Conditions: Esophagogastric Adenocarcinoma
Keywords: Gastric Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
This is a phase II study of OBP-301 with pembrolizumab in advanced gastric and gastroesophageal junction adenocarcinoma that has progressed on at least 2 lines of prior therapy for advanced disease.

Detailed description:
This is a phase II study of OBP-301 with pembrolizumab in advanced gastric and gastroesophageal junction adenocarcinoma that has progressed on at least 2 lines of prior therapy for advanced disease. Pembrolizumab has recently received FDA approval for PD-L1 positive gastric and GEJ adenocarcinoma based on the Keynote-059 study. The efficacy of pembrolizumab monotherapy is modest in PD-L1 positive patients (defined as a combined positive score, CPS, of \> 1), with only a \~15% overall response rate. This study will examine the addition of the oncolytic virus, OBP-301, administered prior to pembrolizumab in this patient population. Patients will be enrolled in a two-stage design, with 18 patients in the first stage. All patients will receive OBP-301 at 2x1012 viral particles (VP)/ tumor injection administered every two weeks x 4 injections as well as standard dose pembrolizumab 200 mg IV every 3 weeks. The tumor will be injected with OBP-301 four times (d1, d15, d29, d43). The preference is to inject the primary tumor endoscopically. Metastatic lesions may be injected on a case-by-case basis after discussion with the PI (Shah). All patients treated with OBP-301 will be eligible for the safety cohort.

Primary Endpoints:

* To examine the efficacy of OBP-301 with pembrolizumab in PD-L1 positive advanced gastric and gastroesophageal junction adenocarcinoma in the 3rd or 4th line setting, as assessed by the RECIST response rate.
* To examine the safety of multiple OBP-301 intratumoral injections in combination with pembrolizumab in advanced gastroesophageal adenocarcinoma.

Secondary Endpoint:

• To examine other measures of efficacy of the combination of OBP-301 with pembrolizumab in advanced gastric and esophageal adenocarcinoma including the disease control rate, duration of response, overall survival and progression free survival.

Arms:
arm 1: All patients will receive Telomelysin (OBP-301) at 2x10\^12 viral particles (VP)/ tumor injection administered every two weeks x 4 injections as well as standard dose pembrolizumab 200 mg IV every 3 weeks. The tumor will be injected with OBP-301 four times (d1, d15, d29, d43). The preference is to inject the primary tumor endoscopically. Metastatic lesions may be injected on a case-by-case basis after discussion with the PI (Shah).

Interventions: intervention 1: Telomelysin
Intervention descriptions: intervention 1: OBP-301, the investigational product (IP) is formulated in 20 mM Tris pH 8.0, 25 mM NaCl with 2.5% glycerin, USP by volume. OBP-301 will be injected into the target tumor lesions.

Protocol document:
Prot_SAP_000.pdf: 
PROTOCOL COVER PAGE 
 TITLE: Phase II study of Telomelysin (OBP-301) in combination with 
pembrolizumab in esophagogastric adenocarcinoma 
NCT#: 03921021 
 Version 8.0, Date: March 2, 2022 
 
 


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t
TITLE: Phase II study of Telomelysin (OBP-301) in combination with pembrolizumab in 
esophagogastric adenocarcinoma 
IRB Protocol #: 1807019403 
IND/IDE # (if applicable): 18482 
Version 8.0, Date: March 2, 2022 
Principal Investigator: 
Manish Shah, MD 
1305 York Avenue, 12P 
P Floor 
New York, NY 10021 
Phone 646-962-6200 
Fax 646-962-1607 
Umas9313@med.cornell.eduU 
Statistician: 
Paul J Christos, PhD 
Healthcare Policy and Research 
402 E. 67Pth
P St, Room 34 
New York, NY 10065 
pac2001@med.cornell.edu 


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Participating Sites: 
 
Sites Investigator(s) 
Academic Center(s) 
1. 
Manish A. SHAH, MD 
mas9313@med.cornell.edu 
Weill Cornell Medicine/ New-York Presbyterian 
2. 
Peter ENZINGER, MD 
Peter_Enzinger@dfci.harvard.edu 
Dana Farber Cancer Institute 
3. 
Jennifer EADS, MD 
Jennifer.Eads@uphs.upenn.edu 
University of Pennsylvania 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff, Investigational Product supplier (Oncolys 
BioPharma Inc.) and applicable independent ethics committees or institutional review boards. 
The contents of this document shall not be disclosed to others without written authorization 
from WCM. 


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TABLE OF CONTENTS 
Table of Contents ....................................................................................................................... 3 
List of Abbreviations .................................................................................................................. 7 
STUDY SYNOPSIS ................................................................................................................... 2 
STUDY SCHEMA ................................................................................................................... 19 
1 BACKGROUND ................................................................................................................ 19 
1.1 Rationale.......................................................................................................................... 19 
1.1.1 Non-Clinical Studies ............................................................................................ 23 
1.1.2 Clinical Studies .................................................................................................... 25 
1.2 Summary of Potential Risks and Benefits ....................................................................... 26 
1.3 Dosage and Treatment Periods ........................................................................................ 28 
1.4 Patient Population ........................................................................................................... 28 
2 OBJECTIVES .................................................................................................................... 28 
2.1 Primary Objective ........................................................................................................... 28 
2.2 Exploratory Objective ..................................................................................................... 29 
3 STUDY DESIGN ............................................................................................................... 29 
3.1 Study Overview ............................................................................................................... 29 
4 STUDY POPULATION..................................................................................................... 30 
4.1 Selection of Study Population ......................................................................................... 30 
4.2 Inclusion Criteria ............................................................................................................. 31 
4.3 Exclusion Criteria ............................................................................................................ 32 
4.4 Registration Procedures ................................................................................................... 32 
4.4.1 Patient Registration – Part 1 (WCMC Only) .................................................................. 32 
4.4.2 Patient Registration – Part 2 (All Sites) .......................................................................... 32 
4.5 Stopping Criteria ............................................................................................................. 33 
4.5.1 Patient Withdrawal Criteria .................................................................................. 33 
4.5.2 Termination or Suspension of the Study .............................................................. 33 
5 STUDY MEDICATION .................................................................................................... 34 
5.1 Investigational Product (IP) Identification ...................................................................... 34 
5.2 Dosage and Treatment ..................................................................................................... 34 
5.2.1 Study Supplies ...................................................................................................... 35 
5.2.2 Storage, Dispensing and Investigational Product Accountability............................ 
5.2.4 Prohibited Concomitant Medications ...................................................................... 41 
5.2.5 Rescue Medications & Supportive Care ................................................................. 45 
6 STUDY PROCEDURES .................................................................................................... 46 


