M7824 (MSB0011359C) in Combination With Gemcitabine in Adults With Previously Treated Advanced Adenocarcinoma of the Pancreas

Background:

- M7824 is an investigational agent in phase IB/II clinical development with dual activity
against TGF-beta signaling (TGF-beta ligand trap ; extracellular domain of human
TGF-beta receptor II) and immune checkpoint ligand inhibition (PD-L1 inhibition;
avelumab, fully human IgG1 mAb directed against human PD-L1) with an acceptable toxicity
profile and early signals of anti-cancer activity including in pancreas cancer.

- Gemcitabine (2 <=,2 <=-Difluordesoxycytidine) is a standard-of-care nucleoside analogue
in pancreas cancer with immunomodulatory mechanisms of actions in pancreas cancer
patients.

- Preclinical studies in authochtenous and syngeneic murine models have shown that
TGF-beta inhibition and PD-L1 inhibition cooperate with gemcitabine to achieve reduction
of tumor growth and extension of survival induce anti-tumor immunity, and reprogram the
immune landscape.

Objectives:

- To determine the safety and tolerability of M7824 in combination with gemcitabine in
subjects with metastatic or locally advanced pancreas cancer.

- To determine best overall response (BOR) rate according to Response Evaluation Criteria
(RECIST 1.1) in advanced pancreas cancer subjects.

Eligibility:

- Histologically confirmed diagnosis of adenocarcinoma of the pancreas.

- Patients must have progressed on prior chemotherapeutic regimen.

- Concurrent treatment with non-permitted drugs and other interventions, prior therapy
with gemcitabine or any antibody / drug targeting T cell co-regulatory proteins (immune
checkpoints) such as anti-PD 1, anti PD-L1, or anti-cytotoxic T lymphocyte antigen-4
(CTLA 4 antibody) is not allowed.

Design:

- The proposed study is a phase IB/II study of M7824 in combination with gemcitabine in a
safety run-in of 6-18 patients and, if safe and tolerated, will proceed to an expansion phase
II cohort with a standard Simon Minimax design .

- INCLUSION CRITERIA:

- Patient must be able to understand and willing to sign a written informed consent
document

- Age greater than of equal to 18 years. Because no dosing or adverse event data are
currently available on the use of M7824 in combination with gemcitabine in patients
<18 years of age, children are excluded from this study, but will be eligible for
future pediatric trials

- Histologically or cytologically proven pancreatic adenocarcinoma (subjects with
endocrine or acinar pancreatic carcinoma are not eligible).

- Patients must have disease that is not amenable to potentially curative resection.

- Subjects must have progressed on or after standard first-line systemic chemotherapy.

- ECOG performance status of 0 to 1

- Must have evaluable or measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional
techniques or as >10 mm with spiral CT scan.

- Adequate hematological function defined by:

- white blood cell (WBC) count greater than or equal to 3x10(9)/L

- with absolute neutrophil count (ANC) greater than or equal to 1.5x10(9)/L

- lymphocyte count greater than or equal to 0.5x10(9)/L,

- platelet count greater than or equal to 120x10(9)/L, and

- Hgb greater than or equal to 9 g/dL (in absence of blood transfusion)

- Adequate hepatic function defined by:

- a total bilirubin level less than or equal to 1.5xULN,

- an AST level less than or equal to 2.5xULN,

- ALT level less than or equal to 2.5Xuln.

- Adequate renal function defined by:

- Creatinine up to 1.5 upper institutional limits OR creatinine clearance (CrCl)
>50 mL/min/1.73 m2 according to the Cockcroft-Gault formula:

CrCl=(140-age) x (weight in kg) x (0.85, if female)/72 x Serum Creatinine (mg/dL)

- The effects of the study treatment on the developing human fetus are unknown; thus, women
of childbearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry, for the duration of
study participation and up to 120 days after the last dose of the drug. Should a woman
become pregnant or suspect she is pregnant while she or her partner is participating in
this study, she should inform her treating physician immediately.

