A Phase 2 Study of Pembrolizumab in Combination With Pelareorep in Patients With Advanced Pancreatic Adenocarcinoma
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma, Stage III Pancreatic Cancer AJCC v8, Stage IV Pancreatic Cancer AJCC v8
Sponsor: Northwestern University

NU Study Number: NU 18I01
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A Phase 2 study of pembrolizumab in combination with pelareorep in patients 
with advanced pancreatic adenocarcinoma
Principal Investigator:
Devalingam Mahalingam MD, PhD
Northwestern University 
Associate Professor, Division of Hematology and Oncology
Developmental Therapeutics Institute (DTI)
233 East Superior Street, Ground Floor, Olson Pavilion
Chicago, IL 60611
Phone: 312-695-6929
Fax: 312-472-0564
E-mail: mahalingam@nm.org
Sub-Investigator(s):
Division of Hematology and Oncology 
                                                    Northwestern University 
Al Benson, MD 
                                                    Aparna Kalyan, MBBS, FRACP
                                                    Sheetal Kircher, MD
                                                    Mary Mulcahy, MD
Biostatistician:
 Hui Zhang, PhD
                                                     hzhang@northwestern.edu
Study Intervention(s):
Pelareorep and Pembrolizumab
IND Number:
PS003760
IND Holder:
Devalingam Mahalingam MD, PhD
Funding Source: 
Oncolytics Biotech Inc: drug support (pelareorep)
                                                    Merck: drug support (pembrolizumab)
Version Date:
 3.23.2020
Coordinating Center:
Clinical Trials Office
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL  60611
http://cancer.northwestern.edu/research/clinical-trials-office/
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Table of Contents
LIST OF ABBREVIATIONS..........................................................................................................................iv
STUDY SCHEMA.........................................................................................................................................vi
STUDY SUMMARY.....................................................................................................................................vii
1.
INTRODUCTION - BACKGROUND AND RATIONALE.......................................................................9
1.1
Disease Background.....................................................................................................................9
1.2
Interventional Background & Overview.........................................................................................9
1.3
Pre-Clinical Experience...............................................................................................................11
1.4
Immune Checkpoint Inhibition in Cancer Treatment...................................................................14
1.5
Pelareorep and Checkpoint Inhibitors.........................................................................................16
1.6
Rationale for Current Study ........................................................................................................17
2.
OBJECTIVES.....................................................................................................................................18
2.1
Primary Objectives......................................................................................................................18
2.2
Secondary Objectives.................................................................................................................18
2.3
Exploratory Objectives................................................................................................................18
3.
PATIENT ELIGIBILITY.......................................................................................................................19
3.1
Inclusion Criteria .........................................................................................................................19
3.2
Exclusion Criteria........................................................................................................................21
4.
TREATMENT PLAN...........................................................................................................................23
4.1
Overview.....................................................................................................................................23
4.2
Treatment Administration............................................................................................................23
4.3
Toxicity Management & Dose Delays/Modifications...................................................................25
4.4
Supportive Care with Pembrolizumab.........................................................................................27
4.5
Concomitant Medications/Treatments ........................................................................................30
4.6
Duration of Therapy ....................................................................................................................31
4.7
Duration of follow-up...................................................................................................................32
4.8
Subject Withdrawal/Discontinuation Criteria...............................................................................32
4.9
Patient Replacement...................................................................................................................33
4.10
Discontinuation of Study Therapy after CR.................................................................................33
5.
STUDY PROCEDURES.....................................................................................................................34
6.
ENDPOINTS and ASSESSMENTS ...................................................................................................37
6.1
Definitions ...................................................................................................................................37
6.2
Methods of Measurement ...........................................................................................................38
6.3
Baseline Documentation of Target and Non-Target Lesions......................................................38
6.4
Evaluation of Target Lesions ......................................................................................................39
6.5
Evaluation of Non-Target Lesions...............................................................................................40
6.6
Overall Response Evaluation......................................................................................................40
6.7
Immune-related response criteria [1] ..........................................................................................40
6.8
Primary Endpoint .......................................................................................................................42
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6.9
Secondary Endpoints..................................................................................................................42
6.10
Exploratory Endpoints.................................................................................................................43
6.11
Assessment of Antineoplastic Activity.........................................................................................43
7.
ADVERSE EVENTS...........................................................................................................................43
7.1
Adverse Event Monitoring...........................................................................................................43
7.2
Definitions & Descriptions...........................................................................................................43
7.3
Adverse Event Reporting............................................................................................................45
7.4
Protocol-Specific Additional Reporting Requirements for Serious Adverse Event Reporting.....47
8.
DRUG INFORMATION ......................................................................................................................49
8.1
Pembrolizumab...........................................................................................................................49
8.2
PELAREOREP............................................................................................................................52
9.
CORRELATIVES/SPECIAL STUDIES...............................................................................................56
10.
STATISTICAL METHODS .................................................................................................................57
11.
STUDY MANAGEMENT ....................................................................................................................57
11.1
Institutional Review Board (IRB) Approval and Consent ............................................................57
11.2
Amendments...............................................................................................................................58
11.3
Registration Procedures .............................................................................................................58
11.4
Data Submission.........................................................................................................................58
11.5
Instructions for Participating Sites...............................................................................................59
11.6
Data Management and Monitoring/Auditing................................................................................59
11.7
Adherence to the Protocol ..........................................................................................................59
11.8
Investigator Obligations ..............................................................................................................60
11.9
Publication Policy........................................................................................................................60
12.
REFERENCES...................................................................................................................................61
13.
APPENDICES....................................................................................................................................64
13.1
Appendix 1: Birth control methods..............................................................................................64
13.2
Appendix 2: New York Heart Association Classification of Heart Failure (NYHA CHA) .............65
13.3
Appendix 3: SAFETY ISSUES....................................................................................................66
13.4
Appendix 4: Table Evaluating Adverse Events...........................................................................67
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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Transaminase
ANC
Absolute Neutrophil Count
APAP
Acetaminophen or paracetamol
ASCO
American Society of Clinical Oncology
AST
Aspartate Transaminase
AUC
Area under the curve
BUN
Blood Urea Nitrogen 
CBC
Complete Blood Count
CEA
Carcinoembryonic antigen
CI
Combination indices
CIVI
Continuous IV Infusion
CK-MB
Creatinine Kinase MB
CPE
Cytopathic Effects
CR
Complete Response
CRF
Case Report Form
CSF
Colony Stimulating Factor
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA4
Cytotoxic T-lymphocyte-associated protein 4
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDTA
Edetic Acid (ethylenediaminetetraacetic acid)
EGFR
Epidermal Growth Factor Receptor
FDA
Food and Drug Administration
FOLFIRI
Irinotecan/Fluorouracil/Leucovorin
5-FU
Fluorouracil
GFR
Glomerular filtration rate
GGT
Gamma-glutamyl-transferase
GM-CSF
Granulocyte-Macrophage-Colony Stimulating Factor
Hb
Hemoglobin 
HCl
Hydrochloride
HIV
Human Immunodeficiency Virus
HSV-1
Herpes simplex virus 1
IRB
Investigational Review Board
ITu
Intratumoral Injection
IV
Intravenous
IL
Interleukin
INF
Interferon
L
Litres
LD
Longest Diameter
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LDH
Lactic dehydrogenase
LHRH
Luteinizing Hormone-Releasing Hormone Analog
LV
Leucovorin
MDSCs
Myeloid derived stem cells
mg
Milligram(s)
MRI
Magnetic Resonance Imaging
MTD 
Maximum Tolerated Dose
NCI
National Cancer Institute
NSCLC
Non-Small Cell Lung Cancer
ORR
Overall response rate
OS
Overall survival
PD
Progressive Disease
PD-1
Programmed death 1
PDGFR
Platelet Derived Growth Factor Receptor
PD-L1 and 2
Programmed death ligand 1 and 2
PET
Positron Emission Tomography
PFS
Progression-Free Survival
PFU
Plaque forming units
PKR
Double-stranded RNA- activated Protein Kinase
PR
Partial Response
PT/PTT
Prothrombin Time/Partial Thromboplastin Time
RECIST
Response Evaluation Criteria In Solid Tumors
iRECIST
Immune- Response Evaluation Criteria In Solid Tumors
REO
Respiratory Enteric Orphan
RNA
Ribonucleic Acid
RP2D
Recommended Phase 2 Dose
RT-PCR
Reverse Transcriptase Polymerase Chain Reaction
SAE
Serious Adverse Event
SCID
Severe Combined Immune Deficient
SCID-NOD
Severe Combined Immune Deficient Non-Obese Diabetic
SCCHN
Squamous Cell Carcinoma of the Head and Neck
SD
Stable Disease
SI
International System of Units
TCID50
Tissue Culture Infective Dose 50
Th1/2
T helper phenotype 1 and 2
TNF
Tumor necrosis factor
Tmax
Time to maximum observed plasma concentration after dose
ULN
Upper Limit of Normal
US
Ultrasound
VSV
Vesicular Stomatitis Virus
WBC
White Blood Cells
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STUDY SCHEMA
1 cycle =21 days (+/-3 days)
Follow-up for survival outcome: every 3 months  by a telephone call or clinic visit at the 
discretion of the investigator.
Note: Follow-up will be for a maximum of 2 years.
Phase II combination study 
Pelareorep + Pembrolizumab
Simon 2-stage optimum design (total 30 patients)
Stage I: sample size 11 evaluable patients. If >=2 meet pre-specified criteria, proceed to
Stage II: At least 7 of 30 responses required to reject null hypothesis.
Primary objective: ORR of the combination by RECIST v 1.1 criteria.
Tumor assessment by CT or MRI at baseline and the last week of Cycles 3, 6, 9 etc. (Every 3 
cycles). For patients that discontinued due to toxicity, tumor evaluations should be performed 
until PD is noted.
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STUDY SUMMARY
Title
A Phase 2 study of pembrolizumab in combination with pelareorep in 
patients with advanced pancreatic adenocarcinoma
Version
  3.23.2020 Amendment 2
Study Design
Phase II, single arm open label, Simon two-stage optimum design
Study Center(s)
Robert H. Lurie Comprehensive Cancer Center, Northwestern University
Objectives
Primary Objectives:

To determine the overall response rate (ORR) by RECIST v 1.1  
criteria of pembrolizumab in combination with pelareorep. 
Secondary Objectives:
1. To determine progression free survival by RECIST v 1.1 criteria,  as 
well as 1-year, 2-year and median overall survival of 
pembrolizumab in combination with pelareorep.
2.To determine safety and tolerability of pembrolizumab and pelareorep 
when administered in combination as determined by NCI CTCAE v 4.03.
 
3. 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.
Sample Size
Up to 30 patients (11 patients will be enrolled in Stage 1 and up to 19 
additional patients will be enrolled in Stage 2, if pre-specified criteria for 
Stage 2 are met in Ph2-S1. The pre-defined criteria states that, for the 
primary objective >=2 or more responses out of 11 are required in Stage 
1 to continue the trial to the full 30 patients).
Total enrollment: 13 patients in Stage I/ 21 patients in Stage 2
Evaluable patients: 11 patients in Stage I/19 patients in Stage 2
Diagnosis & Key 
Eligibility Criteria
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.

Patients must have an ECOG Performance Score ≤ 1.

Patients must have a life expectancy of ≥ 6 months.
Exclusion Criteria: 

Patients who have had chemotherapy or radiotherapy within 4 
weeks prior to day 1 of study drug and those who have not 
recovered from adverse events due to agents administered more 
than 4 weeks before C1D1 are not eligible.

Patients with a known active central nervous system (CNS) 
metastases and/or carcinomatous meningitis are excluded.
See Section 3 for the full list of Eligibility Criteria.
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Treatment Plan
Pembrolizumab will be administered on Day 1 at 200 mg IV over 30 
minutes.
Pelareorep on Day 1 will be administered after completion of 
Pembrolizumab infusion. 
In Cycle 1, Pelareorep will be administered at a dose of 4.5x1010TCID50 
on Days 1, 2, 3 and 8. From Cycle 2 onwards, Pelareorep will be 
administered at a dose of 4.5x1010TCID50 on Days 1 and 8.
Each cycle is 21 days (3 weeks). Up to 32 cycles of pembrolizumab 
and 24 months of Pelareorep (2 years) of therapy can be administered.
Medication schedule and dose
Dose Level
Pelareorep 
4.5x1010 TCID50
Pembrolizumab 
200 mg
Cycle 1
Days 1,2,3,8
Day 1
Cycle 2 +
Days 1, 8
Day 1
Statistical Methodology
This Phase 2 study follows a Simon’s two-stage optimum design to 
evaluate the efficacy of pembrolizumab in combination with Pelareorep.  
The “Go/No Go” criteria in Phase 2 (Stage 1) will be defined using null 
response rate, alternative response rate, power, and alpha. In Stage 1, 
with null rate 10%, alternative rate 35%, power 90%, and 1-sided alpha 
0.025, the Simon two-stage "optimum" design specifies stage 1 sample 
size of 11, stopping for futility if <= 1 response out of 11 in stage 1, and 
adding 19 additional patients if >= 2 responses at stage 1. In Stage 2, at 
least 7 responses out of 30 are required to reject null rate of <10%.
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1.
INTRODUCTION - BACKGROUND AND RATIONALE
A comprehensive summary is included in the Investigator’s Brochures. A brief overview is 
included below with emphasis on combination studies.
1.1 Disease Background
Pancreatic adenocarcinoma (AC) remains one of the most lethal of human malignancies. It is 
the fourth leading cause of cancer-related death in the United States. The majority of patients 
are diagnosed with advanced stage disease, and as such, for the large majority of patients, 
will succumb to their disease.  Despite significant advances in improvements in cancer 
therapy, mortality for pancreatic cancer has remained relatively unchanged. The mainstay of 
treatment for patients with advanced pancreatic adenocarcinoma remains systemic 
combination chemotherapy. The most common combination used in first line setting is 
FOLFIRINOX or gemcitabine plus nab-paclitaxel (Abraxane) chemotherapy. Despite this, 
patient outcomes remain poor, with 5-year survival of less than 10%. Development of new 
therapies for pancreatic AC is greatly needed.
1.2 Interventional Background & Overview
1.2.1
Oncolytic Virotherapy
Oncolytic viruses are viral strains capable of selective killing of malignant cells while 
leaving normal cells essentially unaffected [4].  Some viruses, like Reovirus, have a 
natural tropism for malignant cells while others, like adenovirus or measles, have to 
be genetically engineered in order to recognize specific cancer cell receptors [5].  
Oncolytic viruses were first used in the 1950s as an experimental cancer treatment, 
but modern oncolytic virotherapy began in the 1990s after it was shown that an 
attenuated HSV strain is active in a murine glioblastoma model.  Since then, oncolytic 
viruses belonging up to 10 different families have been tested in clinical trials [5].  
Oncolytic viruses represent a new class of therapeutic agents that promote anti-
tumor responses through multiple mechanisms of action that are dependent on 
selective tumor cell killing and the induction of systemic anti-tumor immunity. The 
molecular and cellular mechanisms of action likely depend on viral replication within 
transformed cells, induction of primary cell death, interaction with tumor cell antiviral 
elements and initiation of innate and adaptive anti-tumor immunity [5].  A unique 
aspect of oncolytic viral treatments is that self-replicating viral factories are 
established within the tumor cells with a potential for continued effect after treatment.
1.2.2
Reovirus
Reovirus Serotype 3 – Dearing Strain is a naturally occurring, ubiquitous, non-
enveloped human Reovirus with a genome that consists of 10 segments of double-
stranded RNA [6].
The Reoviridae family of viruses consists of six genera, three of which infect animals 
(including humans) and three which infect only plants and/or insects [6].  Of the three 
which can infect humans – Reovirus, orbivirus, and rotavirus – the Reovirus appears 
to cause the least pathology. Reoviruses are found throughout the world and their 
pathology appears to result in only minor respiratory or enteric symptoms in humans, 
and to be nonexistent in other animals.  The term Reovirus stands for Respiratory 
Enteric Orphan virus; an orphan virus being one that is not associated with a known 
disease state [7].
The Reovirus is a non-enveloped virus, with a double-shelled capsid, each with 
icosahedral symmetry, and containing 10 linear double-stranded RNA genome 
segments [6].  There are three distinct serotypes based upon neutralization and 
hemagglutination inhibition tests [8].  The prevalence of Reovirus antibodies in adult 
humans has been found to be >50% up to 100%, depending on the study [9-12].
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During naturally occurring Reovirus infections in immunocompetent animals, the 
pathogenic effects appear to be minimal.  The infectious cycle begins when the viral 
particles are converted in the GI tract to intermediate subviral particles (ISVPs) due to 
the action of proteolytic enzymes [13].  Reoviruses initially infect the epithelial cells of 
the ileum [14, 15], and are thought to then cross through the intestinal M cells, 
moving to the Peyer’s patches, then to the mesenteric lymph nodes through 
lymphatic dissemination. Eventually Reoviruses move through the blood stream to 
extraintestinal organs and the central nervous system [16].  Although it can infect 
many different organs, the Reovirus produces very minor, or no, illness.
1.2.3
Pelareorep Mechanism of Action
Pelareorep is the first-in-class immuno oncology- viral agent for systemic 
administration that induces lysis of cancer cells and innate and adaptive immune 
responses that lead to an inflamed tumor phenotype and anti-tumor activity. 
Pelareorep (also known as REOLYSIN) contains a type 3 Dearing Reovirus, which is 
a naturally occurring virus that is not genetically modified. 
Pelareorep’s activity is based on three modes of action, which are complementary 
but not interdependent:

Selective viral replication in permissive cancer cells which leads to tumor 
lysis [17, 18] 

Activation of innate immunity in response to the infection which results in a 
cascade of chemokines/cytokines causing natural killer (NK) cells to 
recognize and attack cancer cells [19] 