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6.1 Schedule of Events .......................................................................................................... 48 
6.1.1 Screening Visit ..................................................................................................... 48 
6.1.2 Treatment Phase ................................................................................................... 48 
6.1.3 Follow up Phase ................................................................................................... 48 
6.2 Informed Consent Form .................................................................................................. 50 
6.3 Demographic Data and Baseline Characteristics............................................................. 50 
6.4 Medical History, Concomitant Disease, Previous and Ongoing Medications ................ 50 
6.5 Safety Assessments ......................................................................................................... 51 
6.5.1 Adverse Events .................................................................................................... 51 
6.5.2 Physical Examination ........................................................................................... 51 
6.5.3 Vital Signs ............................................................................................................ 51 
6.5.4 Electrocardiogram ................................................................................................ 51 
6.5.5 Laboratory Assessments ....................................................................................... 52 
6.6 Efficacy Assessments ...................................................................................................... 53 
6.6.1 Imaging Assessment for the Study ....................................................................... 53 
6.6.2 Definitions of Measurable and Non-Measurable Disease .................................... 53 
6.6.3 Response Criteria ................................................................................................. 54 
6.6.4 Tumor Determination of Stage by Tumor, Lymph Nodes, Metastasis (TNM) 
Classification ....................................................................................................... 54 
6.7 Biopsies and Immune Monitoring ................................................................................... 54 
7 ADVERSE EVENTS ......................................................................................................... 54 
7.1 Definitions ....................................................................................................................... 54 
7.1.1 Definition of an Adverse Event............................................................................ 54 
7.1.2 Severity of an Adverse Event ............................................................................... 55 
7.1.3 Causal Relationship of an Adverse Event ............................................................ 56 
7.1.4 Definition of a Serious Adverse Event ................................................................. 56 
7.1.5 Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse 
Events and Serious Adverse Events .................................................................... 57 
7.2 Documenting Adverse Events ......................................................................................... 57 
7.2.1 Recording of Adverse Events ................................................................................. 58 
7.2.2 Reporting of AE to WCMC IRB ............................................................................. 58 
7.2.3 Follow-up of Adverse Events and Serious Adverse Events .................................... 58 
7.2.4 Reporting of SAE to IRB ........................................................................................ 59 
For multicenter studies, the multicenter core within the Quality Assurance Unit (QAU) 
will distribute the IND Safety Report .............................................................................. 59 
7.2.5 Notification of Serious Adverse Event to Oncolys ................................................. 59 


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7.2.5 Notification of Suspected Unexpected Adverse Reactions ..................................... 59 
7.2.6 Notification of Pregnancies ..................................................................................... 60 
8 STATISTICAL ANALYSES ............................................................................................. 61 
8.1 General Considerations ................................................................................................... 61 
8.2 Definitions for Statistical Data Analysis ......................................................................... 61 
8.3 Handling of Missing Values and of Values outside the Detection Limits ...................... 61 
8.3.1 Data Collection ..................................................................................................... 62 
8.3.2 REDCap ............................................................................................................... 62 
8.4 Analysis Populations ....................................................................................................... 62 
8.4.1 Safety Population ................................................................................................. 62 
8.4.2 Evaluable Population............................................................................................ 62 
8.4.3 Intent-to-Treat (ITT) Population .......................................................................... 62 
8.4.4 Per-Protocol (PP) Population ............................................................................... 62 
8.5 Efficacy Analysis ............................................................................................................ 63 
8.5.1 Primary Efficacy Endpoint ................................................................................... 63 
8.5.2 Secondary Efficacy Endpoints ............................................................................. 63 
8.5.3 Exploratory Analysis ............................................................................................ 63 
8.5.4 Methods for Analysis ........................................................................................... 63 
8.6 Correlative Study ............................................................................................................ 64 
8.7 Safety Analyses ............................................................................................................... 66 
8.7.1 Safety Endpoints .................................................................................................. 66 
8.7.2 Summary of Adverse Events ................................................................................ 66 
8.7.3 Summary of Laboratory Assessments .................................................................. 66 
8.7.4 Summary of Special Laboratory Assessments ..................................................... 66 
8.7.5 Summary of Vital Signs ....................................................................................... 66 
8.7.6 Summary of Physical Examinations..................................................................... 66 
8.7.7 Summary of ECG Measurements ......................................................................... 67 
8.7.8 Concomitant Medications .................................................................................... 67 
8.7.9 Adverse Event Stopping Rule .............................................................................. 67 
8.8 Determination of Sample Size ......................................................................................... 67 
9 REGULATORY REQUIREMENTS ................................................................................. 68 
9.1 Regulatory Approvals ..................................................................................................... 68 
9.2 Institutional Review Board/Ethics Committee Approval ................................................ 68 
9.3 Ethical Conduct of the Study .......................................................................................... 69 
9.4 Participant Informed Consent .......................................................................................... 69 


