Pembrolizumab and Pelareorep in Treating Patients With Advanced Pancreatic Cancer

PRIMARY OBJECTIVES:

I. To determine the overall response rate (ORR) by Response Evaluation Criteria in Solid
Tumors (RECIST) version (v) 1.1 criteria of pembrolizumab in combination with Reovirus
Serotype 3 ? Dearing Strain (pelareorep).

SECONDARY OBJECTIVES:

I. To determine progression free survival by RECIST v 1.1 criteria, as well as 1- year,
2-year and median overall survival with pembrolizumab in combination with pelareorep.

II. To determine safety and tolerability of pembrolizumab and pelareorep when administered in
combination as determined by National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE) v 4.03.

III. To determine the effects (immune response) of pembrolizumab and pelareorep when
administered in combination as determined by analysis of pre-and post-treatment biopsies and
blood-based immune markers.

EXPLORATORY OBJECTIVES:

I. To measure the overall response rate (ORR) by using Immune-Modified Response Evaluation
Criteria in Solid Tumors (iRECIST) criteria, for the combination of pembrolizumab and
pelareorep.

II. To determine progression free survival by iRECIST criteria as well as 1-year, 2-year and
median overall survival with pembrolizumab in combination with pelareorep.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
every 21 days for up to 32 courses in the absence of disease progression, unacceptable
toxicity, development of an inter-current illness that prevents further administration of
treatment, patient decides to withdraw, patients not experiencing clinical benefit in the
judgment of the Investigator, or the treating investigator determines that the patient should
be taken off treatment for any reason. Patients also receive Pelareorep IV over 60 minutes on
days 1, 2, 3, and 8 in course 1 and on days 1 and 8 of subsequent courses. Courses repeat
every 21 days for up to 24 months in the absence of disease progression, unacceptable
toxicity, development of an inter-current illness that prevents further administration of
treatment, patient decides to withdraw, patients not experiencing clinical benefit in the
judgment of the Investigator, or the treating investigator determines that the patient should
be taken off treatment for any reason. Patients who stop study therapy with stable disease
(SD) or better may be eligible for up to 1 year of additional Pelareorep and pembrolizumab
therapy if they progress after stopping study treatment.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Inclusion Criteria:

- Patients must have histologically confirmed advanced (unresectable or metastatic)
pancreatic adenocarcinoma, documented objective radiographic progression and have
failed or not tolerated first-line therapy.

- Note: First-line therapy denotes systemic chemotherapy for advanced pancreatic
adenocarcinoma. Only one line of therapy is permitted in this setting. Intolerant
to first line therapy are patients that have developed >= grade 3 adverse events
related to first line therapy and treating physician deems continuing of systemic
chemotherapy would be detrimental to patient.

- Patients must have confirmation of an existing formalin-fixed paraffin-embedded (FPPE)
tumor sample from archival tissue or from a fresh biopsy of a primary or metastatic
lesion at baseline, either as a block or unstained slides for performance of
correlative studies.

- Note: Patients must undergo a fresh biopsy if archival tissue is not available.

- Patients must have measurable disease as defined by RECIST v 1.1.

- Any major surgery (except biopsies) must have occurred at least 28 days prior to first
day of study treatment.

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance score =<
1.

- Patients must have a life expectancy of >= 6 months.

- Absolute neutrophil count (ANC) >= 1,500 /mcL (with or without growth factor use).

- Platelets >= 100,000 / mcL.

- Hemoglobin >= 9 g/dL, OR >= 5.6 mmol/L with (if clinically indicated)/without
transfusion or erythropoietin [EPO] dependency).

- Serum creatinine =< 1.5 x upper limit of normal (ULN), OR measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
levels > 1.5 x institutional ULN.

- (Note: creatinine clearance should be calculated per institutional standard.)

- Serum total bilirubin =< 1.5 x ULN, OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 x ULN.

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN, OR =< 5 x ULN for subjects with liver metastases.

- Albumin >= 2.5 mg/dL.

- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
subject is receiving anticoagulant therapy. For patients on anticoagulant therapy,
PT/INR must be within therapeutic range.

- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving
anticoagulant therapy. For patients on anticoagulant therapy, PT/INR must be within
therapeutic range

- Thyroid-stimulating hormone (TSH), thyroxine (T4) and corticotropin (ACTH) within
normal range (prior to registration).

- Proteinuria within institutional normal or =< grade 1 OR urinary protein < 1 g/24
hours (hr) (prior to registration).