A specific adaptive immune response triggered by tumor- and viral-
associated antigens displayed by antigen-presenting cells (APCs, infected 
tumor cells and/or dendritic cells) to T cells [20-22] 
Reovirus replication is entirely cytoplasmic and replication does not include any 
intranuclear events [21].  Treatment with PELAREOREP does not constitute gene 
transfer or gene therapy.
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1.3 Pre-Clinical Experience
In the NCI 60-cell screen, the majority of cell lines derived from NSCLC, colon, and ovarian 
cancers were permissive to Reovirus-induced cytopathic effect (CPE).  Breast cancer and 
leukemia cell lines showed varying degrees of susceptibility to Reovirus-induced CPE 
(Shizuko Sei, personal communication). 
1.3.1
Combination of Pelareorep with Chemotherapy 
Studies of Pelareorep in combination with chemotherapeutic agents (like 
gemcitabine, paclitaxel/carboplatin) in human cancer lines, animal models [23-25] 
and in humans [26-30] have shown synergy and/or additive effects.  For example, 
cells from the human colorectal cancer cell line HCT-116 were exposed to either 
Reovirus alone, a cytotoxic agent alone (gemcitabine, fluorouracil, cisplatin and 
doxorubicin), or escalating virus and drug combinations.  Median effects analysis 
revealed that Reovirus was synergistic with the drug across a wide range of drug 
concentrations [24].  Additional cytotoxic drugs including mitomycin and taxanes 
exhibit this effect [23].  Furthermore, in vivo studies using subcutaneous implants of 
RAS transformed fibroblasts (C3H-10T1/2) in immunocompetent C3H mice suggest 
that Reovirus may be useful to overcome resistance to cisplatin and possibly other 
chemotherapies (Oncolytics, data on file). 
1.3.2
Studies of Reovirus as an Infective Agent
Studies in which volunteers were inoculated with the three serotypes of Reovirus 
resulted in symptoms of illness in only approximately one-third of the volunteers [8].  
These symptoms included malaise, rhinorrhea, cough, sneezing, pharyngitis, 
headache, and loose stool.  There have been isolated reports implicating Reovirus 
with other disease processes such as hepatobiliary, neurological, respiratory, or 
exanthematous disease, although these reports are incomplete and may reflect only 
chance associations, or the extent of the virus in the environment. In order to 
ascertain the clinical features of Reovirus infection, one study was undertaken in 
1963 in which each of the three serotypes of Reovirus was inoculated into adult 
volunteers [8].  In this study, 27 male volunteers from various minimal security 
correctional institutions were given intranasal inoculations of one of the three 
serotypes of Reovirus and followed for 23 days for signs of symptomatic illness.  Of 
the nine men receiving Reovirus type 1, only three showed signs or symptoms of 
illness, which included malaise, rhinorrhea, cough, sneezing, pharyngitis and 
headache.  These signs and symptoms typically had an onset within 24 to 48 hours 
and lasted from 4 to 7 days.  There was also one report of “loose stools” in another 
volunteer. Reovirus type 2 inoculations were associated with similar signs, symptoms 
and durations in three of the nine volunteers with such exposure.  Two of the nine 
volunteers receiving Reovirus type 3 inoculations developed mild rhinitis.  None of 
the volunteers showed any other physical signs or symptoms, or any significant 
laboratory abnormality (including routine blood counts, urinalysis, chest X-ray, liver 
function studies, electrocardiogram, and bacteriologic examinations of nose, throat, 
and faeces).  None of these patients developed a fever.  This confirmed that 
Reovirus may cause minor upper respiratory tract illnesses, as had been previously 
suggested and confirmed subsequently [11, 31-33].  Other studies have shown 
Reovirus to be excreted in urine and stool.
1.3.3
Clinical Trials of Pelareorep 
Pelareorep was administered intravenously every 4 weeks in a cohort of 18 patients 
with advanced heavily pretreated solid malignancies in the phase I REO 004 trial 
[34].  Doses up to 3 × 1010 TCID50 were administered with no grade >3 adverse 
effects.  The most common adverse effects were fevers, myalgia and nausea and 
they were grade 1.  The best response was partial response in one patient with 
breast cancer harboring a RAS codon 12 mutation [glycine (GGT) to alanine (GCT)] 
in her tumor.  Seven more patients had stable disease.
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In another phase I trial (REO 005), Pelareorep  was administered to 33 patients in 
doses up to 3 x 1010 TCID50 on a schedule of up to 5 consecutive doses every 4 
weeks [35].  No dose-limiting toxicities were experienced.  The most common toxicity 
was grade 1-2 flu like illness, 2-6 hours after the infusion that responded to 
antipyretics and NSAIDs.  The most common grade >3 toxicity was flu-like illness 
(grade 3) and uncomplicated lymphopenia and neutropenia.  Best response was 
stable disease, with some patients experiencing minor decreases in the sum of the 
maximum diameters of the target lesions.
1.3.4
Clinical trials of Pelareorep in combination with chemotherapy and radiation
As discussed above, co-administration of cytotoxic agents may enhance the 
antitumor effect of reovirus. Radiation therapy may also enhance its antitumor effect. 
Herein we present 4 studies of relevance to the current protocol.  
In a phase I study in 24 patients with advanced malignancies eligible for treatment 
with docetaxel, reovirus was co-administered with docetaxel [36].  Docetaxel was 
given at a dose of 75 mg/m2 every 21 days (with standard steroid premedication). 
Pelareorep was administered in doses up to 3 x 1010 TCID50 5 days a week every 21 
days.  The toxicities were as expected for docetaxel and Pelareorep based on 
previous experience.  Flu-like symptoms was the most common side effect 
attributable to the study drug with only one grade 4 event (in cohort 1, 3 x 109 
TCID50).  They typically occurred 2 to 4 days after reovirus administration and were 
easily controlled with acetaminophen and nonsteroidal anti-inflammatory medication.  
Symptoms seemed to be more common in the first cycle of treatment and milder in 
subsequent cycles.  Only one patient exhibited systemic viral shedding by PCR.  One 
patient had a complete response (breast cancer) and 3 more attained a partial 
response.  Three patients had stable disease.  Neutralizing antibody formation was 
increased in all patients.  In all available post treatment biopsy specimens, there was 
cytoplasmic evidence of viral protein expression.
In a phase I dose escalation study in patients with advanced malignancies, 
Pelareorep was administered in combination with gemcitabine [26, 28].  The side 
effect profile was compatible with previous experience with both Pelareorep and 
gemcitabine.  Of the 10 patients available for response assessment, one patient with 
nasopharyngeal carcinoma attained a partial response by RECIST criteria, while a 
heavily pretreated patient with breast cancer attained a significant clinical 
improvement in her symptoms with minor radiological response.  Compared to phase 
I studies of Pelareorep as monotherapy, the combination with gemcitabine led to 
attenuation in the neutralizing antibody production.
The combination of Pelareorep  with the combination of irinotecan/5-FU/leucovorin 
(FOLFIRI) was studied in a phase I study in patients with RAS mutated metastatic 
colorectal cancer [37].  Patients who had received FOLFIRI in the past were eligible 
and consisted of more than half of the study population (13/21).  The combination 
was safe, well tolerated and no new toxicities were identified. The dose-limiting 
toxicity (DLT) was neutropenia.  Of the 18 patients evaluable for response, 5% 
attained a partial response and 50% had stable disease.  Median progression free 
survival (PFS) for the FOLFIRI-naïve patients was 7.4 months while for the FOLFIRI 
non-naïve patients was not reached.
In another phase I study, 18 patients with advanced solid tumors with measurable 
disease amenable to treatment with localized short-course palliative radiation 
treatment, were treated with radiation in combination with ITu administration of 
reovirus [30].  There was no exacerbation of acute toxicities from radiation.  Again, 
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the side effect profile of reovirus was expected and easily manageable and there was 
no systemic viral shedding.  Three patients had significant partial responses.
1.3.4.1 Pelareorep in pancreatic cancer
Preclinical data indicate activity for reovirus in pancreatic cancer [38, 39]
A Phase I, open-label, dose escalation study of the combination of reovirus 
and gemcitabine that aimed to determine the safety and tolerability of 
systemic reovirus when administered with gemcitabine treatment was 
conducted [28]. Sixteen patients were treated. MTD was not formally 
established but 1x1010 TCID50 of reovirus on Day 1and gemcitabine 1,000 
mg/m2 Day 1 and Day 8 of a 21-day cycle was the preliminary recommended 
Phase II dose.  The combination of reovirus and gemcitabine did not alter 
gemcitabine pharmacokinetics and if reovirus was given on Day 1 of each 
cycle, toxicity was predictable except for elevations in ALT.  However, these 
liver enzyme changes are mild, transient and the clinical relevance of these 
changes is unclear.  The combination of reovirus and gemcitabine shows 
some clinical activity in this highly pretreated patient population.
The Oncolytics’ sponsored REO 017, a single arm Phase II study was 
conducted in the USA (Cancer Therapy & Research Center - CTRC, San 
Antonio, Texas and Montefiore Cancer Center, Bronx, NY) and evaluated 
Pelareorep in combination with gemcitabine in chemotherapy-naïve patients 
with advanced pancreatic adenocarcinoma.  The primary endpoint was the 
clinical benefit rate in terms of Complete Response (CR) + Partial Response 
(PR) + Stable Disease (SD) at 12 weeks in >8 patients out of 33 as the 
alternative hypothesis.  The secondary endpoints included PFS and OS. 
Gemcitabine was administered IV at a dose of 800 mg/m2 on Days 1 and 8 
every 21 days, while pelareorep  was administered IV over 60 minutes at 
1x1010 TCID50 on Days 1, 2, 8 and 9 every 21 days.  The planned 34 patients 
had been enrolled in the study as of September 2012 and data reported by 
Mahalingam et al. [40] in 2015.  The treatment was well tolerated with non-
hematological toxicities including asthenia fever, chills, flu-like syndrome, 
nausea, and vomiting.  Two patients had grade 3 neutropenia.  At a survival 
update in February 2015 including all recruited 34 patients (29 evaluable 
patients for response) one patient had a PR, 23 patients had SD, five 
patients had PD as the best response; overall, 18 patients had a clinical 
benefit measured as PR/SD ≥12 weeks thus meeting the alternative 
hypothesis.  The survival analysis based on 33 evaluable patients shows a 
median PFS of 4 months; median OS was 10.2 months with 1-year and 2-
year survival of 45% and 24% respectively.
Another study was recently completed by NCI and recently reported [41].  
The primary objective of the study was to assess the improvement in PFS 
with pelareorep in combination with carboplatin/paclitaxel relative to 
carboplatin/paclitaxel alone in patients with recurrent or metastatic pancreatic 
cancer. Patients with disease progression could crossover to the Pelareorep 
arm.  The study enrolled 73 patients; 37 were in the control arm, 36 were in 
the test arm.  The median PFS for the control arm was 5.2 months versus 4.9 
months for the test arm Given that the control arm outperformed the pre-
study assumptions for efficacy (over 5 months vs expected 3 months) the net 
result is to be considered in light of the study consequently becoming 
underpowered for the primary endpoint. Despite the negative results when 
comparing the PFS, an Ad-Hoc analysis of the survival data (conducted by 
Oncolytics) showed a possible delayed effect on OS, with a divergence of 
survival curves occurring around year 1, and the strongest efficacy signal for 
improvement in OS occurring around year 2. The comparison of survival 
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probability at year 2 found a potentially promising efficacy signal. The 
probability of survival at year 2 was 20% in the test arm vs 9% in the control 
arm. This difference yields a Z-score of Z=1.27 and two-sided p-value of 0.20 
using the log-log method (Klein et al. 2007).   Most common grade 3-4 
toxicities included neutropenia (53%) and leucopenia (36%) with no overall 
difference between arms. Furthermore, the addition of REOLYSIN to 
carboplatin + paclitaxel was well tolerated and induced CD4+/CD8+ T-cell 
activation.
1.3.5
Summary of Clinical Safety Data
A total of 1417 patients have been enrolled in clinical studies conducted in the US, 
Canada and EU. Of these, 1027 patients have received pelareorep, 936 via 
intravenous (IV) administration and 91 by intratumoral injections (ITu). The remaining 
390 patients were randomized to control arms. 
Pelareorep has been administered as single or multiple doses IT IV, either as a 
mono-therapy or in combination with chemotherapy, immunotherapy (e.g., checkpoint 
point inhibitors), and radiotherapy.  
No Maximum Tolerated Dose (MTD) for intravenous Pelareorep as mono-therapy 
was defined in the two Phase 1 trials (REO 004 and 005) [34, 35]. When combined 
with chemotherapeutic agents, Pelareorep does not appear to enhance either the 
frequency or severity of the adverse effects of the chemotherapeutic agents. 
However, most patients may experience a transient, mild to moderate “flu-like 
syndrome” after IV administration, including fever, chills, headache, fatigue, 
rhinorrhea, cough, myalgia and/or arthralgia, as well as GI symptoms, including 
nausea, vomiting, and diarrhea.  Moderate and transient alterations in hepatic 
function tests and hematology values have also been observed.  See the 
Investigator’s Brochure for additional information.
1.4 Immune Checkpoint Inhibition in Cancer Treatment
PD-1 (programmed death-1) is an important regulator of the lymphocyte activation/de-
activation process.  Upon binding to its ligand, PD-L1, can lead to cell energy and death [42].  
PD-1 expression is up-regulated on tumor infiltrating lymphocytes and PD-L1 expression has 
been shown on a wide variety of solid tumors [42].  PD-L1 expression can be part of the innate 
tumor behavior (innate immune resistance) or it can be induced as part of the tumor adaptation 
to selective pressure from the immune system (adaptive immune resistance) [43]. 
Nivolumab and pembrolizumab are IgG4 (fully human and humanized respectively) 
antibodies targeting PD-1.  These agents are approved by the Food and Drug Administration 
(FDA) for treatment of advanced melanoma and squamous non-small cell lung cancer 
(NSCLC) [2, 44]. Increased PD-L1 expression is associated with an improved response rate 
in patients with melanoma and NSCLC treated with pembrolizumab [45, 46].  On the contrary 
there was no difference based on the PD-L1 status in patients with squamous NSCLC treated 
with nivolumab [47].  Data from patients with advanced melanoma treated with ipilimumab, a 
monoclonal antibody against CTLA4-the prototype checkpoint inhibitor, show that the patients 
deriving most benefit from immunotherapy are those who have tumors harboring highly 
immunogenic neo-epitopes in the cell surface [48].
1.4.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
favorable prognosis in various malignancies.  In particular, the presence of CD8+ T-
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cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to 
suppress immune control.  The normal function of PD-1, expressed on the cell surface 
of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the 
gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4, which has 
been shown to negatively regulate antigen receptor signaling upon engagement of its 
ligands (PD-L1 and/or PD-L2).  The structure of murine PD-1 has been resolved.  PD-1 
and family members are type I transmembrane glycoproteins containing an Ig Variable-
type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 
contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-
2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70, which are involved in the CD3 T-
cell signaling cascade.  The mechanism by which PD-1 down modulates T-cell 
responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an 
overlapping set of signaling proteins.  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural 
Killer cells.  Expression has also been shown during thymic development on CD4-CD8- 
(double negative) T-cells as well as subsets of macrophages and dendritic cells.  The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in 
a variety of cell types, including non-hematopoietic tissues as well as in various tumors.  
Both ligands are type I transmembrane receptors containing both IgV- and IgC-like 
domains in the extracellular region and contain short cytoplasmic regions with no 
known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation 
triggered through the T-cell receptor.  PD-L1 is expressed at low levels on various non-
hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein 
is only detectably expressed on antigen-presenting cells found in lymphoid tissue or 
chronic inflammatory environments.  PD-L2 is thought to control immune T-cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  
PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with 
melanoma (MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in 
tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently 
been approved in the United Stated for the treatment of patients with unresectable or 
metastatic melanoma and disease progression following ipilumumab and, if BRAF 
V600 mutation positive, a BRAF inhibitor.
1.4.2
Rationale for Dose Selection/Regimen/Modification of pembrolizumab 
The clinical development of pembrolizumab, was initiated through an open-label 
Phase I trial (Protocol 001) to evaluate the safety and clinical activity of single agent 
MK-3475.  The dose escalation portion of this trial evaluated three dose levels, 1 
mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting 
toxicities were observed.  This first in human study of MK-3475 showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose levels 
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(1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  Recent 
data from other clinical studies within the MK-3475 program has shown that a lower 
dose of MK-3475 and a less frequent schedule may be sufficient for target 
engagement and clinical activity.
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target 
engagement is durable (>21 days).  This early PK and pharmacodynamic data 
provides scientific rationale for testing a Q2W and Q3W dosing schedule.  
A population pharmacokinetic analysis has been performed using serum 
concentration time data from 476 patients. Within the resulting population PK model, 
clearance and volume parameters of MK-3475 were found to be dependent on body 
weight. The relationship between clearance and body weight, with an allometric 
exponent of 0.59, is within the range observed for other antibodies and would support 
both body weight normalized dosing or a fixed dose across all body weights.  MK-
3475 has been found to have a wide therapeutic range based on the melanoma 
indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 
2 mg/kg Q3W body weight based regimen are anticipated to remain well within the 
established exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. 
The exposure margins are based on the notion of similar efficacy and safety in 
melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-
fold higher dose and exposure). The population PK evaluation revealed that there 
was no significant impact of tumor burden on exposure. In addition, exposure was 
similar between the NSCLC and melanoma indications. Therefore, there are no 
anticipated changes in exposure between different indication settings.
The rationale for further exploration of 2 mg/kg and comparable doses of 
pembrolizumab in solid tumors is based on: 1) similar efficacy and safety of 
pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 
2) the flat exposure-response relationships of pembrolizumab for both efficacy and 
safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of 
tumor burden or indication on distribution behavior of pembrolizumab (as assessed by 
the population PK model) and 4) the assumption that the dynamics of pembrolizumab 
target engagement will not vary meaningfully with tumor type.
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing 
is based on simulations performed using the population PK model of pembrolizumab 
showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) 
are optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) 
will maintain individual patient exposures in the exposure range established in 
melanoma as associated with maximal efficacy response and 3) will maintain individual 
patients exposure in the exposure range established in melanoma that are well 
tolerated and safe. A fixed dose regimen will simplify the dosing regimen to be more 
convenient for physicians and to reduce potential for dosing errors.  A fixed dosing 
scheme will also reduce complexity in the logistical chain at treatment facilities and 
reduce wastage.
1.5 Pelareorep and Checkpoint Inhibitors
Oncoviruses can augment the antineoplastic activity of checkpoint inhibitors as well as 
increase immunogenicity of poorly immunogenic tumors, as shown with the Newcastle 
Disease Virus and anti-CTLA4 antibody in melanoma and prostate adenocarcinoma models 
[49].
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Recent studies suggest that pelareorep may enhance the efficacy of antibodies targeting the 
programmed cell death protein 1 (PD1)/ programmed death ligand 1 (PD-L1) interaction to 
limit the growth of subcutaneous tumors in preclinical models [50, 51]. The combination of 
pelareorep and anti-PD-1 therapies augmented anti-tumor T-cell interferon IFN-gamma 
secretion and NK cell killing of tumor cells in a murine melanoma model [52]. Similarly, in 
pancreatic adenocarcinoma patients given carboplatin and paclitaxel with or without 
pelareorep , only patients who received pelareorep had significantly increased expression of 
the checkpoint molecule CTLA4 (cytotoxic T-lymphocyte-associated protein 4) on both CD4+ 
and CD8+ T-cells subsets [53]. Upregulation of immune checkpoint marker PD-L1 was also 
observed in patients with pancreatic adenocarcinoma treated with pelareorep and 
gemcitabine [54]. Thus, in addition to the role of these checkpoint molecules as biomarkers of 
anergic or exhausted T-cells, they also represent actionable targets, which may be used to 
test diverse combination therapies with pelareorep.
Preclinical studies indicate the combination of oncolytic virus therapy with immune checkpoint 
inhibitors may be more beneficial than either therapy alone. Recently, Liu et al (2015) 
demonstrated that CD8+ enriched splenocytes co-cultured with pelareorep secreted 
increased levels of IFN-gamma, therefore suggesting reovirus recognition by CD8+cells and 
proinflammatory response stimulation via IFN-gamma secretion.[56] Synergistic activity of 
reovirus with immune checkpoint inhibition has recently been demonstrated in vivo, as the 
combination of reovirus with PD-1 blockade prolonged survival of mice compared to mice 
administered either treatment alone. Using an immune-competent mouse model, reovirus 
was injected intratumorally into subcutaneous B16 melanomas of C57BL/6 mice, and anti-
PD-1 was administered intravenously. The combination: induced IFN-gamma secretion in 
response to B16 tumor-associated antigens; enhanced NK cell-mediated tumor cell death; 
and attenuated tumor-specific immunosuppression [52]. These results suggest that reovirus 
oncolytic viro-immunotherapy and immune checkpoint inhibitor therapy can be combined for 
enhanced therapeutic efficacy.
1.6 Rationale for Current Study
In a Phase 1b study, we hypothesized that reovirus, when combined with low doses of 
chemotherapy would lead to increased viral replication and oncolysis in RAS activated 
tumors, with resulting immunogenic response that can be further enhanced by checkpoint 
inhibition using pembrolizumab. However, even when the treatment was tolerated in the first 
11 patients treated in this safety phase of the study, a total of 73% of patients experienced 
grade 3/ 4 toxicity. There were no discontinuations due to therapy but doses were missed or 
delayed in four patients. The Pelareorep dose and schedule used was otherwise well 
tolerated and no PELAREOREP-related excess toxicity was observed in the dose and 
schedule schema tested. Interestingly, there was one patient with a partial response that 
lasted 6 months and two patients with stable disease lasting 126 and 221 days.  
Furthermore, on-treatment tumor biopsies showed reovirus RNA and immune infiltrates [55].
Thus, for this Phase 2 study we hypothesize that the administration of pembrolizumab in 
combination with Pelareorep (without chemotherapy) will still have clinical activity in this 
indication based on the discussion above. Furthermore, by removing chemotherapy, we 
expect to improve the safety profile and compliance to the therapy that may actually improve 
the clinical outcomes seen with the triple combination. For this Phase 2 study, we propose to 
modify the dose scheme of both drugs to optimize their delivery to the tumor site and induce 
an optimal immune response. On one hand, Pelareorep needs to get to the tumor to promote 
immune-cell infiltration and the expression of PD-1 and PD-L1 (i.e., inflamed tumor 
phenotype) so pembrolizumab can exert the maximum benefit. But it is known that the 
majority of the patients develop neutralizing antibodies in the first 30 days of therapy with 
Pelareorep [57]. And although Pelareorep can be delivered to the tumor site in the presence 
of neutralizing antibodies [58.59.60], we propose to increase the viral load administered in the 
first cycle (Days 1, 2, 3, and 8) and to keep boosting the system with a further two 
administrations per cycle (Days 1 and 8) thereafter, to give pembrolizumab a better chance to 
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act. On the other hand, pembrolizumab will be administered as a flat dose of 200 mg every 3 
weeks instead of using a ponderal dosing. This will reduce inter-subject variability. 
Pembrolizumab will be given on Day 1 of each cycle prior to the administration of Pelareorep. 
This Phase 2 trial will have a Simon’s 2-stage design where responses will be evaluated in 
Stage 1 according to RECISTv1.1 criteria. If predefined response criteria (for the primary 
objective, 3 or more responses out of 16 are needed in Stage 1 to continue the trial to the full 
30 patients) are met in Stage 1, additional patients will be evaluated in Stage 2. All patients in 
Phase 2 will also be evaluated by RECIST 1.1 criteria and survival. Also, we expect that 
clinical responses will be correlated with the presence of an “inflamed phenotype” (as 
detected by gene-expression profile) and the emergence of selective T & B cell clones 
against tumor- or viral associated antigens after the start of therapy (T cell clonality in blood).   
1.6.1
Rationale for Pelareorep (REOLYSIN) dose selection for this study 
In studies where REOLYSIN® was combined with chemotherapeutic agents, the MTD 
for REOLYSIN® has also not been reached). Reolysin® was even administered in 
doses up to 3 x 1010 TCID50 5 days a week every 21 days. The AEs and SAEs were 
comparable with those reported for the chemotherapy itself. There is no evidence that 
the addition of REOLYSIN® to any of the chemotherapies led to an increase in the 
frequency or severity of the AEs generally associated with the chemotherapies 
themselves. 
(Ref: Comins C, Spicer J, Protheroe A, Roulstone V, Twigger K, White CM, Vile R, 
Melcher A, Coffey MC, Mettinger KL et al: REO-10: a phase I study of intravenous 
reovirus and docetaxel in patients with advanced cancer. Clinical cancer 
research : an official journal of the American Association for Cancer Research 2010, 
16(22):5564-5572.)
2.
OBJECTIVES
2.1 Primary Objectives
1.
To determine the overall response rate (ORR) by RECIST v 1.1 criteria of 
pembrolizumab in combination with pelareorep.
2.2 Secondary Objectives
1.
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.
2. To determine safety and tolerability of pembrolizumab and pelareorep when 
administered in combination as determined by NCI CTCAE v 4.03.
 