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9.5 Data Confidentiality ........................................................................................................ 70 
10 Data and Safety Monitoring Plan (DSMP) ...................................................................... 70 
11 ADMINISTRATIVE PROCEDURES ............................................................................. 70 
11.1 Financing, Liability/Indemnity/Insurance ...................................................................... 70 
11.2 Recording of Data and Retention of Records ................................................................ 70 
11.3 Publication of Results.................................................................................................... 71 
11.4 Disclosure and Confidentiality ...................................................................................... 71 
12 CLINICAL STUDY REPORT ......................................................................................... 72 
13 Appendix .......................................................................................................................... 72 
13.1 ECOG performance status ............................................................................................. 72 
13.2 Comparison of RECIST 1.1 and iRECIST .................................................................... 72 


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LIST OF ABBREVIATIONS 
 
Ad5 
adenovirus serotype 5 
AE 
adverse event 
AJCC 
American Joint Commission on Cancer 
ALT 
alanine transaminase 
APC 
antigen presenting cell 
AST 
aspartate transaminase 
BSLD 
baseline sum longest diameters 
CAR 
Coxsackie adenovirus receptor 
CBC 
complete blood count 
CBER 
Center for Biologics Evaluation 
cGMP 
current Good Manufacturing Practice 
CR 
complete response 
CRF 
case report form 
eCRF 
electronic case report form 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CV 
coefficient of variation 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 


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GCP 
Good Clinical Practice 
GEJ 
Gastroesophageal Junction 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte-macrophage colony stimulating factor 
HBV 
hepatitis B virus 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HED 
human equivalent dose 
HEK 
human embryonic kidney (cell) 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
hTERT 
human telomerase reverse transcriptase 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IL 
interleukin 
IM 
intramuscular 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IP 
investigational product 
irCR 
immune-related complete response 
irPD 
immune related progressive disease 
irPR 
immune-related partial response 
irRC 
immune-related response criteria 
irSD 
immune-related stable disease 
IRB 
institutional review board 


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IRES 
internal ribosomal entry site 
ITT 
intent-to-treat 
IV 
intravenous 
KPS 
Karnofsky Performance Status Scale 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFD 
maximum feasible dose 
MRI 
magnetic resonance imaging 
mRNA 
messenger RNA 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NOAEL 
no adverse effect level 
NOEL 
no effect level 
NTL 
non-target lesion 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-L1 
Programmed death-ligand 1 
PFS 
progression free survival 
PI 
Principal Investigator 
PP 
per-protocol 
PR 
partial response 
PTT 
prothrombin time 
qPCR 
quantitative polymerase chain reaction 


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RECIST 
response evaluation criteria in solid tumors 
iRECIST 
Immune response evaluation criteria in solid tumors 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected adverse reaction 
TIL 
tumor infiltrating lymphocytes 
TL 
target lesion 
TNF 
tumor necrosis factor 
TNM 
tumor; lymph nodes; metastasis: classification of 
malignant tumors 
TRreg 
regulatory T cell 
TTR 
time to treatment response 
T-VEC 
talimogene laherparepvec 
US 
United States 
USP 
United States Pharmacopoeia 
ULN 
upper limit of normal 
VP 
viral particles 
WCM 
Weill Cornell Medicine 
WCMC 
Weill Cornell Medical College 
WHO-DD 
World Health Organisation Drug Dictionary 
XTT 
cell viability assay 


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STUDY SYNOPSIS 
 
 
Protocol Title: 
Phase II study of Telomelysin (OBP-301) in combination with 
Pembrolizumab in Esophagogastric Adenocarcinoma 
Protocol Number: 
1807019403 
Study Sites: 
1. Weill Cornell Medical College 
2. Dana Farber Cancer Institute 
3. University of Pennsylvania 
Study Phase: 
Phase II 
Study Objective(s): 
Primary Objective: 
• 
To examine the efficacy of OBP-301 with pembrolizumab in PD-L1 
positive 
advanced 
gastric 
and 
gastroesophageal 
junction 
adenocarcinoma in the 3rd or 4th line setting, as assessed by the RECIST 
P 
 
P 
P 
 
P 
response rate. 
• 
To examine the safety of multiple OBP-301 intratumoral injections in 
combination with pembrolizumab in advanced gastroesophageal 
adenocarcinoma. 
Secondary Objectives: 
• 
To examine other measures of efficacy of the combination of OBP-301 
with 
pembrolizumab 
in 
advanced 
gastric 
and 
esophageal 
adenocarcinoma including the disease control rate, duration of 
response, overall survival and progression free survival. 
Exploratory Objectives: 
• 
To examine the tumor-immune microenvironment prior to and 
following OBP-301 and pembrolizumab therapy as assessed by bulk 
RNA sequencing and single-cell RNA sequencing. 
• 
To examine and characterize the immune infiltrate by multi-parameter 
flow cytometry. 


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Study Design: 
This is a phase II study of OBP-301 with pembrolizumab in advanced 
gastric and gastroesophageal junction adenocarcinoma that has progressed 
on at least 2 lines of prior therapy for advanced disease. This study will 
examine the addition of the oncolytic virus, OBP-301, administered prior 
to pembrolizumab in this patient population. Patients will be enrolled in a 
two-stage design, with 18 patients in the first stage. All patients will receive 
12 
OBP-301 at 2x10P 
 
P viral particles (VP)/ tumor injection administered every 
two weeks x 4 injections as well as standard dose pembrolizumab 200 mg 
IV every 3 weeks. The tumor will be injected with OBP-301 four times 
(d1, d15, d29, d43). The preference is to inject the primary tumor 
endoscopically. Metastatic lesions may be injected on a case-by-case basis 
after discussion with the PI (Shah). All patients treated with OBP-301 will 
be eligible for the safety cohort. 
Investigational 
Product 
Administration: 
OBP-301, the investigational product (IP) is formulated in 20 mM Tris pH 
8.0, 25 mM NaCl with 2.5% glycerin, USP by volume. OBP-301 will be 
injected into the target tumor lesions. 
Planned Patients: 
41 patients in total for both stage 1 and 2, to achieve 37 evaluable patients. 
Participant Selection 
Criteria: 
Inclusion Criteria: 
Patients who meet all of the following criteria will be considered for 
inclusion in the study: 
1. Be willing and able to provide written informed consent for the 
trial. 
2. Be >18 years of age on the day of signing the informed consent. 
3. Have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0-2. 
4. Have histologically or cytologically confirmed advanced or 
metastatic gastroesophageal adenocarcinoma, at least 1 cm in size 
and amenable to intratumoral injection. 
5. Patient must have received at least 2 line of systemic therapy for 
advanced disease. 
6. Tumor must be PD-L1 positive, as defined by a combined positive 
score (CPS). 
7. Have one or more measurable lesions based on iRECIST. 
8. Be willing to provide tissue; newly obtained biopsy specimens or 
formalin-fixed, paraffin-embedded (FFPE) block specimens. 
9. Female subjects of childbearing potential have a negative urine or 
serum pregnancy test within 7 days prior to enrollment. If the 
urine test is positive or cannot be confirmed as negative, a serum 