- Female subject of childbearing potential must have a negative urine or serum pregnancy
within 7 days of registration. It is to be repeated on day 1 of study treatment,
before infusion, if it is done greater than 3 days of day 1. If the urine test is
positive or cannot be confirmed as negative, a serum pregnancy test is required.
Female subjects of childbearing potential must be willing to use an adequate method of
contraception (willing to use 2 methods of birth control or be surgically sterile, or
abstain from heterosexual activity), for the course of the study through 120 days
after the last dose of study medication. Should a female patient become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately.

- Note: A female of childbearing potential (FOCBP) is any woman (regardless of
sexual orientation, having undergone a tubal ligation, or remaining celibate by
choice) who meets the following criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy

- Has had menses at any time in the preceding 12 consecutive months (and
therefore has not been naturally postmenopausal for > 12 months).

- Male subjects of childbearing potential must agree to use an adequate method of
contraception or be surgically sterile or abstain from heterosexual activity, starting
with the first dose of study therapy through 120 days after the last dose of study
therapy.

- Patients must have signed an informed consent indicating that the patient is aware of
the neoplastic nature of their disease and have been informed of the procedures of the
protocol, the experimental nature of the therapy, alternatives, potential benefits,
side effects, risks, and discomforts.

- Patients must be willing and able to comply with scheduled visits, the treatment plan,
and laboratory tests.

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks prior first day of
study drug or those who have not recovered from adverse events due to agents
administered more than 4 weeks from cycle 1 day 1 are not eligible.

- Patients who have a diagnosis of immunodeficiency or is receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to the
first dose of study treatment are excluded.

- Note: If patient is on high dose of steroid therapy, it needs to be brought down
to < 10 mg prednisone or equivalent for at least 7 days prior to day 1 of study
treatment.

- Patients receiving any other investigational agents for at least 4 weeks before the
first dose of study treatment are not eligible.

- Patients with a known history of active TB (Bacillus tuberculosis) are excluded.

- Patients with a hypersensitivity to pembrolizumab or any of its excipients are
excluded.

- Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 28 days
prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from
adverse events due to agents administered more than 4 weeks earlier.

- Patients who have had prior chemotherapy, targeted small molecule therapy, or
radiation therapy within 28 days prior to study day 1 or who has not recovered (i.e.,
NCI CTCAE version 4.03 grade =< 1 or at baseline) from adverse events due to a
previously administered agent are not eligible.

- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
therapy.

- Exceptions to this criteria are:

- Subjects with =< grade 2 neuropathy or alopecia are an exception to this
criterion and may qualify for the study.

- Patients receiving palliative radiation are eligible for this study. Palliative
radiation is allowed during treatment as well. Patients with a known additional
malignancy that is progressing or requires active treatment within the past 5 years
are excluded. Exceptions include basal cell carcinoma of the skin or squamous cell
carcinoma of the skin that has undergone potentially curative therapy or in situ
cervical cancer.

- Patients with a known active central nervous system (CNS) metastases and/or
carcinomatous meningitis are excluded.

- Note: Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four
weeks prior to the first dose of trial treatment and any neurologic symptoms have
returned to baseline), have no evidence of new or enlarging brain metastases, and
are not using steroids for at least 7 days prior to trial treatment.

- This exception does not include carcinomatous meningitis, which is excluded
regardless of clinical stability.

- Patients with an active autoimmune disease that has required systemic treatment in the
past 2 years (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs) are excluded.

- Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not
considered a form of systemic treatment.

- Patients with a history of (non-infectious) pneumonitis that required steroids or
current pneumonitis are excluded.

- Patients with an active infection requiring systemic therapy are excluded.

- Patients with a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the subject?s
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator are excluded.

- Patients with a known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial are excluded.

- Patients who are pregnant or breastfeeding, or expecting to conceive or father
children within the projected duration of the trial, starting with the pre-screening
or screening visit through 120 days after the last dose of trial treatment are
excluded.

- Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2
agent are excluded.

- Patients with a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies) are excluded.

- Patients with a known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg]
reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA]
[qualitative] is detected) are excluded.

- Patients who have received a live vaccine within 30 days of planned start of study
therapy are excluded.

- Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
are live attenuated vaccines, and are not allowed.

- Patients with clinically significant cardiac disease (New York Heart Association,
class III or IV including pre-existing arrhythmia, uncontrolled angina pectoris, and
myocardial infarction 1 year prior to registration, or grade 2 or higher compromised
left ventricular ejection fraction are excluded.

- Patients who have dementia or altered mental status that would prohibit informed
consent are excluded.