3.
 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.
2.3 Exploratory Objectives
1.
To measure the overall response rate (ORR) by using iRECIST criteria, for 
the combination of pembrolizumab and Pelareorep
2.
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 
(Please refer to Section 6.0 for details).
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3.
PATIENT ELIGIBILITY
The target population for this study is patients with advanced or metastatic pancreatic 
adenocarcinoma. This will be a single-center trial conducted at Northwestern University. 
A total of 11 patients will be enrolled in Stage 1 and up to 19 additional patients will be enrolled in 
Stage 2. Approximately 4 potentially eligible patients are seen per month, and it is anticipated that 
at least 1-2 per month will be accrued. Potential patients may be referred to the Principal 
Investigator (PI) at Northwestern University, Dr. Devalingam Mahalingam, at (312) 472-1234.
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers 
are not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. Please refer 
to Section 11 for complete instructions regarding registration procedures.
3.1 Inclusion Criteria
3.1.1
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.
3.1.2
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.
Please refer to laboratory manual for more details.
3.1.3
Patients must have measurable disease as defined by RECIST v 1.1.
3.1.4
Any major surgery (except biopsies) must have occurred at least 28 days prior to first 
day of study treatment.
3.1.5
Be at least 18 years of age. 
3.1.6
Patients must have an ECOG Performance Score ≤ 1.
3.1.7
Patients must have a life expectancy of ≥ 6 months.
3.1.8
Patients must demonstrate adequate organ function prior to registration as defined in 
table belowError! Reference source not found.: 
Table 1: Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
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 EPO dependency)
Renal
Serum creatinine, OR
Measured or calculated creatinine clearance
≤ 1.5 x upper limit of normal (ULN), OR
≥ 60 mL/min for subject with creatinine levels > 1.5 x 
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(GFR can also be used in place of creatinine 
or CrCl)
(Note: Creatinine clearance should be 
calculated per institutional standard.)
institutional ULN
Hepatic
Serum total bilirubin
≤ 1.5 x ULN, OR
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 x ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 x ULN,  OR
≤ 5 x ULN for subjects with liver metastases
Albumin
> 2.5 mg/dL
Coagulation
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
3.1.9
Patients must meet the following prior to registration:
TSH, T4  within normal range.
Note:If a thyroid function test is abnormal, but not deemed clinically significant by 
treating physician, approval may be given by principal investigator upon discussion.
Proteinuria within institutional normal or ≤ grade 1 OR Urinary protein < 1 g/24hr.
3.1.10
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 (Refer to Appendix 1). 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 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).
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3.1.11
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 (Refer to Appendix 1).
3.1.12
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.
3.1.13
Patients must be willing and able to comply with scheduled visits, the treatment plan, 
and laboratory tests.
3.2 Exclusion Criteria
3.2.1
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.
3.2.2
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 
<10mg prednisone or equivalent for at least 7 days prior to Day 1 of study treatment.
3.2.3
Patients receiving any other investigational agents for at least 4 weeks before the first 
dose of study treatment are not eligible. 
3.2.4
Patients with a known history of active TB (Bacillus Tuberculosis) are excluded.
3.2.5
Patients with a hypersensitivity to pembrolizumab or any of its excipients are 
excluded.
3.2.6
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.
3.2.7
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[3] 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.
3.2.8
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.
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3.2.9
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.  
3.2.10
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. 
3.2.11
Patients with a history of (non-infectious) pneumonitis that required steroids or 
current pneumonitis are excluded.
3.2.12
Patients with an active infection requiring systemic therapy are excluded.
3.2.13
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.  
3.2.14
Patients with a known psychiatric or substance abuse disorders that would interfere 
with cooperation with the requirements of the trial are excluded.
3.2.15
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.
3.2.16
Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-
L2 agent are excluded.
3.2.17
Patients with a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies) are excluded.
3.2.18
Patients with a known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., 
HCV RNA [qualitative] is detected) are excluded.
3.2.19
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.
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3.2.20
Patients with clinically significant cardiac disease (New York Heart Association, Class 
III or IV (Refer to Appendix 2) 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.
3.2.21
Patients who have dementia or altered mental status that would prohibit informed 
consent are excluded.
4.
TREATMENT PLAN
4.1 Overview
In the Phase 2 study, patients with advanced pancreatic adenocarcinoma who experienced 
disease progression or did not tolerate first-line therapy, will be treated with pelareorep and 
pembrolizumab. Pelareorep will be given at a dose of 4.5x1010 TCID50 over 60 min on Days 
1, 2, 3 and 8 in Cycle 1 only. From Cycle 2 it will be given on Days 1 & 8 (starting after 
completion of pembrolizumab infusion) (Table 2). Pembrolizumab at a dose of 200 mg flat 
dose administered as an intravenous infusion over 30 minutes on Day 1 (Table 2).  Each 
cycle is 21 days (3 weeks). Up to 32 cycles of pembrolizumab and 24 months of Pelareorep 
(2 years) therapy can be administered. Patients will be followed up for a period of 2 years.
4.1.1
Premedication
No premedication is necessary.
However, regarding Pelareorep, acetaminophen may be used for the prophylaxis or 
treatment of the flu-like signs and symptoms especially fever, that are commonly 
associated with Pelareorep.  Given the usual timing of fever and other “flu-like” 
adverse events associated with Pelareorep, treatment with acetaminophen should be 
limited to the days on which Pelareorep is administered and the day following the last 
dose of each cycle. If used for prophylaxis, it is recommended that the first dose be 
given 1 to 3 hours following completion of Pelareorep infusion on Day 1 of the cycle. 
Management of symptoms should take place as necessary (refer to supportive care 
section 4.4.2).
Note: The decision about using acetaminophen should be considered for each 
individual patient, with particular attention to the patient’s hepatic status at the time of 
entry into the trial.  Extra caution should be used if there is a history of viral (HBV or 
HCV) hepatitis and/or a pre-entry elevation of bilirubin above normal.  If the patient 
has metastatic cancer in the liver, the impact of the metastases on overall liver 
function should be considered.  If the values for AST and ALT are less than twice the 
upper limit of normal, acetaminophen may still be used, but careful monitoring of 
hepatic function should be done.
Dosing of acetaminophen:  The recommended dose is 500 (every 6 to 8) to 1000 
mg (every 8 hrs). The MAXIMUM daily (24-hour) dose must NOT exceed 3000 mg. 
Note: Given that there are more than 600 products that contain acetaminophen, it is 
also essential that patients be warned NOT to use other products containing 
acetaminophen at the same time.
4.2 Treatment Administration
Table 2. Treatment administration
Dose Level
PELAREOREP
4.5x1010 TCID50
Pembrolizumab
200 mg
Premedication
Cycle 1
Days 1,2,3,8
Day 1
acetaminophen 1
Cycle 2 +
Days 1, 8
Day 1
acetaminophen 1
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1 Given the usual timing of fever and other “flu-like” adverse events associated with PELAREOREP, 
treatment with acetaminophen should be limited to the days on which PELAREOREP is administered 
and the day following the last dose of each cycle (Refer to Section 4.1.1).
4.2.1
Pembrolizumab

Pembrolizumab will be administered first, BEFORE Pelareorep infusion.

Pembrolizumab does not require any pre-medications unless clinically 
indicated for an infusion reaction. 

Medications should be available at the bedside per institutional guidelines, in 
case an immune-mediated reaction should occur.

Refer to Section 4.4.1 for supportive care details

Pre-treatment assessment of hydration before each infusion is to be done. 
Patients must be instructed to adequately hydrate prior to each study 
treatment dose administration by drinking water and other liquids.

Pembrolizumab 200 mg will be administered as a 30-minute intravenous (IV) 
infusion every 3 weeks. Every effort should be made to target infusion timing 
to be as close to 30 minutes as possible. However, given the variability of 
infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion duration is 30 minutes: -5 min/+10 min).  
-
Dose modifications for pembrolizumab will not permitted in this 
study

Vital signs (i.e., blood pressure, temperature, heart rate) will be charted 
starting prior to pembrolizumab immunotherapy 
4.2.2
Pelareorep

Pelareorep infusion should be given after completion of pembrolizumab 
infusion.

It should be administered intravenously after appropriate premedication, as 
needed (Refer to Section 4.1.1) 

Pre-treatment assessment of hydration before each infusion is to be done. 
Patients must be instructed to adequately hydrate prior to each study 
treatment dose administration by drinking water and other liquids.

PELAREOREP will be given at a dose of 4.5x1010 TCID50 over 60 min (+/-15 
mins) on Days 1, 2, 3 and 8 in Cycle 1 only. From Cycle 2 it will be given on 
Days 1 & 8 (starting after completion of pembrolizumab infusion).
Note: dose modifications are not permitted in this study.

Note: All materials that come into contact with Pelareorep viral preparation 
should be placed in sodium hypochlorite (800 ppm chlorine) and disposed of 
as biohazardous waste.

Missed dose: Dose delays of Pelareorep for > 7 days will be considered a 
missed dose and will not be replaced.
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4.2.3
Second Course Phase (Retreatment Period)
Subjects who stop study therapy with SD or better may be eligible for up to one year 
of additional pelareorep and pembrolizumab therapy if they progress after stopping 
study treatment. Patients must meet the criteria outlined below prior to starting 
this re-treatment phase. Re-treatment must be approved by PI and QAM.
This retreatment is termed the Second Course Phase of this study and is only 
available if the study remains open and the subject meets the following conditions:

Either:
-
Stopped initial study treatment after attaining an investigator-determined 
confirmed CR according to  RECIST v 1.1, AND
o
Was treated for at least 24 weeks with pelareorep and 
pembrolizumab before discontinuing therapy
o
Received at least two treatments with pelareorep and 
pembrolizumab beyond the date when the initial CR was 
declared, OR
-
Had SD, PR or CR and stopped Pelareorep and pembrolizumab 
treatment after 24 months of study therapy for reasons other than 
disease progression or intolerability, AND

Experienced an investigator-determined confirmed radiographic disease 
progression after stopping their initial treatment

Did not receive any anti-cancer treatment since the last dose pelareorep and 
pembrolizumab

Has a performance status of 0 or 1 on the ECOG Performance Scale

Demonstrates adequate organ function as detailed in Section 3.1.8

Female subject of childbearing potential should have a negative serum or 
urine pregnancy test within 72 hours prior to receiving retreatment with study 
medication.  

Female subject of childbearing potential should be 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.  Subjects of child bearing potential are those who have not been 
surgically sterilized or have been free from menses for > 1 year. 

Male subject should agree to use an adequate method of contraception 
starting with the first dose of study therapy through 120 days after the last 
dose of study therapy.  