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pregnancy test will be required. If a serum pregnancy test is 
required it can be performed on the same day as the urine 
pregnancy test. The serum pregnancy test must also be completed 
7 days prior to enrollment. And male / female subjects of 
childbearing potential must agree to use an adequate method of 
contraception starting with signing the informed consent through 
120 days after the last dose of study medication. 
10. Demonstrated adequate organ function as defined in following 
criteria. All screening labs should be performed within 14 days of 
enrollment. Note: Subject must not have taken transfusion, 
hematopoietic agent; granulocyte-colony stimulating factor (G- 
CSF) etc., and/or oxygen supplementation within 7 days before 
the screening labs. 
a. Absolute neutrophil count (ANC)>1,000 /mm3 
b. Platelets>100,000 /mm3 
c. Hemoglobin>8.0 g/dL 
d. Serum total bilirubin<2.0 mg/dL 
e. Aspartate aminotransferase (AST) (SGOT) and alanine 
aminotransferase (ALT) (SGPT)< 3x Upper limit of normal 
(ULN). For subjects with liver metastases< 5x ULN. 
f. Serum creatinine< 2.0 mg/dL; or if serum creatinine > 2.0 
mg/dL, measured or calculated creatinine/clearance >45 
mL/min (Cockcroft-Gault formula). 
11. Life expectancy of ≥ 4 months from the first OBP-301 treatment. 
12. Understand the study requirements and the treatment procedures, 
and is willing to comply with all specified follow-up evaluations, 
and provides written informed consent before any study-specific 
tests or procedures are performed. 
Exclusion Criteria: 
The presence of any of the following criteria will constitute cause for the 
exclusion of the participant: 
1. Is currently participating and receiving study therapy or has 
participated in a study of an investigational agent and received 
study therapy within 4 weeks of study Day 1. 
2. Has an active autoimmune disease that has required systemic 
treatment in past 2 years. 
3. Has a diagnosis of immunodeficiency or is receiving systemic 
steroid therapy (greater than equivalent of prednisone 20 mg/day) 
or any other form of immune-suppressive therapy within 7 days 
prior to study Day 1. 
4. Has known active central nervous system metastases and/or 
carcinomatous meningitis. 
5. Has had prior anti-cancer monoclonal antibody chemotherapy, 
targeted small molecule therapy, or radiation therapy within 2 
weeks prior to study Day 1, who has not recovered from adverse 
events due to a previously administered agent. 
6. Has a known additional malignancy within 3 years of first 
injection of OBP-301 that is progressing or requires active 


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treatment, with the exception of prostate cancer controlled with 
androgen deprivation therapy. 
7. Has received a live vaccine within 30 days of planned start of 
study therapy. 
8. Patients known to have acute or chronic active hepatitis B virus 
(HBV), hepatitis C virus (HCV), or human immunodeficiency 
virus (HIV). 
9. Has any evidence of active, non-infectious pneumonitis or 
interstitial lung disease requiring steroids. 
10. Has an active infection requiring systemic therapy within 2 weeks 
of Day 1. 
11. Has known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
12. Is pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the 
screening visit through 120 days after the last dose of trial 
treatment. 
13. Previous severe hypersensitivity to another monoclonal antibody 
14. Has 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. 
15. Uncontrolled intercurrent illness including, but not limited to, 
uncontrolled diabetes, ongoing or active infection, symptomatic 
congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/psychological incompetence, 
whereby in the opinion of the Investigator the patient is assessed as 
being unable to provide information, consent, or comply with the 
study requirements and procedures. 
16. Patients who are pregnant or breastfeeding, or expecting to 
conceive or father children within the projected timeframe of the 
study, starting from the time of the Screening Visit through 4 
months (120 days) after the last OBP-301 administration. Females 
of childbearing potential must have a negative serum or urine 
pregnancy test at Screening. A female not of childbearing potential 
is one who has undergone bilateral oophorectomy or who has had 
no menses for 12 consecutive months. 
Study Procedures: 
12 
1. OBP-301 2x10P 
 
P VP / tumor injection every 2 weeks x four injections. 
* Up to one additional injection may be considered in discussion with the 
PI (Shah). 
2. Pembrolizumab 200 mg intravenous every 3 weeks 
Study Endpoints: 
Primary Endpoint: 
• 
To examine the efficacy of OBP-301 with pembrolizumab in PD-L1 
positive 
advanced 
gastric 
and 
gastroesophageal 
junction 
adenocarcinoma in the 3rd or 4th line setting, as assessed by the RECIST 
P 
 
P 
P 
 
P 
response rate. 