EXCLUSION CRITERIA:

- Prior systemic therapy with gemcitabine (patient with prior weekly low-dose
radiosensitizing gemcitabine (75mg/m2) are eligible)

- Patients who are receiving any other investigational agents

- Prior therapy with any antibody / drug targeting T cell coregulatory proteins (immune
checkpoints) such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody.

- Anticancer treatment within designated period before enrollment including:

- minor surgical procedure (such as biliary stenting) within 14 days

- major surgical procedure or radiation treatment within 28 days

- chemotherapy or experimental drug treatment with published half-life known to be
72 hours within 14 days

- experimental drug treatment with unpublished or half-life greater than 72 hours
within 28 days

- radiotherapy for measurable lesions delivered in a normal organ-sparing technique
within 21 days (except for palliative radiotherapy)

- Concurrent treatment with non-permitted drugs including herbal remedies with
immunostimulating properties (for example, mistletoe extract) or known to potentially
interfere with major organ function (for example, hypericin).

- Previous malignant disease (other than the target malignancy to be investigated in
this trial) within the last 3 years. Subjects with a history of cervical carcinoma in
situ, superficial or no-invasive bladder cancer, or basal cell or squamous cell
carcinoma in situ previously treated with curative intent are NOT excluded.

- Rapidly progressive disease which, in the opinion of the Investigator, may predispose
to inability to tolerate treatment or trial procedures.

- Subjects with active central nervous system (CNS) metastases causing clinical symptoms
or metastases that require therapeutic intervention are excluded. Subjects with a
history of treated CNS metastases (by surgery or radiation therapy) are not eligible
unless they have fully recovered from treatment, demonstrated no progression for at
least 2 months, and do not require continued steroid therapy. Subjects with CNS
metastases incidentally detected during Screening which do not cause clinical symptoms
and for which standard of care suggests no therapeutic intervention is needed are
eligible.

- Receipt of any organ transplantation, including allogeneic stem-cell transplantation,
except of transplants that do not require immunosuppression (e.g., corneal transplant,
hair transplant)

- Significant acute or chronic infections including tuberculosis (history of exposure or
history of positive tuberculosis test; plus, presence of clinical symptoms, physical
or radiographic findings)

- Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent with the exceptions:

- diabetes type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not
requiring

immunosuppressive treatment are eligible;

- subjects requiring hormone replacement with corticosteroids are eligible if the
steroids are administered only for the purpose of hormonal replacement and at doses
less than or equal to 10 mg of prednisone or equivalent per day;

- administration of steroids for other conditions through a route known to result in a
minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is
acceptable.

- Known severe hypersensitivity reactions to monoclonal antibodies (Grade greater
than or equal to 3 NCI-CTCAE v4.03), any history of anaphylaxis or history of
uncontrolled asthma.

- Known severe hypersensitivity to gemcitabine.

- Female patients who are pregnant or breastfeeding. Because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment
of the mother with M7824 in combination with gemcitabine, breastfeeding should be
discontinued.

- Known alcohol or drug abuse.

- Clinically significant cardiovascular / cerebrovascular disease as follows:
cerebral vascular accident / stroke (< 6 months prior to enrollment), myocardial
infarction (< 6 months prior to enrollment), unstable angina, congestive heart
failure (New York Heart Association Classification Class greater than or equal to
II), or serious cardiac arrhythmia.

- Clinically relevant diseases (for example, inflammatory bowel disease) and / or
uncontrolled medical conditions, which, in the opinion of the Investigator, might
impair the subject s tolerance or ability to participate in the trial.

- Vaccine administration of live vaccines within 21 days of enrollment.

- Patients with known contrast allergies requiring pre-medication with steroids.

- HIV, HCV, HBV positive patients on antiviral drugs are excluded due to the
absence of previous experience on combination of antiviral and this trial drugs
and possible interaction.