Does not have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might 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.
Subjects who restart treatment will be retreated at the same dose and dose interval 
as when they last received study therapy. Treatment will be administered for up to 
one additional year.
4.3 Toxicity Management & Dose Delays/Modifications
4.3.1
Safety Evaluations
Safety visits will be performed during Cycle 1 on Day 15. It is mandatory for Cycle 1. 
Beyond cycle 1 it will be done only if clinically indicated, at the discretion of the 
treating physician (Refer to section 5.0 study procedures table for details).
4.3.2
Dose delays/ modifications
No dose reductions for pembrolizumab or pelareorep are allowed in this phase 2 trial. 
Note: A cycle can be delayed, but will not be skipped. 
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For Pelareorep: Pelareorep dose can be held for 7 days. Dose delays of Palereorep 
for > 7 days will be considered a missed dose and will not be replaced. Patients that 
have missed Pelareorep for > 6 weeks will be removed from study. 
For Pembrolizumab: Dose can be delayed for significant immune AEs but no dose 
reductions are permitted. Treatment with pembrolizumab can be withheld for up to 12 
weeks. 
Toxicities MUST be managed as described in the pembrolizumab (Keytruda) 
package insert instructions for toxicity management [2] and/or Investigator’s brochure 
(IB).
Treatment should be withheld for any of the following:

Grade 2 pneumonitis

Grade 2 or 3 colitis

Symptomatic hypophysitis

Grade 2 nephritis

Grade 3 hyperthyroidism

Grade 2 Aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) 3-5 x upper limit of normal (ULN) or Grade 2 total bilirubin 1.5-3 x ULN 
(in patients who had normal baseline LFTs)

AST/ALT ≥8 <10  X ULN (if had elevated AST/ALT with liver metastasis at 
baseline). 

Any other severe or Grade 3 treatment-related adverse reaction
-
Treatment will resume in patients whose adverse reactions recover 
to Grade 0-1. Treatment with pembrolizumab can be delayed for up 
to 12 weeks.
-
Exception: For any laboratory value that is a Grade 3 adverse event 
which is expected and unrelated, patient can continue to be treated 
-
I) if it is in the best interest of the patient 2) following discussion and 
approval of the PI
Treatment should be permanently discontinued for any of the following:

Any life-threatening adverse reaction

Grade 3 or 4 pneumonitis or recurrent pneumonitis grade 2

Grade 3 or 4 nephritis

AST/ALT > 5 x ULN (if patient had normal baseline LFTs)

AST/ALT ≥ 10 X ULN (if had elevated AST/ALT with liver metastasis at 
baseline)

Total bilirubin > 3 x ULN

Grade 3 or 4 infusion-related reactions

Inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks

Persistent Grade 2 or 3 adverse reactions that do not recover to Grade 0-1 
within 12 weeks after last dose

Any severe or Grade 3 treatment-related adverse reaction that recurs

Exception: For any laboratory value that is a Grade 3 adverse event 
which is expected and unrelated, patient can continue to be treated 
      I) if it is in the best interest of the patient 2) following discussion and   
approval of the PI
Patients experiencing any toxicity as described in this section in any cycle will have 
their treatment held until toxicity resolves to baseline or Grade 1.  Upon resolution, 
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pembrolizumab and PELAREOREP, may recommence at the same dose level (i.e., 
there will be no dose reductions.  
4.4 Supportive Care with Pembrolizumab
4.4.1
Supportive care with pembrolizumab
Subjects should receive appropriate supportive care measures as deemed 
necessary by the treating physician. Suggested supportive care measures for the 
management of adverse events with potential immunologic etiology are outlined 
below. Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids, as well as, additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each disorder, attempts should be made to rule out 
other causes, such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be 
applied when the treating physician determines the events to be related to 
pembrolizumab.
It may be necessary to perform conditional procedures such as 
bronchoscopy, endoscopy, or skin photography as part of evaluation of the 
event.
4.4.1.1 Pneumonitis

For Grade 2 events, treat with systemic corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.

For Grade 3-4 events, immediately treat with intravenous steroids.
-
Administer additional anti-inflammatory measures, as 
needed.

Add prophylactic antibiotics for opportunistic infections in the 
case of prolonged steroid administration.
4.4.1.2 Diarrhea/Colitis
Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, 
with or without fever) and of bowel perforation (such as peritoneal signs and 
ileus).
 
All subjects who experience diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids.  If sufficient oral fluid intake is 
not feasible, fluid and electrolytes should be substituted via IV 
infusion. For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis.
 
For Grade 2 diarrhea/colitis, administer oral corticosteroids.
 
For Grade 3 or 4 diarrhea/colitis, treat with intravenous 
steroids followed by high dose oral steroids.
 
When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks.
4.4.1.3 Type 1 Diabetes Mellitus (T1DM)
(If new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis
(DKA)
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For T1DM or Grade 3-4 Hyperglycemia:
 
Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.
 
Evaluate patients with serum glucose and a metabolic panel, 
urine ketones, glycosylated hemoglobin, and C-peptide.
4.4.1.4 Hypophysitis
 
For Grade 2 events (defined as moderate per general CTCAE 
criteria), treat with corticosteroids. When symptoms improve to 
Grade 1 or less (defined as mild per general CTCAE criteria), 
steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered.
 
For Grade 3-4 events (defined as either severe or medically 
significant but not immediately life-threatening, OR life-threatening 
consequences, per general CTCAE criteria), treat with an initial 
dose of IV corticosteroids followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is 
tapered.
4.4.1.5 Hyperthyroidism or Hypothyroidism
Thyroid disorders can occur at any time during treatment. Monitor patients 
for changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical 
signs and symptoms of thyroid disorders.
 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):
-
In hyperthyroidism, non-selective beta-blockers (e.g. 
propranolol) are suggested as initial therapy.
-
In hypothyroidism, thyroid hormone replacement therapy, 
with levothyroxine or liothyroinine, is indicated per standard 
of care.
 
Grade 3-4 hyperthyroidism:
-
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less 
than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered.
4.4.1.6 Hepatic
 
For Grade 2 events, monitor liver function tests more frequently 
until returned to baseline values (consider weekly). Treat with 
IV or oral corticosteroids
 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 
to 48 hours.
 
When symptoms improve to Grade 1 or less, a steroid taper 
should be started and continued over no less than 4 weeks.
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4.4.1.7 Renal Failure or Nephritis
 
For Grade 2 events, treat with corticosteroids.
 
For Grade 3-4 events, treat with systemic corticosteroids.
 
When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks.
4.4.1.8 SJS and TEN management

For signs or symptoms of SJS or TEN, withhold KEYTRUDA® and 
refer the patient for specialized care for assessment and treatment.

If SJS or TEN is confirmed, permanently discontinue KEYTRUDA®.
4.4.1.9 Immune-mediated myocarditis management

For suspected immune-mediated myocarditis, ensure adequate 
evaluation to exclude other etiologies, and administer corticosteroids 
as appropriate.
4.4.1.10
Management of Infusion Reactions:
Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of infusion.
Table 3 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475).
Table 3 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for < =24 hrs
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator.
Subject may be premedicated
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab (MK-
3475) with:
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine).
Acetaminophen 500-
1000 mg po (or equivalent 
dose of antipyretic).
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).
Otherwise dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should
be permanently discontinued from further 
trial treatment administration.
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Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration.
4.4.1.11
Diet/Activity/Other Considerations

Diet
Subjects should maintain a normal diet unless modifications are 
required to manage an AE such as diarrhea, nausea or vomiting.

Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk. 
Since many drugs are excreted in human milk, and because of the 
potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible for enrollment. 
Starting with the pre- screening or screening visit through 120 days 
after the last dose of trial treatment, subjects should not breast 
feed.
4.4.2
Supportive care for pelareorep

Flu-like symptoms, such as fever, chills, headache, rhinorrhea, cough, 
myalgia, arthralgia, and or others may be treated symptomatically with 
aspirin, acetaminophen, ibuprofen, antihistamines and/or other medications 
at the discretion of the Investigator.  

Diarrhea may be treated with loperamide (Imodium) or as otherwise deemed 
necessary by the Investigator.  Nausea and vomiting may be treated with 
metoclopramide or 5HT3 receptor antagonists or as deemed necessary by 
the Investigator.

Breastfeeding precautions in Pelareorep: breast feeding patients are 
excluded from this study.
4.5 Concomitant Medications/Treatments
4.5.1
Permitted

Supportive and palliative care (e.g. pain control), including palliative 
radiation, as required throughout the study.

Corticosteroids (oral or IV) in doses of up to prednisone 1 mg/kg or 
equivalent for management of pembrolizumab-related immune adverse 
events.
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
Anti-emetics or anti-diarrheal agents as required (see Sections 4.4.1 and 
4.4.2).

Acetaminophen may be used for the prophylaxis or treatment of the flu-like 
signs and symptoms especially fever, that are commonly associated with 
PELAREOREP). Given the usual timing of fever and other “flu-like” adverse 
events associated with Pelareorep, treatment with acetaminophen should be 
limited to the days on which Pelareorep is administered and the day following 
the last dose of each cycle .
Note: Given that there are more than 600 products that contain 
acetaminophen, it is also essential that patients be warned NOT to use other 
products containing acetaminophen.

Concurrent bisphosphonates are allowed. 

The use of erythropoietin will be in strict compliance with FDA 
recommendations in the current prescribing information. 

The use of blood transfusions is permitted at the discretion of the treating 
physician. 

Anticoagulant therapy is also permitted. 
4.5.2
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening 
and Treatment Phase (including retreatment for post-complete response relapse) of 
this trial:

Antineoplastic systemic chemotherapy or biological therapy Immunotherapy 
not specified in this protocol

Investigational agents other than pembrolizumab and PELAREOREP

Radiation therapy 
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.  

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, varicella/zoster, yellow 
fever, rabies, BCG, and typhoid vaccine. 

Systemic glucocorticoids for any purpose other than to modulate symptoms 
from an event of clinical interest of suspected immunologic etiology.  The use 
of physiologic doses of corticosteroids may be approved after consultation 
with the DSMC and PI.
Note: Subjects who, in the assessment by the investigator, require the use of 
any of the aforementioned treatments for clinical management should be 
removed from the trial. Subjects may receive other medications that the 
investigator deems to be medically necessary.
The Exclusion Criteria describes other medications which are prohibited in this 
trial.
4.6 Duration of Therapy
Total duration of therapy on study can be up to 2 years. Patients may continue to receive 
cycles of treatment until any of the following occur:
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
Disease progression 

[Note: A subject may be granted an exception to continue on treatment with 
confirmed or unconfirmed radiographic progression , if clinically stable or 
clinically improved]

Development of an inter-current illness that prevents further administration of 
treatment

Intolerable toxicity (that does not respond to either supportive care or dose reduction) 

Unacceptable adverse event(s)

Patient decides to withdraw from either study treatment or the as a whole study

Patients not experiencing clinical benefit in the judgment of the Investigator.

The treating investigator determines that the patient should be taken off treatment for 
any reason (i.e. changes in condition, inability to comply with study treatment or 
procedures).
4.7 Duration of follow-up

After the end of treatment each subject will be followed for 30 days for adverse event 
monitoring (serious adverse events will be collected for 90 days after the end of 
treatment). 

Subjects who discontinue for reasons other than progressive disease will have post-
treatment follow-up for disease status until disease progression, initiating a non-study 
cancer treatment, withdrawing consent or becoming lost to follow-up. After 
documented disease progression each subject will be followed by telephone for 
overall survival until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
4.8 Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  
A subject must be discontinued from study therapy for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
Note: Every effort must be made to contact the treating physicians providing ongoing 
care to determine whether adverse events occur and to obtain a date of death, if it 
occurs.  This is in order to maximize the safety data obtained from the trial and 
therefore maximize the safety of future patients treated with PELAREOREP and 
pembrolizumab

Confirmed radiographic disease progression
Note: A subject may be granted an exception to continue on treatment with confirmed 
or unconfirmed radiographic progression if clinically stable or clinically improved.

Unacceptable adverse events 

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up
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33

Completed 24 months of uninterrupted treatment with Pelareorep and 24 months of 
uninterrupted treatment with pembrolizumab or 32 administrations with 
pembrolizumab, whichever occurs later.
The patient will be withdrawn from the study and the standard 30 day follow up visit 
after receiving their last dose will take place.  
Note: 24 months of study medication is calculated from the date of first dose. 
Subjects who stop pembrolizumab after 24 months may be eligible for up to one year 
of additional study treatment if they progress after stopping study treatment provided 
they meet the requirements detailed in 4.2.3.

Administrative reasons
A subject will be discontinued from all study procedures for any of the following reasons:

Death

Withdrawal of consent

Confirmed lost to follow up-Lost to follow-up is defined as 3 attempts made by 
chosen method of contact.
4.9 Patient Replacement

If a patient withdraws consent or drops out before 1st evaluation, patient is only 
evaluable for toxicity. An additional patient will be added for response evaluation.
-
However, if patient drops out before 1st scan due to clinical progression, they are 
evaluable and an additional patient will not be added for response evaluation.

If a patient drops out for toxicity related to study drug before 1st evaluation, patient is 
evaluable for toxicity. An additional patient will be added for response evaluation. 

If a patient drops out after signing consent and before receiving any study drug, this 
patient will be replaced.
4.10 Discontinuation of Study Therapy after CR 
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with the study therapy and had at least two 
treatments with PELAREOREP and pembrolizumab beyond the date when the initial CR was 
declared.  Subjects who then experience radiographic disease progression may be eligible 
for up to one year of additional study treatment via the Second Course Phase at the 
discretion of the investigator if no cancer treatment was administered since the last dose of 
pelareorep and pembrolizumab, the subject meets the safety parameters listed in the 
Inclusion/Exclusion criteria, and the trial is open. Subjects will resume therapy at the same 
dose and schedule at the time of initial discontinuation. 
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5.
STUDY PROCEDURES
Cycle 1
(Day 1 of each cycle has a +/- 
3 day window)
Cycles 2, 3, 4 +
(Day 1 of each cycle has a +/- 
3 day window)
End 
of 
Tre
atm
ent
≤30 
days
(+/-1 
wk)
Follo
w-Up
Q3 
month
s20
(+/-1 
month
)
Re-
Treat
ment
(seco
nd 
cours
e 
phase
)21
Test/Procedure/T
reatment
Baseli
ne
(-14 
days)1
D1
D224
D
3
D
8
D15
22
D1
D224
D8
D15
22
Medical History 
X
Physical2
X
X11
X
X
X11
X
X
Demographics
X
Height
X
Weight
X
X
X
X
Performance 
status (ECOG)
X
X
X
X
X
X
X
Toxicity 
assessment
X3
X
X
X
X
X
X
X
X
X
Vital signs4
X
X
X
X
X
X
X
X
X
X
Hematology, 
PT/INR/PTT5
X
X11,23
X
X
X11,23
X
X
Chemistries and 
special tests6
X
X11,23
X
X
X11,23
X
X
Thyroid tests7
X
X11,23
ACTH 8
X
X
CA 19-925
X
X25
X
Urinalysis9
X
X11,23
X11,23
X
HIV/Hepatitis10
X
ECG13
X
Pregnancy test12
X
X12,23
Tumor 
evaluation14
X1
X
X
X14
Tumor blocks (if 
available)15
X
Biopsy16
X16
X16
Concomitant 
medications 
X
X
X
X
X
X
X
T cell clonality 
assay/immune 
analysis17
X
X
X
X
Pelareorep18
X
X
X
X
X
X
X21
Pembrolizumab19
X
X
X21
Note: Each cycle is 3 weeks (21 days). Up to 32 cycles of pembrolizumab and 24 months of 
Pelareorep (2 years) of therapy can be administered. 
1 Within 2 weeks (14 days) of registration, unless otherwise noted. Baseline imaging can be done 
within 21 days before registration.
2 Every physical exam will be a full physical exam and will be standard of care
3 For Pre-Study visit, toxicity assessment is the recording of baseline signs and symptoms.
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4 Vital signs (i.e., blood pressure, temperature, heart rate) will be charted prior to pembrolizumab 
immunotherapy, prior to Pelareorep infusion, and 60 minutes (+/-15 mins) after the end of the 
Pelareorep infusion on Day 1 for all cycles; prior to Pelareorep infusion and 60 minutes (+/-15 mins) 
after the end of Pelareorep infusion on Cycle 1 Day 2, Day 3, and Day 8. From Cycle 2 onwards, 
vitals will be charted prior to pembrolizumab immunotherapy, prior to Pelareorep infusion, and 60 
minutes (+/-15 mins) after the end of the Pelareorep infusion on Day 1 for all cycles; prior to 
Pelareorep infusion and 60 minutes (+/-15 mins) after the end of Pelareorep infusion on Day 8.
5 Hemoglobin, hematocrit, RBC, WBC with differential count, platelets. In addition, coagulation tests 
which includes INR or PT and PTT will be done.
6 Electrolytes (sodium, potassium, calcium); Renal function (blood urea nitrogen (BUN) and 
creatinine); Liver function (total bilirubin, total protein, albumin, ALT, AST, and alkaline 
phosphatase) and others (glucose).  
Additional special tests: magnesium, uric acid, direct bilirubin, GGT and LDH.
7 Thyroid tests: TSH with reflex T3 and T4. Thyroid function will be evaluated at baseline (performed 
within 14 days of registration) and prior to the start of the next treatment cycles e.g. 4, 7, 10, etc.
8 Endocrine test ACTH to be done at baseline. If the test is not done at baseline, it should be done on 
C1D1 (for both instances, it DOES NOT need to be resulted for treatment to start) Physician may 
repeat it during the study, if there is clinical evidence of hypopituitarism or adrenal dysfunction.
9 Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, microscopic, 
and nitrite
10 HbsAg, anti-HCV testing and HIV virus testing to be done at baseline.
Note: If patient had a hepatitis screening done > 14 days and < 30 days from registration, then it 
does not need to be repeated.
Note: If history of HIV is positive and test results (antibodies HIV1 and HIV 2) are available, then 
HIV testing is not required at baseline. 
11 These tests (physical exam, hematology, chemistry, thyroid tests, and urinalysis) must be done 
within 3 days of the start of treatment on Day 1 of each cycle. Note: For Cycle 1 only, these 
procedures and labs can be eliminated if baseline procedures and labs were done within 3 days of 
the start of treatment on Cycle 1 Day 1.
12 Pregnancy test within 7 days of study treatment for females of child bearing potential. If urine test is 
positive then a serum pregnancy test is required. It is to be repeated on C1 Day 1 before infusion, if 
done more than 3 days prior to Day 1.
13 ECG will be performed at baseline. It may be performed in subsequent visits if clinically indicated.
14 Baseline tumor assessment with full trunk CT or MRI scanning (as appropriate), including a brain 
MRI if clinically indicated and per treating physician’s discretion. Baseline imaging can be done 
within 21 days before registration. CT and/or MRI will also be performed the last week of Cycles 3, 
6, 9 (+/-7 days), etc. (Every 3 cycles [+/-7 days]).
For patients that discontinued due to toxicity, tumor evaluations should be performed until PD is 
noted.
15 If available, archival tissue from diagnosis (FFPE) will be acquired for immune testing.
16 If archival tissue is not available, then a baseline biopsy of a primary or metastatic lesion (including 
ascites) which is accessible for either direct or needle biopsy is to be done within 14 days of 
registration. 
     Post treatment biopsy will be performed on Cycle 1 between Day 4 and Day 15.
17 Blood sample for T cell clonality/immune analysis on C1D1, C1D8, C2D1, C3D1, C4D1 and EOT.
Note: This blood sample is for correlative studies. The sample will be stored at NU biorepository, to 
be analyzed at a later date. 
18 Pelareorep will be given at a dose of 4.5x1010 TCID50 over 60 min on Days 1, 2, 3 and 8 in Cycle 
1 only. From Cycle 2 it will be given on Days 1 & 8 (starting after completion of pembrolizumab 
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infusion) (Table 2). Dose delays of Pelareorep for > 7 days will be considered a missed dose and 
will not be replaced. Pre-treatment assessment of hydration before each infusion is to be done. 
Patients must be instructed to adequately hydrate prior to each study treatment dose administration 
by drinking water and other liquids.
19 Pembrolizumab will be administered on Day 1 of each cycle (before pelareorep infusion) at 200 mg 
IV over 30 minutes. Pre-treatment assessment of hydration before each infusion is to be done. 
Patients must be instructed to adequately hydrate prior to each study treatment dose administration 
by drinking water and other liquids.
20 Follow-up Visits every 3 months by a telephone call or clinic visit at the discretion of the 
investigator.  These visits or phone calls are to determine survival outcome.
Note: Follow-up will be for a maximum of 2 years.
21 Subjects who stop study therapy with SD or better may be eligible for up to one year of additional 
pelareorep and pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets certain conditions as outlined in the protocol (See section 
4.2.3).
Subjects who restart treatment will be retreated at the same dose and dose interval as when they 
last received study therapy.  Treatment will be administered for up to one additional year.
22 D15 is a safety visit. It is mandatory for Cycle 1. Beyond cycle 1 it will be done only if clinically 
indicated, at the discretion of the treating physician.
23 All Day 1 labs (except ACTH and CA 19-9) to be resulted before study drug administration.
24D2 visit is mandatory only for Cycle 1. Beyond Cycle 1 it is optional and  will be done only if clinically 
indicated, at the discretion of the treating physician.
25 Blood test for  CA 19-9 will be done at baseline, D1 of each odd numbered cycle (e.g C3D1,C5D1 
etc) and at EOT visit. This is a  standard of care test. (Note:The test need not be resulted for 
treatment to start).
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6.
ENDPOINTS AND ASSESSMENTS
Response assessments will be made  using the  RECIST v1.1 criteria. Measurable and non-
measurable lesions are defined below. Disease progression will be determined using RECIST v 
1.1 criteria. The iRECIST criteria will be used for exploratory endpoints.
Below is a summary of the RECIST version 1.1 guidelines as a quick reference that can be 
utilized for this study.  If there are items not outlined below, further detail and clarification for 
RECIST 1.1 can be obtained from the European Journal of Cancer, 2009.45:p.228-247, by 
Eisenhaur, et al. 
Comparison of RECIST 1.1 and iRECIST can be obtained at:
“iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics” 
Seymour, et al (Volume 18, No. 3, e143–e152, March 2017) 
(http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30074-8/fulltext
“i” indicates immune responses assigned using iRECIST. RECIST=Response Evaluation 
Criteria in Solid Tumours. iUPD=unconfirmed progression. iCPD=confirmed progression. 
iCR=complete response. iPR=partial response. iSD=stable disease.
6.1 Definitions 
Only subjects with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint. 