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• 
To examine the safety of multiple OBP-301 intratumoral injections in 
combination with pembrolizumab in advanced gastroesophageal 
adenocarcinoma. 
Secondary Endpoints: 
• 
To examine other measures of efficacy of the combination of OBP-301 
with 
pembrolizumab 
in 
advanced 
gastric 
and 
esophageal 
adenocarcinoma including the disease control rate, duration of 
response, overall survival and progression free survival. 
Exploratory Analysis (optional): 
Correlative endpoints include the following: 
• 
To examine the tumor-immune microenvironment prior to and 
following OBP-301 and Pembrolizumab therapy as assessed by 
bulk RNA sequencing and single-cell RNA sequencing. 
• 
To examine and characterize the immune infiltrate by multi- 
parameter flow cytometry. 
Statistical Analysis: 
The primary endpoint will be the objective response rate (RR), as measured 
by iRECIST criteria. Sample size recommendations for the phase II design 
1 
are determined according to Simon’s two-stage Minimax designP 
P. 
We project a RR of 15% (historical RR for pembrolizumab alone), below 
which the combination regimen will be unacceptable, and a RR of 30% 
(expected RR rate for OBP-301 + pembrolizumab), above which the 
combination regimen will be considered worthy of further exploration. The 
null hypothesis that the RR is less than or equal to 15% will be tested against 
the alternative hypothesis that the RR is greater than or equal to 30%. 
The sample size computations were performed assuming a 10% level of 
significance and 80% power. If 2 or fewer patients respond out of the first 
18 evaluable patients, the study arm will be terminated and declared to have 
a negative result. If 3 or more patients respond out of the first 18 evaluable 
patients, enrollment will be extended to 37 patients. The treatment will be 
declared effective and worthy of further testing if 9 or more patients respond 
among the 37 patients entered. This two-stage design yields a ≥ 0.80 
probability of a positive result if the true RR is ≥ 30%. It yields a ≥ 0.90 
probability of a negative result if the true RR is ≤ 15%. A 95% confidence 
interval constructed around the expected RR of 30% can be estimated to be 
within ± 14.8% of the observed RR proportion. Assuming 10% are 
unevaluable/ineligible, we anticipate that a total of 41 patients will be 
enrolled in the study (assuming the study proceeds to the second stage). 
Table 1. Numbers of observed responders required to accept or reject HR0 
Rat each stage. Under this design, HR0R will not be rejected at Stage 1. 


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N 
Accept HR0 
Reject HR0 
Stage 1 
18 
≤ 2 
--- 
Stage 2 
37 
≤ 8 
≥ 9 
Analysis Plan for Endpoints: 
Primary Endpoint: The primary endpoint is the objective response 
proportion; a 95% confidence interval will be estimated for the 
response proportion via binomial proportions. 
Secondary endpoints: Secondary endpoints include the disease 
control rate (the study will be adequately powered (≥80%) to detect 
an expected disease control rate of 60% in the combination regimen 
versus 33% historical control), duration of response, progression-free 
survival (PFS), and overall survival (OS). Median PFS and OS, 
including survival curves, will be estimated using Kaplan-Meier 
methodology. Greenwood’s formula will be used to calculate 95% 
confidence intervals for the Kaplan-Meier estimates. 
The frequency of subjects experiencing toxicities will be tabulated. 
Toxicities will be assessed and graded according to CTCAE v. 4.0 
terminology. Exact 95% confidence intervals around the toxicity 
proportions will be calculated to assess the precision of the obtained 
estimates. All analyses will be performed in SAS Version 9.4 (SAS 
Institute, Inc., Cary, North Carolina) and STATA Version 15.0 (Stata 
Corporation, College Station, Texas). 
Study Duration: 
Approximately 24 months 
Screening evaluations may be conducted up to 4 weeks before the first 
anticipated OBP-301 administration. Each patient will be in the study for 
96 weeks ( i.e 24 months) following the first intratumoral injection of 
OBP-301. 


 
Stage IV gastric or gastroesophageal junction adenocarcinoma that has received atleast 2 lines of therapy and eligibile of 
Pembrolizumab monotherapy 
Screening/Registration 
OBP-301 2x10^12 VP every 2 weeks X4 (intra-tumoral injection) 
+ 
Pembrolizumab 200 mg q3week 
Continue treatment until progression or 24 months of treatment 
Page 19 
 
STUDY SCHEMA 
 
 
1 
BACKGROUND 
1.1 
Rationale 
Despite advances in developing targeted therapies across solid tumor malignancies, progress in 
cancers of the upper gastrointestinal tract (esophagus and gastric cancers) has been limited. Recent 
advances in gastroesophageal cancers have included the use of trastuzumab in HER2 positive 
gastric and esophageal adenocarcinoma and ramicirumab (VEGFR2 Ab inhibitor) either with or 
without chemotherapy in the 2nd line setting for metastatic disease. Despite these advances, median 
survival for metastatic disease ~10 months and more than 80% of patients diagnosed with an 
esophageal or gastric cancer will ultimately die of their disease. However, the advent of immune 
checkpoint inhibitor therapy has transformed solid tumor oncology. The Programmed Death 
Ligand-1 (PD-L1) and its receptor (PD-1) are important regulators of T cell activity2, and their 
inhibitors have now demonstrated antitumor activity in several malignancies3, 4 including 
melanoma5, 6, lung7-10, renal cell11, and bladder cancers12. There has also been demonstration of 
activity of PD-1/ anti-PD-L1 antibody immune checkpoint inhibitors in upper GI malignancies. 
Activity has been demonstrated with the PDL-1 antibody MEDI14736 in gastroesophageal cancers 
a modest 25% (eg.4/16) response rate in patients with gastric or esophageal adenocarcinoma13. 
Similarly, nivolumab and pembrolizumab, both PD-1 inhibitors, have also demonstrated modest 
activity in treating esophageal carcinoma14, 15. Although activity is modest, those that respond tend 
to have durable responses of 12 months or greater with no patients stopping therapy for an adverse 
event [14] [14]. Our own experience in Keynote-059 in advanced GEJ cancer supported the recent 
approval of pembrolizumab in the 3rd line setting for gastroesophageal cancers[16] (Figure 1). 


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Figure 1. CT images of a patient with metastatic GEJ adenocarcinoma treated with 
pembrolizumab. Two lesions in the left lung are encircled in red, top and bottom 
panels. Patient achieved a RECIST partial response. 
 
