute Neutrophil Count (ANC) ≥ 1500/mm³

- Hemoglobin ˃9.0 g/dL

- Platelets ˃100,000/mm³

- Serum creatinine clearance (CL)>60 mL/min by the Cockcroft-Gault formula or by
24-hour urine collection for determination of creatinine clearance. NOTE:
Patients with a creatinine Cl ≥ 45 mL/min however ≤ 60 mL/min may be considered
for enrollment provided they fulfill all other eligibility criteria, these
subjects will receive pemetrexed carboplatin concurrent with durvalumab during
the combination phase of treatment. Patients with a creatinine CL<45 mL/min
should not be enrolled.

- Albumin ≥ 2.8 g/dL

- Total Bilirubin ≤ 1.5x Upper Limit of Normal (ULN)

- Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) ≤ 2.5x ULN (≤ 5x
ULN in patients with liver metastases)

- Women must either be of non-reproductive potential or must have a negative serum
pregnancy test upon study entry.

- Women must not be pregnant or breastfeeding.

- Patient 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.

- Patient must not have involvement in the planning and/or conduct of the study. No
previous enrollment in the present study.

- Patients may not have participated in another clinical study with an investigational
product during the last 4 weeks.

- Patients must not have any prior systemic therapy (chemotherapy, immunotherapy,
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies, and other investigational agent) for mesothelioma.

- No previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or any other
agent targeting immune checkpoints.

- Patients must not have non-pleural mesothelioma e.g. mesothelioma arising in
peritoneum, tunica vaginalis or any serosal surface other than the pleura.

- Patients must not have an active second malignancy other than non-melanoma skin cancer
or cervical carcinoma in situ.

- Patients must not have mean QT interval corrected for heart rate (QTc) ≥470 ms
calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction.

- Patients must not have symptomatic or uncontrolled brain metastases requiring
concurrent treatment, inclusive of but not limited to surgery, radiation and/or
corticosteroids (prednisone >10 mg or equivalent). Surgery, radiation and/or
corticosteroids (any dose >10 mg prednisone equivalent) must have been completed ≥ 2
weeks prior to registration.

- Patients must not have uncontrolled seizures.

- Patients must not have current or prior use of immunosuppressive medication within 28
days before the first dose of durvalumab, 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. Standard
steroid premedication given prior to chemotherapy or as prophylaxis for imaging
contrast allergy should not be counted for this criterion.

- No active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease, diverticulitis with the exception of diverticulosis,
celiac disease, irritable bowel disease; Wegner syndrome) within the past 2 years.
Subjects with vitiligo, alopecia, Grave's disease, or psoriasis not requiring systemic
treatment (within the past 3 years) are not excluded.

- No history of primary immunodeficiency.

- No history of allogeneic organ transplant.

- No history of hypersensitivity to durvalumab, cisplatin, carboplatin, pemetrexed or
any of their excipients.

- No 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 psychiatric illness/social
situations that would limit compliance with study requirements or compromise the
ability of the subject to give written informed consent.

- No active infection including tuberculosis (clinical evaluation including: physical
examination findings, radiographic findings, positive PPD test, etc.), hepatitis B
(known positive HBV surface antigen [HBsAg] result), hepatitis C, or human
immunodeficiency virus (positive HIV 1/2 antibodies as defined by a positive ELISA
test). Patients with a past or resolved HBV infection (defined as the presence of
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients
positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction
is negative for HCV RNA. HIV testing is not required in absence of clinical suspicion.

- No known history of leptomeningeal carcinomatosis.

- Patients must not have received live attenuated vaccination within 30 days prior to
study entry or within 30 days of receiving durvalumab.

- Patients must not have any condition that, in the opinion of the investigator, would
interfere with evaluation of study treatment or interpretation of patient safety or
study results.