Measurable Disease - the presence of at least one measurable lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 

Measurable Lesions - lesions that can be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is to be recorded) with a 
minimum size of:
-
10mm by CT scan (CT scan slice thickness no greater than 5 mm.
-
10mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be rescored as non-measureable).
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-
20 mm by chest x-ray

Nonmeasurable Lesions - all other lesions, including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis as well 
as truly non-measureable lesions. Lesions considered truly non-measurable lesions. 
Lesions considered truly non-measurable include; leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement 
of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measureable by reproducible imaging techniques.
All measurements should be taken and recorded in metric notation, using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Clinical lesions will only be considered measurable when they are superficial (e.g. 
skin nodules and palpable lymph nodes). For the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
6.2 Methods of Measurement

CT and MRI: CT and MRI are the best currently available and reproducible methods 
to measure target lesions selected for response assessment.  Conventional CT and 
MRI should be performed with cuts of 10 mm or less in slice thickness contiguously.  
Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. 
This applies to tumors of the chest, abdomen and pelvis.  Head and neck tumors and 
those of extremities usually require specific protocols. See RECIST v1.1 guidelines 
for additional specifications on CT and MRI measurements.

Chest X-ray: Chest CT is preferred over chest x-ray; particularly when progression is 
an important endpoint, since CT is more.

Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.  Ultrasound examinations cannot be reproduced 
in their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will 
be taken from one assessment to the next.  If new lesions are identified by ultrasound 
in the course of the study, confirmation by CT or MRI is advised.  If there is a concern 
about radiation exposure at CT, MRI may be used instead of CT in selected 
instances.  

Endoscopy and Laparoscopy: The utilization of endoscopy and laparoscopy for 
objective tumor evaluation is not advised.  

Tumor Markers: Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper normal limit, they must normalize for a patient to 
be considered in complete clinical response when all lesions have disappeared. 

Cytology and histology: These techniques can be used to differentiate between PR 
and CR in rare cases (e.g., after treatment to differentiate between residual benign 
lesions and residual malignant lesions in tumor types such as germ cell tumors).
6.3 Baseline Documentation of Target and Non-Target Lesions

When more than one measureable lesion is present at baseline all lesions up to a 
maximum of five (5) lesions total (and a maximum of two (2) lesions per organ) 
representative of all involved organs should be identified as target lesions and will be 
recorded and measured at baseline. 
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
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements. 

Lymph nodes merit special mention since they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. To be identified as 
target lesions lymph nodes must meet the criterion of a short axis of ≥ 15 mm by CT 
scan.  Only the short axis of these nodes will contribute to the baseline sum. See 
RECIST v1.1 guidelines for further detail.

A sum of diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. The 
baseline sum diameters will be used as reference by which to characterize the 
objective tumor regression in the measurable dimension of the disease. 

All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up.
Table 4 - Time point response: patients with target (+/- non-target) disease.
Target Lesions
Non-target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response; PR = partial response; SD = stable disease;  
PD = progressive disease, and NE = inevaluable
Table 5 - Time point response: patients with non-target disease only.
Non-target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease, and NE = inevaluable
6.4 Evaluation of Target Lesions

Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
<10mm.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (including baseline if that is 
the smallest). In addition, the sum must also demonstrate an absolute increase of at 
least 5 mm. Appearance of one or more new lesions is also considered progression.

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
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study. SD criteria must have been met at least once after study entry at a minimal 
interval (in general not less than 6-8 weeks).

Note: Target lesions (e.g. lymph nodes) that become too small to measure but still 
visible should be assigned a default value of 5 mm (derived from CT scan slice 
thickness).

Note: When non-nodal lesions “fragment,” the longest diameters of the fragmented 
portions should be added together to calculate the target lesion sum.

Note: The finding of “New Lesion” should be unequivocal, i.e. not attributable to 
differences in scanning technique, change in imaging modality or findings thought to 
represent something other than tumor (e.g. some new bone lesions may be simply 
healing or flare of pre-existing lesions; or necrosis of a liver lesion may be reported 
on a CT scan report as a “new” cystic lesion. This may be particularly important when 
there is evidence of CR or PR in target lesions.
6.5 Evaluation of Non-Target Lesions

Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10mm 
short axis)

Non CR/Non PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.

Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
Appearance of one or more new lesions is also considered progression.

Note: While some non-target lesions may actually be measurable, they need not to 
be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol.

Note: A modest increase in one or more non-target lesion(s) is usually not sufficient 
to qualify as unequivocal progression. The designation of overall progression solely 
on the basis of change in the non-target disease in the face of SD or PR of target 
lesions will therefore be extremely rare.
6.6 Overall Response Evaluation
See Tables 4 and 5 (Section 6.3).
6.7 Immune-related response criteria [1]
The principles used to establish objective tumour response are largely unchanged from 
RECIST 1.1, but the major change for iRECIST is the concept of resetting the bar if RECIST 
1.1 progression is followed at the next assessment by tumour shrinkage. iRECIST defines 
iUPD on the basis of RECIST 1.1 principles; however, iUPD requires confirmation, which is 
done on the basis of observing either a further increase in size (or in the number of new 
lesions) in the lesion category in which progression was first identified in (i.e., target or non-
target disease), or progression (defined by RECIST 1.1) in lesion categories that had not 
previously met RECIST 1.1 progression criteria. However, if progression is not confirmed, but 
instead tumour shrinkage occurs (compared with baseline), which meets the criteria of iCR, 
iPR, or iSD, then the bar is reset so that iUPD needs to occur again (compared with nadir 
values) and then be confirmed (by further growth) at the next assessment for iCPD to be 
assigned. If no change in tumour size or extent from iUPD occurs, then the timepoint 
response would again be iUPD. This approach allows atypical responses, such as delayed 
responses that occur after pseudoprogression, to be identified, further understood, and better 
characterized.
(Reference: iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics” Seymour, et al (Volume 18, No. 3, e143–e152, March 2017) 
[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30074-8/fulltext])
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Assignment of timepoint response using iRECIST
Target lesions, non-target lesions, and new lesions defined according to RECIST 1.1 
principles; if no pseudoprogression occurs, RECIST 1.1 and iRECIST categories for complete 
response, partial response, and stable disease would be the same.
*Previously identified in assessment immediately before this timepoint. “i” indicates immune 
responses assigned using iRECIST. iCR=complete response. iPR=partial response. 
iSD=stable disease. iUPD=unconfirmed progression. non-iCR/non-iUPD=criteria for neither 
CR nor PD have been met. iCPD=confirmed progression. RECIST=Response 
EvaluationCriteria in Solid Tumours.

For the immune-related response criteria, measurable new lesions are taken into 
account. For tumor assessmenttwo lesions per organ, up to 5 visceral lesions are 
calculated. Measurable Lesions are  lesions that can be accurately measured in at 
least one dimension (longest diameter in the plane of measurement is to be 
recorded) with a minimum size of:
-
10mm by CT scan (CT scan slice thickness no greater than 5 mm.
-
10mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be rescored as non-measureable).
-
20 mm by chest x-ray
 [ 2 new lesions per organ,  upto 5 visceral lesions)provide the total tumor burden] 
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Formula for tumor burden: SPDindex+SPDnew
1.
irCR, complete disappearance of all lesions (whether measurable or not, and no new 
lesions), confirmation by a repeat, consecutive assessment no less than 4 wk from 
the date first documented.
2.
irPR, decrease in tumor burden ≥50% relative to baseline, confirmed by a 
consecutive assessment at least 4 wk after first documentation.
3.
irSD, not meeting criteria for irCR or irPR, in absence of irPD.
4.
irPD, increase in tumor burden ≥25% relative to nadir (minimum recorded tumor 
burden), confirmation by a repeat, consecutive assessment no less than 4 wk from 
the date first documented.
6.8 Primary Endpoint 
To determine the overall response rate (ORR) by RECIST v 1.1 criteria for the combination of 
pembrolizumab with Pelareorep. 
To address the primary objective, 2 or more responses (CR or PR) out of 11 are needed in 
Stage 1 to continue the trial to the full 30 patients. If the trial continues to the full 30 patients. 
Then ORR will be estimated using a two stage method.
Evaluable patient: A patient needs to have taken one dose of either study drug, and 
completed the first scan to be evaluable for this primary endpoint. 
Note: If a patient drops out of the study before the first scan, due to clinical progression, they 
are evaluable and will not be replaced. 
6.9 Secondary Endpoints 
To determine progression free survival by RECIST v1.1 criteria, as well as 1-year, 2-year 
and median overall survival with pembrolizumab in combination with Pelareorep.
Evaluable patient: Any patient who has taken one dose of either study drug will be 
evaluable for this endpoint.
2.To determine safety and tolerability of pembrolizumab and pelareorep when administered in 
combination as determined by NCI CTCAE v 4.03.
Evaluable patient: Any patient who has taken one dose of either study drug will be evaluable 
for this toxicity endpoint.
 
3. 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.
Evaluable patient: Any patient who has taken one dose of both study drugs and has given the 
pre-dose and atleast one post dose blood and/or tissue samples will be evaluable for this 
toxicity endpoint.
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6.10 Exploratory Endpoints
To measure the overall response rate (ORR) by using iRECIST criteria, for the combination 
of pembrolizumab and Pelareorep
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
6.11 Assessment of Antineoplastic Activity
Patients will be assessed by CT or MRI following the  RECIST Guidelines (version 1.1)]. 
Tumor measurements will be performed at baseline (on cycle 1 day 1 or up to 7 days before 
study treatment initiation) and every 3 weeks thereafter (Appendix 4). Tumor assessments 
will be performed with RECIST1.1 criteria
Post treatment scans should be performed every 3 months after treatment ends (if patient 
has not progressed during treatment) and repeated until the patient has progressed.  
Confirmation of a complete or partial response (CR or PR) is required with repeat imaging 4 
weeks after criteria of response first met.
7.
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University. The level of risk 
attributed to this study requires high intensity monitoring as outlined in the DSMP. In addition, the 
study will abide by all safety reporting regulations, as set forth in the Code of Federal 
Regulations.  
7.1 Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical trial, 
are done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial (see Section 5 for time points). In addition, certain adverse 
events must be reported in an expedited manner to allow for optimal monitoring and patient 
safety and care. 
All patients experiencing an adverse event, regardless of its relationship to study drug, will be 
followed until: 

the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline; 

any abnormal laboratory values have returned to baseline; 

there is a satisfactory explanation other than the study drug for the changes 
observed; or

death.

If an AE remains unresolved at the conclusion of the study, the investigator and 
DSMC will make a clinical assessment whether continued follow-up of the AE is 
warranted.
7.2 Definitions & Descriptions
7.2.1
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention. 
Recording of AEs should be done in a concise manner using standard, acceptable 
medical terms. In general, AEs are not procedures or measurements, but should 
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reflect the reason for the procedure or the diagnosis based on the abnormal 
measurement. Preexisting conditions that worsen in severity or frequency during the 
study should also be recorded (a preexisting condition that does not worsen is not an 
AE). Further, a procedure or surgery is not an AE; rather, the event leading to the 
procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome should be 
recorded as the AE whenever possible.  However, a complete description of the 
signs, symptoms and investigations which led to the diagnosis should be provided. 
For example, if clinically significant elevations of liver function tests are known to be 
secondary to hepatitis, “hepatitis” and not “elevated liver function tests” should be 
recorded. If the cause is not known, the abnormal test or finding should be recorded 
as an AE, using appropriate medical terminology (e/g/ thrombocytopenia, peripheral 
edema, QT prolongation).
The Investigator is responsible for ensuring that all AEs identified during the reporting 
period are followed until they are resolved or until they become chronic with no 
resolution expected.  Follow-up of all AEs must be documented in the patient’s 
medical record and on the CRF.
7.2.2
Severity of AEs
All non-hematologic adverse events will be graded according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The CTCAE v4 is 
available at http://ctep.cancer.gov/reporting/ctc.html
If no CTCAE grading is available, the severity of an AE is graded as follows:

Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.

Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.

Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.

Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.

Fatal (grade 5): the event caused death.
7.2.3
Serious Adverse Events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed consent, 
through 90 days after the last administration of study drug, must be reported upon 
discovery or occurrence. Please refer to section 7.4 for protocol specific  additional 
requirements to SAE reporting.
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that:

Results in death.
-
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.

Is life-threatening.
-
The patient was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more 
severe.
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
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Is an important medical event.
-
Any event that does not meet the above criteria, but that in the judgment 
of the investigator jeopardizes the patient, may be considered for 
reporting as a serious adverse event. The event may require medical or 
surgical intervention to prevent one of the outcomes listed in the 
definition of “Serious Adverse Event“. 
-
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to Oncolytics and Merck in the 
same timeframe as SAEs to meet certain local requirements. Therefore, these events 
are considered serious by Merck for collection purposes.