 
 
March 2022 Update 
Although Pembrolizumab has demonstrated activity in the 3rd line treatment setting, more recent 
studies have demonstrated efficacy of immunotherapy in the first line treatment setting for 
metastatic disease (Keynote-59016 and Checkmate-64917). As a result, immunotherapy is now 
approved in the first line treatment setting, and the FDA has withdrawn approval of 
pembrolizumab in the 3rd line treatment setting. It is still available for compassionate use. 
Oncolys Biopharma has agreed to reimburse pembrolizumab for patients enrolled on this study. 
Immunotherapy for gastroesophageal adenocarcinoma has primarily been examined as 
monotherapy, with response rates ranging from 10-15%, and patient selection only marginally 
improved by PD-L1 status. A novel concept in immuno-oncology is the use of cancer specific 
oncolytic viral therapy to induce an immunogenic cell death in the tumor to augment the immune 
activation driven by PD-1 inhibition. This involves selective replication within neoplastic cells, 
resulting in a direct lytic effect on tumor cells, and induction of systemic antitumor immunity.18 
OBP-301 is a telomerase- 
specific, replication-selective 
adenovirus 
in 
which 
the 
human 
telomerase 
reverse 
transcriptase 
(hTERT) 
promoter 
drives 
viral 
replication efficiently killing 
only cancer cells19-22. OBP- 
301 has been examined in a 
phase I study in solid tumor 
patients, with an established 
safe dose of 1x1012 viral 
particles/tumor injection. In 
this study, there was evidence 
Figure 2. Antitumor activity of the combination of OBP-502 in 
combination with PD-1 Ab inhibitor. (A) study schema, CT26 and 
PAN02 are murine colon and pancreatic tumor models. OBP-and PD-1 
Ab were administered 3 times as indicated. (B) Tumor growth curves 
with control, PD-1 Ab, OBP-502, or the combination. 
of systemic immune response 
with the development of a 
neutralizing Ab response in all 
tested 
patients, 
and 
up 
regulation of serum IL-6 and 


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IL-10 levels in 8/9 and 7/9 patients respectively23. Notably, 7/16 patients had stable disease at 56 
days, suggesting preliminary efficacy. The most common side effects were local irritation and 
erythema from the injection (3/16 grade 3), as well as fever, chills, and fatigue (grade 1-2) in 30- 
40% of patients23. There is preclinical evidence that OBP-301 is synergistic with anti-PD-1 
therapy (Fig 2), providing the rationale for this proposal. 
Specifically, in a murine model of pancreas and colon cancer, the combination of PD-1 inhibition 
with the murine equivalent of OBP-301 (OBP-502), the combination therapy was associated with 
immunogenic cell death24. OBP-502 induced a significant accumulation of tumor infiltrating 
lymphocytes within the tumors compared with control. The combination of OBP-502 and PD-1 
Ab significantly suppressed CT26 colon cancer subcutaneous tumors and successfully eradicated 
4/12 (33% of mice. When these 4 tumor-free mice were then re-challenged by inoculation with 
CT26 colon cancer cells, 2/4 (50%) remained tumor free, indicating continued immune 
surveillance24. 
The optimal treatment for human cancer requires a therapeutic ratio that increases cytopathic 
efficacy to target tumor cells, rather than surrounding normal cells. Thus, focus on the genetic and 
epigenetic targets present only in cancer cells is providing an expanding repertoire of clinically 
applicable targeted therapeutics, including the use of oncolytic viral vectors. 
Oncolytic immunotherapy employs viruses that are designed to preferentially replicate in and lyse 
cancer cells and through this process trigger anti-tumor immunity. Following the first description 
of a virus engineered to replicate selectively in cancer cells over 20 years ago, the field of oncolytic 
immunotherapy has expanded dramatically. Over 10 different viral species have now been 
assessed or are under assessment in human studies, including the oncolytic virus-based product 
(Onyx-015 adenovirus), which entered a Phase III clinical trial in the United States (US), and a 
similar virus, H101, which was approved for use in combination with chemotherapy as a treatment 
for head and neck cancer by the Chinese State Food and Drug Administration in November 2005. 
More recently, a Phase III pivotal trial of talimogene laherparepvec (T-VEC), an oncolytic herpes 
virus expressing granulocyte-macrophage colony stimulating factor (GM-CSF) in patients with 
advanced melanoma met its primary endpoint, demonstrating a significant improvement in durable 
response rate versus GM-CSF alone (16% vs 2%, p<0.0001) 25. Based on these results, in October 
2015, IMLYGIC (talimogene laherparepvec) was granted approval as the first oncolytic viral 
therapy in the US indicated for the Local Treatment of Unresectable Cutaneous, Subcutaneous and 
Nodal Lesions in Patients With Melanoma Recurrent After Initial Surgery 26. The European 
Medicines Agency also recommended authorizing Imlygic for the treatment of adults with 
unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC and IVM1a) with 
no bone, brain, lung or other visceral disease 27. 
Conditionally replicative oncolytic viruses are engineered for selective replication in cancer cells 
that express certain oncogenic phenotypes 28, 29. To this end, multiple viral backbones have been 
employed, although the most commonly utilized is derived from the adenovirus serotype 5 (Ad5). 
OBP-301 is a novel, replication-competent Ad5-based adenoviral construct that incorporates a 
human telomerase reverse transcriptase gene (hTERT) promoter. The hTERT promoter encodes 
for the catalytic protein subunit of telomerase, a polymerase that acts to stabilize telomere lengths 
and is highly expressed in tumors but not in normal, differentiated adult cells. The adenoviral 
reproductive cycle is a highly orchestrated process. At the molecular level, the adenoviral genome 
contains 8 transcriptional units that are activated at different phases of infection. They are referred 
to as early (E1A), immediate early (E1B, E2, E3, E4), intermediate (IX and IVa2), and late genes. 
In the construct of OBP-301, the normal transcriptional regulatory element of the E1A gene is 


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E1B 
IRES 
E1A 
replaced by the hTERT promoter and additional modifications to enhance specificity include the 
replacement of the normal transcriptional element of viral E1B gene by an internal ribosomal entry 
site (IRES) sequence to minimize “leakiness”). Furthermore, OBP-301 is the first replication- 
competent adenovirus that retains a fully functional viral E3 region, which codes for proteins that 
regulate the immune response to the virally infected cell 28. 
 
