Study of Pembrolizumab With REOLYSIN® and Chemotherapy in Patients With Advanced Pancreatic Adenocarcinoma

Reovirus Serotype 3 - Dearing Strain (REOLYSIN®) is a naturally occurring, ubiquitous,
non-enveloped human reovirus. It's primary mode of activity is to infect and selectively
target tumors with activating Ras pathway mutations. Up to 70% of pancreatic cancers have
activating Ras pathway mutations and/ or over-expressions.

This is an open label, Phase 1b study of REOLYSIN® and chemotherapy in combination with
pembrolizumab in patients with advanced (unresectable or metastatic) histologically confirmed
pancreatic adenocarcinoma that progressed after (or did not tolerate) first-line therapy. It
is thought that Reovirus when combined with chemotherapy would lead to increased viral
replication and oncolysis preferentially in RAS activated tumors, with resulting immunogenic
response than can be further enhanced by checkpoint inhibition using pembrolizumab. The study
is designed to characterize the efficacy and safety of REOLYSIN® given intravenously in
combination with one of the three chemotherapy backbone regimens, Gemcitabine, Irinotecan or
Leucovorin/ 5-fluorouracil (5-FU), and pembrolizumab, the treatment cycle of which will be
repeated every 3 weeks. It will follow a 3+3 design with no dose escalations. 3 patients will
be initially enrolled. If no dose limiting toxicities (DLT) are observed, the cohort will be
expanded. Provided patients do not develop intolerable toxicity (that does not respond to
either supportive care or dose reduction) or clinically meaningful disease progression,
treatment with additional cycles may be continued so long as patients experience clinical
benefit in the judgement of the Investigator.

Inclusion Criteria: Each patient MUST:

- Have histologically confirmed advanced or metastatic pancreatic adenocarcinoma and
have failed or did not tolerate first-line therapy.

- Have either archival tissue available for immune testing OR if not, a baseline biopsy
of a primary or metastatic lesion (including ascites) which is accessible for a biopsy
that can be accomplished with reasonable safety.

- Be available and agree to; a post-treatment tumor biopsy of either a primary or
metastatic lesion (including ascites).

- Have measurable disease.

- Have no continuing acute toxic effects (except alopecia) of any prior anticancer
treatment, i.e., all such effects must have resolved to Common Terminology Criteria
for Adverse Events (CTCAE), version 4.02 [2], Grade ≤1. Any major surgery (except
biopsies) must have occurred at least 28 days prior to study enrolment.

- Have an ECOG Performance Score ≤ 2.

- Have baseline laboratory results as follows:

- Absolute neutrophil count (ANC) ≥ 1.5 x 10E9 [SI units 10E9/L].

- Platelets ≥ 100 x10E9 [SI units 10E9/L] (without platelet transfusion)

- Serum creatinine ≤ 1.5 x ULN.

- Creatinine clearance (measured over 24 hours) OR calculated creatinine clearance
(Cockcroft-Gault formula) of ≥ 60 mL/min.

- Bilirubin ≤ 1.5 x ULN.

- AST/ALT ≤ 3 x ULN (≤ 5 x ULN if patients have liver metastasis).

- TSH, T4 and ACTH must be within normal range.

- Proteinuria with normal or grade 1 OR Urinary protein < 1 g/24hr.

- Negative pregnancy test for females of childbearing potential.

- 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.

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

Exclusion Criteria: Each patient MUST NOT:

- Receive concurrent therapy with any other investigational anticancer agent while on
study.

- Be on immunosuppressive therapy or have known HIV infection or active hepatitis B or
C.

- Receive radiotherapy within 28 days prior to receiving study drug.

- Be a pregnant or breast-feeding woman. Female patients of childbearing potential must
agree to use effective contraception, must be surgically sterile, or must be
postmenopausal. Male patients must agree to use effective contraception or be
surgically sterile. Barrier methods are a recommended form of contraception.

- Have clinically significant cardiac disease (New York Heart Association, Class III or
IV) including pre-existing arrhythmia, uncontrolled angina pectoris, myocardial
infarction 1 year prior to study entry, or grade 2 or higher compromised left
ventricular ejection fraction.

- Have dementia or altered mental status that would prohibit informed consent.

- Have any other severe, acute, or chronic medical or psychiatric condition or
laboratory abnormality that may increase the risk associated with study participation
or study drug administration or may interfere with the interpretation of study results
and, in the judgment of the Principal Investigator, would make the patient
inappropriate for this study.

- Have HIGH BURDEN/SYMPTOMATIC brain metastases. LOW VOLUME / ASYMPTOMATIC and
pre-treated clinically stable brain metastases ARE allowed.