A Phase II Open-Label, Multi-Center Study of MEDI4736 Evaluated as Single Agent or in Combination with Tremelimumab in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of
all pancreatic tumors, is a malignancy with an extremely poor prognosis, as
shown by a 1-year survival rate of around 18% for all stages of the disease and
an estimated 5-year survival rate of less than 5%. The low survival rates
associated with PDAC primarily reflect the fact that tumors progress rapidly
with few specific symptoms and are thus at an advanced stage at diagnosis in
most patients (almost 80% of patients at diagnosis; Hidalgo et al 2015).
The poor prognosis reflects the limited treatment options available,
highlighting the need for the development of newer therapeutic options. Very
few patients with truly localized disease can be cured by surgery.
This study will utilize an open-label design due to the different treatment
administration schedules and treatment durations.

1.MEDI4736 monotherapy

2.MEDI4736 + tremelimumab combination therapy

In this study the efficacy and safety of MEDI4736 evaluated as single agent or
in combination with tremelimumab in patients with metastatic PDAC. MEDI4736 is
a human mAb of the immunoglobulin G 1 kappa subclass that inhibits the binding
of PD-L1 and tremelimumab is a mAB which binds to the cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4). Both PD-L1 and CTLA-4 proteins play
a role in the suppression on the immune system which the tumor uses in order to
escape the immune system. The proposed treatments may have the potential to
provide meaningful clinical benefit by generating durable clinical responses,
thereby improving quality of life (QoL) and potentially extending survival.

To determine the efficacy and safety of MEDI4736 evaluated as a single agent or
in combination with tremelimumab in patients with metastatic pancreatic ductal
adenocarcinoma (PDAC) whose disease has progressed on 5-FU-containing or
gemcitabine-containing first-line therapy.

This is a Phase II, open-label, multi-center study to determine the efficacy
and safety of MEDI4736 evaluated as single agent or in combination with
tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma
(PDAC) whose disease has progressed on
5-FU-containing or gemcitabine-containing first-line chemotherapy.

The patients will be randomized in a 1:1 ratio to receive treatment with

- MEDI4736 monotherapy
- MEDI4736 + tremelimumab combination therapy

MEDI4736 monotherapy:

1,5 g MEDI4736 via IV infusion every 4 weeks for up to 12 months (up to 13
doses)

MEDI4736 and tremelimumab combination therapy:

1,5 g MEDI4736 by IV infusion every 4 weeks and 75 mg tremelimumab by IV
infusion every 4 weeks starting at week 0 (up to 4 doses), followed by 1,5 g
MEDI4736 monotherapy by IV infusion every 4 weeks (starting at week 16) to
complete a total of 12 months of therapy (up to a total of 9 additional doses)

On several days during the study patients will undergo the following
assessments: - anamnesis (at screening also medical history) - physical
examination - WHO performance status - vital signs (blood pressure, pulse,
respiratory rate, temperature) - length - weight - CT or MRI scan - ECG - blood
and urine assessments - tumor biopsy (if applicable) - pregnancy test

Related side effects reported in subjects receiving MEDI4736 alone are:
fatigue, nausea, diarrhea, decreased appetite, rash, vomiting, itchiness,
difficulty breathing, fever, low thyroid, increased liver enzymes, cough,
muscle pain, stomach pain, dizziness.

Related and serious side effects reported in subjects receiving MEDI4736 alone
are: Blockage in the urinary tract, fluid in the space surrounding the lung and
inflammation of the lung, increase in calcium in the blood, joint pain,
worsening of cancer, spinal cord swelling, increase in liver enzymes and
blockage of the tract between the liver and small intestine, irregular heart
beat or rhythm, chest pain and fluid in the abdomen, dehydration, disorder in
the blood vessels of the organs, swelling of the tumor, lack of muscle control
during walking or picking up objects.

Related side effects reported in subjects receiving MEDI4736 and tremelimumab
together are: fatigue, diarrhea, high level of amylase, high level of ALT,
itching, decreased appetite, low level of TSH, high level of AST, inflammation
of the large intestine, rash, high level of lipase.

Related and serious side effects reported in at least 2 subjects receiving
MEDI4736 and tremelimumab together are: diarrhea, inflammation of the large
intestine, inflammation of the lung, high level of AST, high level of ALT, high
level of amylase.