 
 
hTERT promoter 
 
 
 
 
 
 
ITR 
ITR 
 
ΔE1 
Adenovirus type 5 genome 
 
∆E1 = delta E1 adenovirus vector, E1A, E1B = transcriptional units, hTERT = human telomerase 
reverse transcriptase, IRES = internal ribosomal entry site, ITR = inverted terminal repeat 
Figure 3    The construct of OBP-301 
 
 
Specificity to cancer is derived by exploiting differential (normal versus tumor) cell surface or 
intracellular aberrations in gene expression that arise in malignancies. Telomerase activation is 
considered to be a critical step in carcinogenesis, and its activity is closely correlated with hTERT 
expression. Thus, expression of hTERT is generally low in differentiated adult cells, and active 
in cells with proliferative capacity such as tumors, gastrointestinal endothelium, or stem cells 30, 31 
with the majority of malignant tumors shown to demonstrate high telomerase activity. Previous 
studies have demonstrated control over the expression of exogenous genes to telomerase-positive 
cancer cells by the hTERT promoter 32 and the hTERT promoter is an excellent candidate for 
generating cancer-specific oncolytic adenovirus. 
There are several mechanisms by which adenoviruses in general, and OBP-301 in particular, can 
destroy tumor cells in vivo. Direct cell lysis occurs following viral replication and data from 
animal models have shown that non-replicating adenovirus in rodent tissue will induce both an 
acute (2-4 days) and chronic (14 days) inflammatory infiltration. During the acute phase, tumor 
necrosis factor (TNF-α) and interleukin (IL)-1 and IL-6 are produced in high concentrations locally 
within the tissue. These cytokines have both direct cytopathic effects and indirect effects through 
immune effector cell recruitment into the local tissue. Finally, adenovirus infection of a tumor cell 
may augment tumor antigen presentation and enhance tumor antigenicity, leading in turn to 
improved recognition and destruction of tumors by cytotoxic T cells. 
In vitro studies have validated the selective infectivity and direct cytolysis of OBP-301 in cancer 
cells and in vivo, intratumoral injection has demonstrated anti-tumor activity without significant 


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toxicity. Additionally, distant viral uptake was observed following intratumoral injection, 
evidenced by the presence of adenoviral protein in non-injected tumors following treatment of the 
contralateral tumor. These encouraging pre-clinical findings of safety and directed anti-tumor 
activity were supportive of the continuing clinical development of OBP-301 as an oncolytic 
therapeutic agent. 
Summary of Non-Clinical and Clinical Studies 
1.1.1 Non-Clinical Studies 
The pre-clinical experience with OBP-301 is described in further detail in the Investigator's 
Brochure 33. Non-clinical studies have investigated OBP-301 mechanism of action and clinical 
proof-of-concept in a) cytotoxicity studies using normal and tumor cells, and b) tumor-bearing 
xenograft mouse models. The safety of OBP-301 has been characterized in animal models that 
exhibit tumors (xenograft models) as well as in non-tumor models (normal cotton rats, Sigmodon 
hispidus). The primary safety studies for OBP-301 were conducted in cotton rats, a species 
selected based on information available in the literature, which suggested that this was a relevant 
and semi- permissive model for adenoviral safety characterization and reflecting a pre- 
investigational new drug application (pre-IND) discussion with the Center for Biologics 
Evaluation and Research (CBER) at the US Food and Drug Administration (FDA). 
Due to issues with the generation of homologous recombinants when using an human embryonic 
kidney cell (HEK)293 cell substrate for OBP-301 manufacture, transfer to a HeLa cell-based 
production system was implemented after pre-clinical studies had been initiated. The HEK293 
cell-based material may have contained wild-type Ad5, which may have contributed to the 
observed oncolytic activity. Comparability studies undertaken in the rodent toxicology species, 
consisting of extended product characterization and a comparison of the toxicological effect of the 
HEK293 and HeLa OBP-301 material, have demonstrated equivalence between OBP-301 virus 
produced through either production system. 
1.1.1.1 Non-clinical Pharmacology 
In vitro studies have demonstrated cytopathic activity of OBP-301 on a variety of human tumor 
cell lines derived from different organs relevant to the clinical setting, as evaluated by a cell 
viability assay (XTT assay). OBP-301 oncolytic activity in tumor cells was found to be similar 
compared to another engineered oncolytic virus, and was similar to or slightly weaker than that of 
wild-type Ad-5 depending on the target tumor cell type. Cytopathic activity of OBP-301 in human 
normal cell lines was also evaluated, using a variety of methods (XTT assay, plaque assay, 
Coomassie Blue staining), including assays for E1A mRNA and protein expression, which served 
as surrogates for viral replication. A correlation between the expression of E1A, hTERT activity 
and viral replication at the early stage of infection appeared to be present. In normal cells, 
OBP-301 is less cytotoxic than wild-type Ad5, while in tumor cell lines, OBP-301 showed 
cytopathic effects equivalent to wild-type Ad5. This is indicative of selective replication in the 
tumor cells. 
In mechanism-of-action studies, there appeared to be a correlation between E1A expression 
(assessed by immunoblot) and hTERT mRNA expression levels in tumor cells at the early stage 
of infection. In addition, a correlation between Coxsackie adenovirus receptor (CAR) expression 
and cytopathic effect of OBP-301 was noted for tumor cells. In vivo, the human tumor-bearing 
xenograft mouse model was utilized in order to define a potentially efficacious dose and regimen. 