Is a new cancer (that is not a condition of the study);

Is associated with an overdose.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any serious adverse 
event, or follow up to a serious adverse event, including death due to any cause 
whether or not related to Pelareorep and/or pembrolizumab, must be reported within 
24 hours to QA/DSMC and within 2 working days to Merck Global Safety and 
Oncolytics.
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Pelareorep and or pembrolizumab that is brought 
to the attention of the investigator at any time following consent through the end of 
the specified safety follow-up period specified in the paragraph above, or at any time 
outside of the time period specified in the previous paragraph also must be reported 
immediately to QA/DSMC, Oncolytics and to Merck Global Safety.
All subjects with SAEs must be followed up for outcome.
7.2.3
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria:

Is unanticipated in terms of nature, severity, or frequency

Places the research subject or others at a different or greater risk of harm

Is deemed to be at least possibly related to participation in the study.   
7.3 Adverse Event Reporting
7.3.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF. Routine AEs will be reviewed by the Data and Safety Monitoring Committee 
(DSMC) according to the study’s phase and risk level, as outlined in the DSMP. 
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Any adverse event which changes CTCAE grade over the course of a given episode 
will have each change of grade recorded on the adverse event case report 
forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for 
seriousness, as required by both Merck and Oncolytics.
7.3.2
Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment 
and is attributed (possibly, probably, or definitely) to the agent(s) must also be 
reported accordingly.
1.
Identify the type of adverse event using the NCI CTCAE v 4.03[3].
2.
Grade the adverse event using the NCI CTCAE v 4.03[3].
3.
Determine whether the adverse event is related to the protocol therapy.  
a.
Attribution categories are as follows:
i.
Definite: AE is clearly related to the study treatment.
ii.
Probable: AE is likely related to the study treatment.
iii.
Possible: AE may be related to the study treatment.
iv.
Unlikely: AE not likely to be related to the study treatment.
v.
Unrelated: AE is clearly NOT related to the study treatment.
4.
Determine the prior experience of the adverse event.
a.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:
i.
the current protocol
ii.
the drug package insert
iii.
the current Investigator’s Brochure
7.3.3
Expedited Reporting of SAEs/Other Events
7.3.3.1 Reporting to the Northwestern University QAM/DSMC
All SAEs must be reported to the assigned QAM within 24 hours of becoming 
aware of the event. Completion of the Oncolytics SAE Form for Oncolytics 
and NU SAE form for QA/DSMC and Merck, provided as a separate 
documents, is required.
The completed form should assess whether or not the event qualifies as a 
UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

A description of the event, severity, treatment, and outcome (if 
known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DSMC at their next 
meeting.
7.3.3.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow their 
local IRB guidelines for reporting to their local IRBs.
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
Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification. 

Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment)

Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the NU 
IRB within 5 working days of notification.

All other deaths of NU subjects not previously reported, other non-
NU subject deaths that were unanticipated and unrelated, and any 
other SAEs that were not previously reported as UPIRSOs will be 
reported to the NU IRB at the time of annual continuing review.
7.3.3.3 Reporting to the FDA 
The FDA will be notified within 7 calendar days of any SAE that is associated 
with study treatment, is unexpected, and is fatal or life-threatening.
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not fatal or 
life-threatening. This includes any previous SAEs that were not initially 
deemed reportable, but are later determined to meet the criteria for reporting 
(i.e. by the DSMC).
All other SAEs will be reported on an annual basis as part of the annual FDA 
report.
7.3.3.4 Reporting to Oncolytics Biotech Inc and Merck
SAE reports and any other relevant safety information are to be forwarded to 
the Global Safety facsimile number:  +1-215-993-1220 for Merck and 
sae_reports@oncolytics.ca or 403-283-0858 for Oncolytics.
The NU SAE form is to be used for reporting to Merck and the 
Oncolytics SAE form is to be used for reporting to Oncolytics.
A copy of all 15 Day Reports and Annual Progress Reports is submitted as 
required by FDA, European Union (EU), Pharmaceutical and Medical 
Devices agency (PMDA) or other local regulators. Investigators are required 
to cross reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of 
submission.  Additionally investigators are required to submit a copy of these 
reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-
1220) for Merck and sae_reports@oncolytics.ca or 403-283-0858 for 
Oncolytics, at the time of submission to FDA. 
7.4 Protocol-Specific Additional Reporting Requirements for Serious Adverse Event 
Reporting 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. Hospitalization related to convenience (e.g. 
transportation issues etc.) will not be considered a SAE.
7.4.1
Events of Clinical Interest
Selected non-serious and serious AEs are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to DSMC and within 2 working days to 
Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220).and 
Oncolytics at sae_reports@oncolytics.ca or 403-283-0858
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For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject 
must be reported within 24 hours to DSMC and within 2 working days to Merck 
Global Safety and Oncolytics if it causes the subject to be excluded from the trial, or 
is the result of a protocol-specified intervention, including but not limited to washout 
or discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to 
an ECI, whether or not related to Pelareorep and or pembrolizumab, must be 
reported within 24 hours to DSMC and within 24 hours to Merck Global Safety and 
Oncolytics
Events of clinical interest for this trial include:

an overdose of Merck product, as defined in Section  7.4.3 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is 
not associated with clinical symptoms or abnormal laboratory results. 

an elevated AST or ALT lab value that is greater than or equal to 3X the 
upper limit of normal and an elevated total bilirubin lab value that is greater 
than or equal to 2X the upper limit of normal and, at the same time, an 
alkaline phosphatase lab value that is less than 2X the upper limit of normal, 
as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
-
*Note: These criteria are based upon available regulatory guidance 
documents. The purpose of the criteria is to specify a threshold of abnormal 
hepatic tests that may require an additional evaluation for an underlying 
etiology.
7.4.2
Management and Reporting of Pregnancy
Although pregnancy and lactation are not considered AEs, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. The pregnancy is to be 
immediately reported to QA/DSMC, Oncolytics Biotech Inc., and Merck & Co Inc.
Pregnancies and lactations that occur after the consent form is signed but before 
treatment allocation/randomization must be reported by the investigator if they cause 
the subject to be excluded from the trial, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure.
Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of any of the study 
drugs, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, must be reported by the investigator. All 
reported pregnancies must be followed to the completion/termination of the 
pregnancy. The anticipated date of birth or termination of the pregnancy should be 
provided at the time of the initial report. Pregnancy outcomes of spontaneous 
abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, 
intrauterine death, miscarriage, stillbirth and neonatal death occurring ≤ 30 days after 
birth must be reported as SAEs. If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
The Investigator must follow the procedures outlined in protocol Section 7.3.3 for 
reporting SAEs. Such events must be reported within 24 hours to QA/DSMC and 
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Oncolytics (sae_reports@oncolytics.ca or 403-283-0858), and within 2 working days 
to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220). The 
outcome of the pregnancy should be reported to Oncolytics Biotech Inc. and Merck & 
Co Inc. as soon as it is known.  If the pregnancy ends for any reason before the 
anticipated date initially reported the Investigator should notify Oncolytics Biotech Inc. 
and Merck & Co Inc. the following working day.
7.4.3
Definition of an Overdose of Pembrolizumab for This Protocol and Reporting of 
Reporting of Overdose to QA/DSMC and Merck
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose 
of 1,000 mg or greater (≥5 times the indicated dose).  No specific information is 
available on the treatment of overdose of pembrolizumab. Appropriate supportive 
treatment should be provided if clinically indicated. In the event of overdose, the 
subject should be observed closely for signs of toxicity.  Appropriate supportive 
treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of 
pembrolizumab, the adverse event(s) is reported as a serious adverse event, even if 
no other seriousness criteria are met.
If a dose of pembrolizumab meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the 
overdose is reported as a non-serious Event of Clinical Interest (ECI), using the 
terminology “accidental or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 
hours to QA/DSMC and within 2 working days hours to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220)
8.
DRUG INFORMATION
8.1 Pembrolizumab
8.1.1
Other names
MK-3475, KEYTRUDA
8.1.2
Classification and type agent
Humanized monoclonal antibody against PD-1 protein.
8.1.3
Mode of action
Highly selective anti-PD-1 humanized monoclonal antibody which inhibits 
programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on T-cells to 
block PD-1 ligands (PD-L1 and PD-L2) from binding. Blocking the PD-1 pathway 
inhibits the negative immune regulation caused by PD-1 receptor signaling (Hamid, 
2013). Anti-PD-1 antibodies (including pembrolizumab) reverse T-cell suppression 
and induce antitumor responses. 
8.1.4
Storage and stability
Please refer to pharmacy manual for detailed instructions. 
Pembrolizumab is provided as a white to off-white lyophilized powder (50 mg/vial) or 
as a liquid solution (100 mg/vial) in Type I glass vials intended for single use only. 
Pembrolizumab powder for solution for injection is a sterile, non-pyrogenic lyophilized 
powder for intravenous infusion supplied in single-use glass vial containing 50 mg of 
pembrolizumab. The product is preservative-free, white to off-white powder, and free 
from visible foreign matter.
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Pembrolizumab solution for Infusion is a sterile, non-pyrogenic aqueous solution 
supplied in single-use Type I glass vial containing 100 mg/4 mL of pembrolizumab. 
The product is preservative-free, latex free solution which is essentially free of 
extraneous particulates. Pembrolizumab solution for Infusion vials are filled to a 
target of 4.25mL (106.25mg) to ensure recovery of 4.0mL (100mg).
Clinical supplies must be stored in a secure, limited-access location under the 
storage conditions specified on the label. Pembrolizumab vials should be stored a 
refrigerated conditions (2°C to 8°C). Do not freeze; do not shake.  Prior to 
reconstitution, the vials of lyophilized powder can be out of refrigeration 
(temperatures at or below 25°C (77°F) for up to 24 hours.
Receipt and dispensing of trial medication must be recorded by an authorized person 
at the trial site.
Clinical supplies may not be used for any purpose other than that stated in the 
protocol.
8.1.5
Protocol dose specifics
Pembrolizumab 200 mg will be administered as a 30-minute intravenous (IV) infusion 
every 3 weeks. Every effort should be made to target infusion timing to be as close to 
30 minutes as possible. However, given the variability of infusion pumps, a window of 
-5 minutes and +10 minutes is permitted (i.e., infusion duration is 30 minutes: -5 
min/+10 min). 
 
Dose modifications to pembrolizumab will not permitted in this study
8.1.6
Preparation

Pembrolizumab powder for solution for Infusion is reconstituted with 2.3 mL 
of Sterile Water for Injection, USP by injecting the water along the walls of 
the vial and not directly on the lyophilized powder (resulting concentration 25 
mg/mL).

Slowly swirl the vial. Allow up to 5 minutes for the bubbles to clear. Do not 
shake the vial.

Limit the number of punctures of each vial to two (one for reconstitution, one 
for withdrawal)

Visually inspect the reconstituted solution for particulate matter and 
discoloration prior to administration. Reconstituted Pembrolizumab is a clear 
to slightly opalescent, colorless to slightly yellow solution. Discard 
reconstituted vial if extraneous particulate matter other than translucent to 
white proteinaceous particles is observed.

Reconstituted vials and pembrolizumab infusion solutions are to be further 
diluted to final concentration of the diluted solution should be between 1 
mg/mL to 10 mg/mL.

Withdraw the required volume from the vials of Pembrolizumab and transfer 
into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, 
USP. Mix diluted solution by gentle inversion 10-15 times to mix the solution. 

If normal saline is not available, 5% Dextrose Injection, USP or regional 
equivalent (5% dextrose) is permissible, Please note, the preferred diluent is 
0.9% Sodium Chloride and 5% dextrose is only permissible if normal saline is 
not available.

The bag must be filled to at least 30% of its capacity

Pembrolizumab should not be mixed with other diluents. 
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
Discard any unused portion left in the vial. The product does not contain a 
preservatives. 
Store the reconstituted and diluted solutions of Pembrolizumab either:

At room temperature for no more than 4 hours from the time of reconstitution. 
The 4 hour countdown begins when the vial is pierced, and includes room 
temperature storage of reconstituted drug product solution in vials, room 
temperature storage of admixture solutions in the IV bags and the duration of 
infusion.

IV bags and/or reconstituted vials can be also stored refrigerated at 2—8 
degrees 0C (36—46 degrees 0F) for up to 20 hours.  If refrigerated, allow the 
vials and/or IV bags to come to room temperature prior to use.

Do not freeze.
8.1.7
Route of administration

Administer infusion solution intravenously over 30 minutes, with a window of 
-5 and +10 minutes, through a peripheral line or indwelling catheter, using a 
sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or 
add-on filter.

Maximum rate of infusion should not exceed 6.7 mL/min. through a 
peripheral line or indwelling catheter. Pembrolizumab 200 mg will be diluted 
in 50 or 100 ml NS.

Do not co-administer other drugs through the same infusion line.

Ensure the entire contents of the bag are dosed and all remaining drug 
solution in the line is administered according to institutional guidelines for 
saline flushing. 
8.1.8
Incompatibilities
The following infusion bag materials are compatible with pembrolizumab (MK-3475): 
PVC plasticized with DEHP, Non-PVC (polyolefin), EVA, PE lined polyolefin. 
8.1.9
Availability & Supply
Clinical Supplies will be provided by Merck as summarized in Table below. Clinical 
supplies will be affixed with a clinical label in accordance with regulatory 
requirements
Product Descriptions
Product Name & Potency
Dosage Form
Commercial Keytruda  100 mg/ 4mL
Liquid for infusion
Merck will supply pembrolizumab directly to the NU Investigational Pharmacy at no 
charge to subjects participating in this clinical trial. The contact for drug ordering will 
be Debra Perlow (debra.perlow@merck.com) or Tammy Moll 
(:tammy.moll@merck.com). The Merck Drug Request Form, provided by Merck, 
should be completed and emailed to these contacts. It is imperative that only drug 
product designated for this protocol number be used for this study. Drug is protocol 
specific, but not patient specific
Clinical Supplies Disclosure of pembrolizumab
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor 
and/or designee are not blinded to treatment. Drug identity (name, strength) is 
included in the label text; random code/disclosure envelopes or lists are not provided.
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8.1.10
Side effects
Pembrolizumab is generally well tolerated and demonstrates a favorable safety 
profile. Pembrolizumab is an immunomodulatory agent, and based on this 
mechanism of action, immune mediated adverse events are of primary concern. 
Important identified risks for pembrolizumab are of an immune mediate nature, 
including: 

pneumonitis

colitis

thyroid disorders (hypothyroidism/hyperthyroidism)

hepatitis 

hypophysitis

Type I diabetes mellitus 

uveitis, and 

nephritis
After a recent review of data, events newly characterized as identified risks also 
include pancreatitis, myositis, and severe skin reaction; these are included in the 
reference safety information in the current IB. The majority of immune-mediated 
adverse events were mild to moderate in severity, were manageable with appropriate 
care, and rarely required discontinuation of therapy.  
In addition to the previously noted identified risks, infusion-related reactions are a risk 
but are not considered immune mediated; these are also further described in the 
current IB.
Please refer to current IB for a complete list of side effects.
8.1.11
Safety and monitoring plan
All participants will be carefully followed for safety. Safety evaluations include a 
physical exam, vital signs, performance status assessment, and safety laboratory 
tests. Medications should be available at the bedside per institutional guidelines, in 
case an immune-mediated reaction should occur.
8.1.12
Return and Retention of Pembrolizumab
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to and returned by the 
subjects and the amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused pembrolizumab vial(s) shall 
be returned to the designated facility for destruction. 
Please refer to pharmacy manual for the address of the designated facility. 
All used and/or partially used investigational product will be destroyed at the site per 
institutional policy. It is the Investigator’s responsibility to arrange for disposal of all 
empty containers, provided that procedures for proper disposal have been 
established according to applicable federal, state, local and institutional guidelines 
and procedures, and provided that appropriate records of disposal are kept.
8.2 PELAREOREP
8.2.1
Other names 
REOLYSIN
8.2.2
Classification - type of agent
Reovirus® Serotype 3 – Dearing Strain
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Double-stranded RNA; icosahendric; no envelope,70nm
8.2.3
Mode of action-
Pelareorep is an isolate of reovirus type 3 Dearing. Pelareorep contributes to cell 
lysis through selective viral replication and promotes anti-tumor immunity through 
activation of NK cells and adaptive immune response. 
8.2.4
Storage and stability
Please refer to pharmacy manual for detailed instructions.
Pelareorep  is a clear to translucent, colorless to light-blue liquid containing up to 
3x1011 TCID50 of Reovirus Serotype 3 – Dearing strain per mL.  The final formulations 
of pelareorep will contain designated amounts of TCID50 in a phosphate-buffered 
solution. Most supplied vials will contain 4.5 x1010 TCID50 per 1 mL, but pharmacist 
should check the label of each individual vial. 
Three lots of drug product have been on stability studies for up to 60 months (when 
stored at -70º C) and viral titre data has been included in the table below.  Recent 
data demonstrates that the Reovirus remains active when stored at ≤-20ºC.  .  Before 
distribution to the sites, PELAREOREP will continue to be stored at ≤-70ºC Updated 
stability information will be provided as additional data is collected.  PELAREOREP 
should be stored at ≤-20 ºC or ≤-60 ºC within the cryobox or carton to protect from 
light. The drug storage should not be switched between ≤-20 ºC and ≤-60 ºC, and the 
supply should be maintained at one temperature. 
8.2.5
Protocol dose specifics
No premedication is necessary. PELAREOREP will be given over 60 min mins at a 
dose of 4.5x1010TCID50 IV daily on Days 1, 2, 3 & 8 of Cycle 1 (starting after 
completion of pembrolizumab infusion on day 1). From Cycle 2 onwards pelareorep 
at a dose of 4.5x1010TCID50 IV daily will be administered on Days 1 and 8. 
The treatment cycle will be repeated every 21 days.
8.2.6
Preparation
When removing the drug from its original shipment box, wear gloves and face shield 
or safety glasses.
When preparing pelareorep  inside the biosafety cabinet or Barrier-Isolator, wear 
appropriate personal protective equipment per protocol requirement or wear standard 
PPE of impervious smart sleeve gown, powder-free sterile gloves, and surgical mask 
(wear face shield or safety glasses if there is a risk of splashing).
When transporting the drug to the final patient care area and when the drug is in a 
secured secondary container, wearing of PPE is not required. 
When cleaning biosafety cabinet, wear surgical mask, impervious gown, double 
gloves (i.e. nitrile), and protective eyewear (also wear a face shield if there is a risk of 
splashing). 
When handling spill cleanup or removing/ handling waste containers, wear double 
gloves (i.e. nitrile), impervious gown, mask, and protective eyewear (also wear a face 
shield if there is a risk of wear of splashing). 
Pelareorep is a clear to translucent, colorless to light-blue liquid containing up to 
3x1011 TCID50 of Reovirus Serotype 3 – Dearing strain per mL.  The final formulations 
of pelareorep will contain designated amounts of TCID50 in a phosphate-buffered 
solution.
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Prior to clinical use, the test drug will be prepared by the pharmacy.  Pelareorep will 
be thawed and diluted to the appropriate concentration using 0.9% Sodium Chloride 
Injection, EP.  Time from the thawing and dilution process to administration to the 
patient must be less than 7 hours (plus 1 hour of infusion) and a detailed Drug 
Handling Guideline/Pharmacy Manual will be provided to the investigation sites for 
the process.  Reovirus is known to be a very stable and resistant virus in the 
environment and there are no concerns with maintaining the thawed and diluted virus 
for up to 8 hours under these conditions.
Purified pelareorep will be provided to the pharmacy at each study site in glass vials.  
The dilution or mixing will be done by the pharmacy at the study sites.  Vial labels will 
indicate the product, lot number and concentration.  The procedure will be 
undertaken with appropriate precautions including mask, gown and gloves.  The 
procedure will be undertaken in a specifically prepared biological safety cabinet 
under aseptic conditions.  The dose will be prepared by a pharmacist.  Drug Handling 
Guidelines/Pharmacy manual will be provided for each batch with specific 
manipulation instructions.  Pelareorep must be stored at ≤ -20oC in glass vials (1 
mL volume).  If preferred, it is acceptable for sites to continue to store product 
as previously recommended at ≤-60 ºC.
The prepared Pelareorep infusion must be kept refrigerated at 2-8 ºC up to 7 
hours (prior to 1 hour infusion at room temperature) or at room temperature for 
30 minutes (prior to 1 hour infusion at room temperature). 
Note: All material that comes into contact with the viral preparation will be placed in 
sodium hypochlorite (800 ppm chlorine) and disposed of as biohazardous waste.  
8.2.7
Route of administration for this study
Intravenous (IV)
8.2.8
Incompatibilities
Please refer to section 4.5.2
8.2.9
Availability & Supply 
Purified Pelareorep will be provided to the pharmacy at each study site in glass vials.
REOLYSIN® (pelareorep) is a clear to translucent, colorless to light-blue liquid 
containing 4.5x1010 TCID50 of Reovirus Serotype 3 – Dearing strain per mL. The 
product is supplied as 1 mL of pelareorep contained within a 2 mL glass vial. The 
final formulations of pelareorep will contain designated amounts of TCID50 in a 
phosphate-buffered solution.
8.2.10
Side effects
Please see current Investigator’s Brochure for a complete list of adverse events. 
Likely to Occur:

Mild “flu-like” symptoms such as:

Fever 

Chills 

Tiredness or general weakness 

Mild gastrointestinal symptoms such as:
-
Nausea 
-
Vomiting 
-
Diarrhea 
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Less Likely, some may be serious (occurs in 1-10):

Mild and transient changes in ALT (SGOT) levels

Laboratory abnormalities: 
-
Neutropenia 
-
Thrombocytopenia,
-
increased ALT and LDH 
-
Proteinuria 
Rare, some may be serious (occur in less than 1%):
Patients who receive REOLYSIN® only (no chemotherapy or radiation therapy)

Temporary effect on liver

Temporary effect on heart

Temporary changes in kidney function

Temporary impairment to eye function

Hypotension
Please refer to current IB for details on side effects of REOLYSIN in combination with 
chemotherapy
8.2.11
Nursing implications
Please refer to the Pharmacy Manual and the Biosfaety Manual for complete set of 
instructions for handling, administration and disposal of pelareorep.
A few critical precautions are listed below:

When connecting / disconnecting tubing, needles or syringes outside of 
biosafety cabinet, staff need to follow standard precautions including wearing 
eye protection (safety glasses).  Consider wrapping a gauze or alcohol wipe 
around the luer-lock, syringe, or needle when connecting or withdrawing it 
from the tubing or connection to prevent droplet contamination if appropriate. 

Pelareorep shall NOT be handled with bare hands.  

Staff must wear double gloves, surgical mask, and protective eyewear 
whenever opening the secondary and primary container housing pelareorep.

Observe standard hand hygiene after removing gloves each time.

When nursing performs specimen collection, double gloves, wear a surgical 
mask and protective eyewear are required. The precautions taken during 
administration of the drug should also be taken when drawing blood and 
collecting other specimens for patients.

Patients should be instructed to use a designated toilet whenever possible. 
The facility should be decontaminated after the study subject is released 
from the treatment area.

Please refer to Pharmacy Manual for details regarding appropriate drug 
disposal. 

Pregnant or nursing staff should not administer or handle pelareorep. 

Either a central line or a peripheral line can be used for administration, so 
long as the line is flushed after the pelareorep infusion.
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
Pelareorep on Day 1 will be administered after the end of pembrolizumab 
infusion. 

Pre-treatment assessment of hydration before each infusion is to be done. 
Patients must be instructed to adequately hydrate prior to each study 
treatment dose administration by drinking water and other liquids.

When discharged, the patient and the family will receive an outpatient 
information sheet regarding infectious precautions that they should follow 
both at home and in public [See Appendix 3]. 
NOTE: These instructions are available in a ‘patient information sheet’ as stand- 
alone document 
Note: All material that comes into contact with the viral preparation will be placed in 
sodium hypochlorite (800 ppm chlorine) and disposed of as biohazardous waste.  
8.2.12
Return and Retention of Study Drug
The Principal Investigator will designate a pharmacist who will be responsible for 
tracking all pelareorep requested and delivered to the study site and its 
administration to individual patients.  Any unused supply of pelareorep will destroyed 
on site upon completion of the trial. Oncolytics will provide instructions for the return 
or destruction of unused product upon the completion of the trial.
All materials that were in contact with the viral preparation will be placed in sodium 
hypochlorite (800 ppm chlorine) and disposed of as biohazardous waste.
The site investigator is responsible for keeping accurate records of the clinical 
supplies received from Funders or a designee, the amount dispensed to and returned 
by the subjects and the amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. 
It is the site Investigator’s responsibility to arrange for disposal of all empty 
containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept.
9.
CORRELATIVES/SPECIAL STUDIES
Clinical responses will be correlated with the presence of an “inflamed phenotype” (as detected by 
gene-expression profile) and the emergence of selective T & B cell clones against tumor- or viral 
associated antigens after the start of therapy (T cell clonality in blood).  

Patients will have biopsies (or available archival tumor tissue) before treatment 
initiation and on-therapy (if feasible) between C1D4-C1D15 to assess an inflammatory gene 
expression profile in the tumor and tumor microenvironment.

Assays to evaluate adaptive immunity (T cell clonality) will be performed on tumor 
tissue as well. Biopsies are to be performed if a lesion is easily accessible, the biopsy is not 
contraindicated and the patient consents.

Assays to evaluate adaptive immunity on peripheral blood will be performed on C1D1 
(before any therapy), C1D8 (before pelareorep infusion) and C2D1, C3D1 and C4D1 before 
treatment initiation and at end of treatment.

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Please note: Currently, blood samples and tumor samples will be collected and stored and 
analysis will be done in the future, when adequate resources are available. The above samples 
will be collected by the PCF-CTU personnel and the samples will be stored in the NU 
biorepository till further processing and analysis is done. Please see the laboratory manual for 
detailed sample collection, processing and shipping information.
10. STATISTICAL METHODS
This Phase 2 trial follows a Simon’s two-stage design to evaluate the efficacy of pembrolizumab 
in combination with pelareorep.  The “Go/No Go” criteria in Phase 2 (Stage 1) will be defined 
using null response rate, alternative response rate, power, and alpha. In Stage 1, with null rate 
10%, alternative rate 35%, power 90%, and 1-sided alpha 0.025, the Simon two-stage "optimum" 
design specifies stage 1 sample size of 11, stopping for futility if <= 1 response out of 11 in stage 
1, and adding 19 additional patients if >= 2 responses at stage 1. In Stage 2, 7 responses out of 
30 are required to reject null rate <10%.
To address the primary objective, >=2  responses out of 11 are needed in Stage 1 to continue the 
trial to the full 30 patients.  If the trial continues to the full 30 patients, then ORR will be estimated 
using a two stage method (Porcher R, Desseaux K. What inference for two-stage phase II trials.  
BMC Medical Research Methodology 2012;12:117.)  Kaplan-Meier curves will be used to 
determine 1-year, 2 year and median overall survival.  For the secondary objectives, Kaplan-
Meier curves will be used to determine 1-year, 2 year and median progression-free survival.  
These analyses will be done at the end of Stage 1 and Stage 2.  Pre- and post-treatment biopsies 
and immune markers will be assessed for change using paired statistical methods such as paired 
t-tests or signed rank tests.
11. STUDY MANAGEMENT
11.1 Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations. The IRB should approve the consent form and protocol.
Correlative Samples  
Correlative study (sample type)
e.g. Pharmacokinetics (blood)
Inflammatory gene 
expression profile
(biopsy)
Evaluation of 
adaptive immunity 
(T cell clonality)
[in biopsy]
Evaluation of 
adaptive immunity 
(T cell clonality)
[in blood]
Mandatory or Optional
mandatory
mandatory
mandatory
Timing (+/- windows)
Archival tissue or 
biopsy before 
treatment. Optional  
‘on therapy biopsy’ 
between C1D4-
C1D15
See section 5.0 and 
lab manual
See section 5.0 and  
lab manual
Volume Needed (blood only)
N/A
N/A
6mL
Tube type needed (blood only)
N/A
N/A
EDTA
Tissue thickness and/or # slides 
(tissue only)
See lab manual
N/A
N/A
Processing center
PCF-CTU
PCF-CTU
PCF-CTU
Sample handling/processing 
instructions
See lab manual
See lab manual
See lab manual
Storage
NU Biorepository
NU Biorepository
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In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and 
to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full explanation 
of the study and will be given the opportunity to review the consent form. Each consent form 
must include all the relevant elements currently required by the FDA Regulations and local or 
state regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the 
study, the patient will be asked to give consent to participate in the study by signing an IRB 
approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion.
11.2  Amendments
Amendments to the protocol will be initiated and maintained by the assigned Medical 
Writer. Requests for revisions may come from multiple sources, including but not limited to 
the Principal Investigator, study team, drug company, or FDA. All amendments will be 
subject to the review and approval of the appropriate local, institutional, and governmental 
regulatory bodies, as well as by [insert Funding Sponsor name if applicable]. Amendments 
will be distributed by the lead institution (Northwestern) to all participating sites upon 
approval by the Northwestern University IRB.
11.3 Registration Procedures
For potential patients, study teams are asked to inform the assigned QAM 
(croqualityassurance@northwestern.edu) of the date and time that the patient will need to be 
registered.  
BEFORE a patient can be treated on study, the following items must be completed and 
submitted to confirm eligibility and receive a subject identification number: 

Patient’s signed and dated informed consent form (upload to NOTIS and 
keep original hard copy in a secure location/study chart)

Copy of the pathology report (upload to NOTIS)

Signed and dated Eligibility Checklist (upload to NOTIS and keep original 
hard copy in a secure location/study chart)
The assigned QAM will review the registration documents. Once review is complete, he or 
she will register the patient, assign a subject identification number, provide a cohort 
assignment (as applicable) and send a confirmation of registration to involved personnel. 
Registration will then be complete and the patient may begin study treatment. 
11.4 Data Submission
Data collection for this study will be done through NOTIS. Access to the trial in NOTIS is 
granted to appropriate roles identified at the time of participating site activation, or upon 
request. Site users will not be able to access the study in NOTIS until all required and study 
specific trainings are completed. 
Once a patient is confirmed and registered to the study, eCRFs should be submitted 
according to the study procedures table.  Generally, for all phase II/III patients, data are 
due with 10 days of a visit or end of cycle.  A set amount of data may also be requested for 
any screen failures, as is defined by the study. In most instances, this will include collection 
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of adverse events and baseline data from the time of registration to the date of screen 
failure
11.5 Instructions for Participating Sites
Before the study can be initiated at any site, the following documentation must be provided to 
the Clinical Research Office at Northwestern University:

Signed and completed Letter of Invitation to participate in the study.

Signed copy of Northwestern University’s Data Monitoring Committee policy 
pertaining to data submission.

Draft informed consent form should for review/approval prior to submission to the 
local IRB

A copy of the official IRB approval letter for the protocol and informed consent. 

CVs and medical licensure for the local PI and any sub-investigators who will be 
involved in the study at the site.

Form FDA 1572 appropriately filled out and signed with appropriate documentation.
Additional activities may be required prior to site activation (i.e. contract execution, study-
specific training). Full requirements will be outlined in a memo upon receipt of the signed 
Letter of Invitation.
11.6 Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data and Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to NOTIS for additional information). The level of risk attributed to this study requires 
High Intensity Monitoring as outlined in the DSMP. The assigned QAM, with oversight from 
the Data and Safety Monitoring Committee, will monitor this study in accordance with the 
study phase and risk level. 
11.7 Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study patient requires alternative treatment, the study shall be conducted exactly 
as described in the approved protocol. 
11.7.1
Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
For any such emergency modification implemented, an IRB modification form must 
be completed within 5 business days of making the change, and the QAM must be 
notified within 24 hours of such change. 
11.7.2
Other Protocol Deviations
All other deviations from the protocol must be reported in a timely manner to the 
assigned QAM using the NU CTO Deviation form.
A protocol deviation is any unplanned variance from an IRB approved protocol that: 

Is generally noted or recognized after it occurs.

Has no substantive effect on the risks to research participants.

Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected.

Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
A protocol deviation may be considered an instance of Reportable New Information 
(RNI) if it:
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
Has harmed or increased the risk of harm to one or more research 
participants.

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the investigator(s).

Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies.
11.8 Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site 
in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration 
of Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators 
and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study 
completion.
The Principal Investigator at each institution or site will be responsible for assuring 
that all the required data will be collected, entered onto the appropriate eCRFs, and 
submitted within the study-specific timeframes. Periodically, monitoring visits may be 
conducted and the Principal Investigator will provide access to his/her original 
records to permit verification of proper entry of data. The study may also be subject 
to routine audits by the Audit Committee, as outlined in the DSMP. 
11.9 Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with 
the DSMC Data Release Policies and Processes. The assigned QAM will prepare a 
preliminary data set for DSMC approval no later than 3 months after the study 
reaches its primary completion date, as defined by ClinicalTrials.gov. This is the date 
that the final patient was examined or received an intervention for the purposes of 
final collection of data for the primary outcome, whether the clinical trial concluded 
according to the pre-specified protocol or was terminated. If the investigator would 
like data release to be approved by the DSMC prior to when study design specifies, 
and/or prior to three months after a study’s primary completion date, the PI must 
send a written request for data approval to the QAM which includes justification. 
Requests must be made a minimum of six to eight weeks in advance of the expected 
deadline. The request will be presented to the DSMC at their next available meeting. 
Any DSMC decisions regarding data release will be provided to the PI. If the request 
is approved, the QAM will present the data set to the DSMC for approval. A final, 
DSMC-approved dataset, as applicable, will then be released 6-8 weeks after the 
request was made. The investigators are expected to use only DSMC-approved data 
and statistical analyses any time they are disseminating trial data. The investigators 
must send a copy of the draft abstract/poster/manuscript to the study’s biostatistician 
and assigned QAM to confirm that the DSMC-approved data and statistical analyses 
are used appropriately. Once the biostatistician and QAM gives final approval, the 
publication may be submitted to external publisher.
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Coffey, M.C., et al., Reovirus therapy of tumors with activated Ras pathway. Science, 1998. 
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19.
Hall, K., et al., Reovirus-mediated cytotoxicity and enhancement of innate immune responses 
against acute myeloid leukemia. Biores Open Access, 2012. 1(1): p. 3-15.
20.
Prestwich, R.J., et al., Tumor Infection by Oncolytic Reovirus Primes Adaptive Antitumor 
Immunity. Clinical Cancer Research, 2008. 14(22): p. 7358-7366.
21.
Adair, R.A., et al., Cytotoxic and immune-mediated killing of human colorectal cancer by 
Reovirus-loaded blood and liver mononuclear cells. Int J Cancer, 2013. 132(10): p. 2327-38.
22.
Gujar, S.A. and P.W. Lee, Oncolytic virus-mediated reversal of impaired tumor antigen 
presentation. Front Oncol, 2014. 4: p. 77.
23.
Sei S, Y.Q.-e., Mussio J, Coffey MC,. Parchment JE, Shoemaker RH,  Tomaszewski JE. , 
Synergistic antitumor activity of oncolytic Reovirus and chemotherapeutic agents against 
non-small cell lung cancer. European Journal of Cancer Supplements, 2006. 4(12): p. 103.
24.
Wadler S., et al., The oncolytic Reovirus, REOLYSIN®, augments the anticancer effects of 
cytotoxic agents in vitro against the ras-mutated human colon cancer cell line HCT116. . 
European Journal of Cancer Supplements 2004. 2(8): p. 135.
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25.
Qiao, J., et al., Cyclophosphamide facilitates antitumor efficacy against subcutaneous tumors 
following intravenous delivery of Reovirus. Clin Cancer Res, 2008. 14(1): p. 259-69.
26.
Arkenau, H., Evans, J, et al. A phase I study of the combination of intravenous Reolysin 
(REO) and gemcitabine (GEM) in patients (pts) with advanced cancer. in ASCO Annual 
Meeting. 2009. J Clin Oncol 27:15s, 2009 (suppl; abstr 3584).
27.
Karapanagiotou, E.M., et al., Phase I/II trial of carboplatin and paclitaxel chemotherapy in 
combination with intravenous oncolytic Reovirus in patients with advanced malignancies. Clin 
Cancer Res, 2012. 18(7): p. 2080-9.
28.
Lolkema, M.P., et al., A phase I study of the combination of intravenous Reovirus type 3 
Dearing and gemcitabine in patients with advanced cancer. Clin Cancer Res, 2011. 17(3): p. 
581-8.
29.
Ocean, A.J., Bekaii-Saab, T.S. , Chaudhary, I., Palmer, R., Christos, P.J., Mercado, A., 
Florendo, E.O., Rosales, V.A., Ruggiero, J.T., Popa, E.C., Wilson, M., Haroon Ghalib, M., 
Hou, Y., Shah, U., Rajdev, L., Elrafei, T., Gill, G.M., Coffey, M.C., Shah, M.A., Goel, S. A 
multicenter phase I study of intravenous administration of reolysin in combination with 
irinotecan/fluorouracil/leucovorin (FOLFIRI) in patients (pts) with oxaliplatin-
refractory/intolerant KRAS-mutant metastatic colorectal cancer (mCRC). in 2013 
Gastrointestinal Cancers Symposium (January 24 - 26, 2013). 2013. Journal of Clinical 
Oncology.
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Vidal-Boixader, L., Karavasilis, V, Beirne, D, et al. Phase I trial of intratumoral administration 
of Reovirus type 3 (Reolysin) in combination with radiation in patients with advanced 
malignancies in ASCO Annual Meeting. 2007. JCO 2007; 25 (18S, abstr 14009).
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Jackson GG, M.R., Cooper RS   Reovirus type 1 as an etiologic agent of the common cold. J 
Clin Invest, 1961. 40: p. 1051.
32.
Jackson GG, M.R., Johnson GC, Dowling MF Contribution of volunteers to studies on the 
common cold. Am Rev Resp Dis, 1962. 88: p. 120-127.
33.
Jarudi NI, H.D., Golden Reovirus keratoconjunctivitis. B Can J Opthal, 1973. 8(371-373).
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Gollamudi, R., et al., Intravenous administration of Reolysin, a live replication competent RNA 
virus is safe in patients with advanced solid tumors. Invest New Drugs, 2010. 28(5): p. 641-9.
35.
Vidal, L., et al., A phase I study of intravenous oncolytic Reovirus type 3 Dearing in patients 
with advanced cancer. Clin Cancer Res, 2008. 14(21): p. 7127-37.
36.
Comins, C., et al., REO-10: a phase I study of intravenous Reovirus and docetaxel in patients 
with advanced cancer. Clin Cancer Res, 2010. 16(22): p. 5564-72.
37.
Ocean, A., et al. A multicenter phase I study of intravenous administration of reolysin in 
combination with irinotecan/fluorouracil/leucovorin (FOLFIRI) in patients (pts) with oxaliplatin-
refractory/intolerant KRAS-mutant metastatic colorectal cancer (mCRC). in ASCO GI cancers 
symposium. 2013. J Clin Oncol 31, 2013 (suppl 4; abstr 450).
38.
Carew, J.S., et al., Reolysin is a novel Reovirus-based agent that induces endoplasmic 
reticular stress-mediated apoptosis in pancreatic cancer. Cell Death & Disease, 2013. 4(7): p. 
e728.
39.
Etoh, T., et al., Oncolytic viral therapy for human pancreatic cancer cells by Reovirus. Clin 
Cancer Res, 2003. 9(3): p. 1218-23.
40.
Mahaligam D, W.Y., Ting LW, Sarantopoulos J, Vemulapalli S, Aparo S, Coffey M, Gill and 
K.G. G, and Mita M. . A Study of REOLYSIN in Combination with Gemcitabine in Patients 
with Advanced Pancreatic Adenocarcinoma. in 24th EORTC-NCI-AACR Symposium on 
‘Molecular Targets and Cancer Therapeutics’. 2012. Dublin, Ireland.
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Bekaii-Saab, T., Noonan, A.M., Lesinski, G., Mikhail, S., Ciombor, K., Pant, S., Aparo, S., 
Tahiri, S., Thompson, A., Sexton, J., Marshall, J.L., Mace, T., Wu, C., El-Rayes, B., Timmers, 
C., Geyer, S., Zwiebel, J., Villalona-Calero, M.A., A MULTI-INSTITUTIONAL RANDOMIZED 
PHASE 2 TRIAL OF THE ONCOLYTIC VIRUS REOLYSIN IN THE FIRST LINE 
TREATMENT METASTATIC ADENOCARCINOMA OF THE PANCREAS (MAP). Annals of 
Oncology, 2014. 24 (suppl 4).
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Keir, M.E., et al., PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 2008. 
26: p. 677-704.
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Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
Cancer, 2012. 12(4): p. 252-64.
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44.
Boland, G.P., et al., Biological response to hormonal manipulation in oestrogen receptor 
positive ductal carcinoma in situ of the breast. Br J Cancer, 2003. 89(2): p. 277-83.
45.
Kefford, R., Ribas, A, Hamid, O, et al. Clinical efficacy and correlation with tumor PD-L1 
expression in patients (pts) with melanoma (MEL) treated with the anti-PD-1 monoclonal 
antibody MK-3475. in ASCO Meeting 2014. J Clin Oncol 32:5s, 2014 (suppl; abstr 3005).
46.
Garon, E.B., et al., Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer. N Engl 
J Med, 2015.
47.
Rizvi, N.A., et al., Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, 
for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 
063): a phase 2, single-arm trial. Lancet Oncol, 2015. 16(3): p. 257-65.
48.
Snyder, A., et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma. N 
Engl J Med, 2014. 371(23): p. 2189-99.
49.
Zamarin, D., et al., Localized oncolytic virotherapy overcomes systemic tumor resistance to 
immune checkpoint blockade immunotherapy. Sci Transl Med, 2014. 6(226): p. 226ra32.
50.
Rajani, K., et al., Abstract 1360: Combination therapy of Reovirus and PD-1 blockade 
effectively establishes tumor control via innate and adaptive immune responses. Cancer 
Research, 2015. 75(15 Supplement): p. 1360.
51.
Liu, J., Spurrel, J., Shi, Z.Q., Chen, W.Q., Morris, D.G. Oncolytic viral therapy with immune 
modulation is an effective novel treatment strategy for non-small cell lung cancer. in 106th 
Annual Meeting of the American Association for Cancer Research. 2015. Philadelphia, PA: 
AACR.
52.
Rajani, K., et al., Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls 
Tumor Growth Through Innate and Adaptive Immune Responses. Mol Ther, 2016. 24(1): p. 
166-174.
53.
Noonan, A.M., et al., Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) 
in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma. Mol Ther, 2016. 24(6): p. 
1150-8.
54.
Mahalingam, D., et al., P-175Oncolytic Virus Therapy in Pancreatic Cancer: Clinical Efficacy 
and Pharmacodynamic Analysis of REOLYSIN in Combination with Gemcitabine in Patients 
with Advanced Pancreatic Adenocarcinoma. Annals of Oncology, 2015. 26(suppl 4): p. iv51.
55.
Mahalingam D, et al., A study of REOLYSIN in combination with pembrolizumab and 
chemotherapy in patients (pts) with relapsed metastatic adenocarcinoma of the pancreas 
(MAP). Journal of Clinical Oncology, 2017. 35(Supplement): p. e15753.
56.       Liu, J., et al., Oncolytic viral therapy with immune modulation is an effective novel treatment 
strategy for non-small cell lung cancer. Cancer Res, 2015. 75(15 Suppl): p. Abstract 5355
57.      Gollamudi, R., et al., Intravenous administration of Reolysin, a live replication competent RNA 
virus is safe in patients with advanced solid tumors. Invest New Drugs, 2010. 28(5): p. 641-9.
58.      Adair, R.A., et al., Cell carriage, delivery, and selective replication of an oncolytic virus in tumor 
in patients. Sci Transl Med, 2012. 4(138): p. 138ra77.
59.      Ilett, E.J., et al., Dendritic cells and T cells deliver oncolytic reovirus for tumour killing despite 
pre-existing anti-viral immunity. Gene Ther, 2009. 16(5): p. 689-99.
60.       Ilett, E.J., et al., Internalization of oncolytic reovirus by human dendritic cell carriers protects 
the virus from neutralization. Clin Cancer Res, 2011. 17(9): p. 2767-76.
61.      Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer.
Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak 
EL, Muzikansky A, Lawrence C, Fuchs CS J Clin Oncol. 2007;25(30):4787. 
 
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13. APPENDICES
13.1 Appendix 1: Birth control methods
Barrier Methods
Intrauterine Device Methods
Hormonal Methods

Male condom plus 
spermicide 

Cap plus 
spermicide 

Diaphragm plus 
spermicide 

Copper T

Progesterone T

Levonorgestrel-releasing

Implants

Hormone shot or 
injection

Combined pill

Minipill

Patch
NOTE: choice contraception should be discussed with primary treating oncologist to discuss the risks 
and benefits of different modalities of contraception. 
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13.2 Appendix 2: New York Heart Association Classification of Heart Failure (NYHA CHA)
Class
Symptomatology
I
No symptoms. Ordinary physical activity such as walking and climbing stairs does 
not cause fatigue or dyspnea
II
Symptoms with ordinary physical activity. Walking or climbing stairs rapidly, 
walking uphill, walking or stair climbing after meals, in cold weather, in wind or 
when under emotional stress causes undue fatigue or dyspnea.
III
Symptoms with less than ordinary physical activity. Walking one to two blocks on 
the level and climbing more than one flight of stairs in normal conditions causes 
undue fatigue or dyspnea.
IV
Symptoms at rest. Inability to carry on any physical activity without fatigue or 
dyspnea.
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13.3 Appendix 3: SAFETY ISSUES
Please note: These instructions will be available as a stand-alone document in the form of a 
‘Patient Information sheet’ and will be submitted to the IRB
Patients will handed a safety precaution sheet with instructions to be followed on study or until the 
investigator advises otherwise.
 
Treatment with Pelareorep
What to do while you are on study:
The cancer treatment you are receiving is called PELAREOREP.  This new treatment uses a type 
of virus called Reovirus, a virus commonly found in natural situations throughout the world (such 
as ponds and ditches).  Most adults (up to 100%) have been exposed to Reovirus at some point 
in their day-to-day life.  People exposed to this virus in their community often do not have any 
symptoms, or occasionally have only very minor breathing or stomach upsets.  Even though 
Reovirus is usually asymptomatic, your study doctor believes that it is appropriate to take some 
precautions to minimize exposure to Reovirus for individuals in close proximity to you, such as 
your family. 
During the 5 days of PELAREOREP treatment and for up to 2 days afterwards, it is 
recommended that you adopt the common practices that you would normally observe around 
family and friends if you had a cold or flu.  These include standard behaviors you would use to 
prevent passing on a cold or flu virus such as:

washing your hands with soap after using the bathroom, 

avoid sharing drinks and eating utensils, 

using detergent to wash your dishes, either by hand or in a dishwasher, 

avoiding close contact with pregnant women and infants.  

You are also asked to avoid direct contact with severely immune-compromised 
individuals such as patients who have had a recent bone-marrow transplant or patients 
with AIDS.
If you have any questions about any of these recommendations please ask your study doctor.
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13.4 Appendix 4: Table Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention 
not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product 
that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from 
the event as it occurred (Note: This does not include an adverse event that, had it occurred in a more 
severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to 
conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an 
inpatient admission, regardless of length of stay, even if the hospitalization is a precautionary measure 
for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition 
that has not worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that 
is diagnosed prior to the use of a Merck product and is documented in the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to 
diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is 
reportable to the Sponsor within 24 hours and to Merck within 2 working days to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is 
considered a serious adverse event for collection purposes. An overdose that is not associated with an 
adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours 
to the Sponsor and to Merck within 2 working days..
Other important medical events that may not result in death, not be life threatening, or not require 
hospitalization may be considered a serious adverse event when, based upon appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of 
time and units
Action taken 
Did the adverse event cause Merck product to be discontinued?
Relationship 
to Merck 
Product 
Did Merck product cause the adverse event? The determination of the likelihood that Merck product 
caused the adverse event will be provided by an investigator who is a qualified physician. The 
investigator’s signed/dated initials on the source document or worksheet that supports the causality noted 
on the AE form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are intended as 
reference guidelines to assist the investigator in assessing the likelihood of a relationship between the 
test drug and the adverse event based upon the available information.
The following components are to be used to assess the relationship between Merck product and 
the AE; the greater the correlation with the components and their respective elements (in number and/or 
intensity), the more likely Merck product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to Merck product such as: reliable 
history, acceptable compliance assessment (pill count, diary, etc.), expected 
pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time 
Course
Did the AE follow in a reasonable temporal sequence from administration of Merck 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
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68
investigational medicinal product)?
Likely 
Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors
Relationship
The following components are to be used to assess the relationship between the test drug and the 
AE: (continued)
to Merck Product
(continued) 
Dechallenge
Was Merck product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are 
only used one time.)
Rechallenge
Was the subject re-exposed to Merck product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the trial is a single-dose drug trial); or (3) Sponsor’s 
product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY MERCK 
PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL 
POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS 
PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous 
knowledge regarding Merck product or drug class pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified 
physician according to his/her best clinical judgment, including consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of Merck product relationship).
Yes, there is a reasonable 
possibility of Merck product 
relationship.
There is evidence of exposure to Merck product.  The temporal sequence of the 
AE onset relative to the administration of Merck product is reasonable.  The AE is 
more likely explained by Merck product than by another cause.
No, there is not a reasonable 
possibility of Merck product 
relationship
Subject did not receive the Merck product OR temporal sequence of the AE onset 
relative to administration of Merck product is not reasonable OR the AE is more 
likely explained by another cause than the Merck product.  (Also entered for a 
subject with overdose without an associated AE.)
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14. HISTORY OF AMENDMENTS (SUMMARY OF CHANGES)
Amendment 1 –January 23rd  , 2019
Sections(s) Affected
Prior Version
Amendment 1 
Changes
Rationale
Section 5
Study procedures table
Footnote 24
There was no footnote 
alongside D2 of each 
cycle to indicate if it 
was mandatory or 
optional
New footnote 24 
inserted alongside D2 
of each cycle. It states 
that 
“D2 visit is mandatory 
only for Cycle 1. 
Beyond cycle 1 it is 
optional and  will be 
done only if clinically 
indicated, at the 
discretion of the 
treating physician”
To reduce burden on 
patients and increase 
flexibility.
Section 8.2.10
Side effects of 
Pelareorep
List of some of the 
known side effects of 
Pelareorep
A SUSAR was received 
from Oncolytics. The 
AE reported was 
hypotension. This has 
been added to the 
“Rare, some may be 
serious (occur in less 
than 1%) “category of 
side effects of 
Pelareorep.
Based on SUSAR 
received  from 
Oncolytics on 12.4.18 
which was submitted 
as RNI on 
12.7.18
Section 3.1.9
Eligibility criteria
Required patients to 
have ACTH values 
within normal range 
prior to registration.
(This required the 
ACTH test to be  
resulted before  
registration)
TSH , T4 were required 
to be within normal 
range for eligibilty to be 
met
Removed the 
requirement for patients 
to have normal ACTH 
before registration.
(This removes the 
requirement for ACTH 
to be resulted before 
registration. ACTH 
results will be kept as  
a baseline and will be 
followed up as clinically 
indicated).
Inserted a note stating 
that “If a thyroid 
function test is 
abnormal but not 
deemed clinically 
significant by treating 
physician, approval 
may be given by 
Ensuring ease of 
recruitment while 
preserving safety.
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NU Study Number: NU 18I01
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70
principal investigator 
upon discussion.”
Section 5.0 
Study procedures table
Footnote 23
Footnote 25
Stated that all day 1 
labs are to be resulted 
before treatment. 
Footnote 23: Inserted 
‘except ACTHand 
Ca19-9’ , which does 
not need to be resulted 
before study drug 
treatment. 
For added clarity
(to align with update 
made to section 3.1.9)
Section 5.0 
Study procedures table
Footnote 25 
N/A
Added test 
CA 19-9 to be done at 
baseline, D1 of each 
odd cycle and End of 
treatment visit. The test 
need not be resulted for 
treatment to begin.
(This is a standard of 
care test done on 
pancreatic cancer 
patients)
Corresponding row in 
the table added.
For completeness of 
the list of tests that 
are being done on 
patients.
Section 5.0 
Study procedures table
Footnote 1 and 14
Baseline imaging 
window was 14 days
Inserted langauge to 
indicate 
“Baseline imaging can 
be done within 21 days 
before registration.”
For flexibility and 
ease of recruitment.
Section 5.0 
Study procedures table
The visit conducted 30 
days after last dose of 
treatment was termed 
as ‘End of study 
visit’(EOS)
The term has been 
changed to 
‘end of treatment’
(EOT) visit
Correction 
(aimed at use of 
appropriate 
terminology)
Section 6.7 
Endpoints section 
(Immune-related 
response criteria) 
Previous language 
regarding number of 
lesions to be measured 
for iRECIST was 
different from RECIST.
This would lead to 
skewed analysis.
Language updated to 
make the RECIST and 
iRECIST sample the 
same targets and  
measured in the same 
dimension.
Correction of 
discrepancy in order 
to prevent 
discordance. 
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Amendment 2 –3.23. 2020
Sections(s) Affected
Prior Version
Amendment 2 
Changes
Rationale
Title page
Alfred Rademaker, PhD 
was listed as the 
statistician
Removed Alfred 
Rademaker, PhD
Added Hui Zhang, PhD 
as statistician
Alfred Rademaker has 
retired from NU. 
New statistician has 
been assigned for 
this study
Section 4.3.1
Dose 
delays/modifications
[for Pembrolizumab]
List of 
conditions/scenarios 
when pembrolizumab 
should be withheld or 
permanently 
discontinued. Included 
in this list are Grade 3 
adverse events
Added an exception to 
the Grade 3 
description:
“ For any laboratory 
value that is a Grade 3 
adverse event which is 
expected and 
unrelated, patient can 
continue to be treated 
I) if it is in the best 
interest of the patient 2) 
following discussion 
and approval of the PI”
For flexibility.
This is in response to 
DSMC 
recommendation and 
serves as CAPA for 
an RNI
Section 4.6
Duration of therapy
Disease progression is 
listed as one of the 
criterion
Added  a note: to this 
criterion:
“ A subject may be 
granted an exception to 
continue on treatment 
with confirmed or 
unconfirmed 
radiographic 
progression , if clinically 
stable or clinically 
improved”
For flexibility. 
To be  consistent with 
Section 4.8 and to be 
in alignment with the 
objectives and 
endpoints of this 
study.
Section 11
Study management
Previous version of 
template language
Updated with most 
current version of 
template language
Administrative update
Throughout
N/A
Minor corrections 
For consistency 
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