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In the first study, multiple intratumoral injections of OBP-301 E3 (-) and E3 (+) both resulted in 
equivalent inhibition of tumor growth. A second study demonstrated OBP-301 replication in non- 
injected distant tumors, as evaluated by RT-PCR for E1A mRNA and immunohistochemistry using 
an anti-E1A antibody, indicating the potential for OBP-301 to reach and then replicate in distally 
located tumors. The dose of 3.6 × 109 viral particles (VP)/animal intratumoral injection in the 
xenograft model achieved the anticipated anti-tumor effect, and no drug-related death has been 
observed. 
1.1.1.2 Toxicology 
In total, 4 single dosing toxicological studies with OBP-301, including 2 single non-Good 
Laboratory Practice (GLP) study and 2 GLP studies, have been undertaken. Most of the data 
gathered from non-GLP and GLP studies assessed the route in animals most similar to human 
intratumoral dosing, being the intramuscular (IM) route. Toxicity evaluation following IM 
injection of OBP-301 in rats did not show a formal no effect level (NOEL). However, the low 
dose group, 109 VP/animal (approximately 1010 VP/kg) showed only sporadic, minimal-to-mild, 
transient microscopic changes in the liver on Day 28, and these changes were no longer apparent 
by day 85 after treatment. Therefore, this dose was designated to be the No Adverse Effect Level 
(NOAEL). A higher IM dose, 1011 VP/kg (dose group 3 in FXT00014) as well as the highest dose, 
showed minimal-to-mild sporadic hepatocellular damage on histopathological evaluation. No 
animals experienced morbid changes, weight loss, or deaths when 1011 VP/animal (approximately 
1012 VP/kg) was administered via either the intravenous (IV) or IM route. 
In the pilot repeated dose study, rats (15 males and 15 females) were assigned into 3 groups, Group 
1: Control group, Group 2: 7 days repeated dosing and Group 3: 14 days repeated dosing. Both 
groups 2 and 3 had a 7-day Follow-Up Period following the dosing phase. The results of this study 
demonstrated that repeat dosing of IM administered OBP-301 to cotton rats at 1 × 1011 VP/animal 
for 7 or 14 day was well tolerated. No significant differences were observed in animals dosed for 
either 7 or 14 days. 
4TIn the single dose toxicity study of intra-hepatic injection, histopathologic findings were observed 
including adhesion, fibrinous inflammation, granulomatous inflammation, and necrosis in the liver 
on Day 5 and adhesion and fibrosis in the liver on Day 14 in both genders at 1 × 1011 VP/kg. 
However, no mortality, or observations of clinical signs, body weight and food consumption 
changes were reported. Systemic distribution of virus away from the injection site was noted in 
these studies with quantitative PCR (qPCR) data at 1011 VP/animal indicating the presence of viral 
DNA in the liver (and to a lesser extent in the lung) out to and including Day 85. These data 
showed continued presence of viral DNA in normal liver, which may signify that the toxicity on 
histopathologic evaluation in the liver was test article related (highest dose only, other dose groups 
were not evaluated for persistence). However, the continued presence of viral DNA in the highest 
dose group did not result in accrual of toxicity with lesions identified on Day 85, particularly the 
liver lesions noted above, no more severe than those observed at earlier time points. In addition, 
the pattern of persistence was consistent with results from other replication-competent oncolytic 
adenoviruses (see December 2005 RAC Meeting Documents Tab 2397, Protocol Number 0510- 
732: A Phase I/II Dose Escalation Trial of Intratumoral Injection with Oncolytic Adenoviral 
Vector INGN 007 (VRX-007) in Patients with Advanced Solid Tumours). IM 
4Tcompared to IV 
administration was shown to limit toxicity, and all toxicities were reflected in the biomarker 
surrogates of clinical pathology. 


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Dosing in human patients will utilize a conservative dose extrapolation paradigm and offers an 
adequate safety margin for systemic toxicity. The human equivalent dose (HED) is calculated on 
a body weight-adjusted basis (to 1010 VP/kg × 70 kg, or 7 × 1011 VP; the HED). The highest 
proposed clinical dose of 1 × 1012 VP (equivalent to ~1.4 × 1010 VP/kg) is equivalent to the 
NOAEL dose in the animal studies. 
1.1.2 Clinical Studies 
Clinical trials of OBP-301 administered by intratumoral injection have been conducted in patients 
with advanced cancer under the following protocols: 
Completed studies 
• OBP-301-001: an open-label, dose-escalation study. The first human study evaluating 
sequential  doses  of  a  single  (1 × 1010  to  1 × 1012  VP/tumor)  and  repeated 
(1 × 1012 VP/tumor) intratumoral injection of OBP-301 in patients with advanced solid 
carcinoma. The first patient was enrolled on 30 October 2006 and the last patient 
completed follow-up on 24 October 2011. Twenty-two patients (n = 13 female, n = 9 
male) were treated and analysed. Patients with the following tumor types participated in 
the Phase 1 trial: 5 patients with melanoma, 4 with squamous cell carcinoma of the head 
and neck, 3 with breast cancer, 2 with soft-tissue sarcoma, and 1 each with squamous cell 
carcinoma primary unknown, carcinoma of the salivary gland, non-small cell lung cancer, 
neuroendocrine tumor, basal cell carcinoma, carcinoma of the gall bladder, pancreatic 
carcinoma, and cancer of the vulva. Of these, 3 patients (1 patient with carcinoma of the 
breast and the 2 patients with carcinoma of the gall bladder and pancreatic carcinoma, 
respectively) had visceral administration of OBP-301, all into the liver. The study was 
conducted under the current IND for OBP-301. 
OBP-301 was found to be well tolerated in this Phase I study. No dose-limiting toxicities 
(DLTs) were experienced by any of the 22 patients treated with OBP-301 in this study; 
therefore, the maximum tolerated dose (MTD) could not be determined. Analysis of all 
safety data from this study demonstrated an acceptable safety profile with intratumoral 
injection of OBP-301 with types of events reported that were similar to those reported in 
patients receiving other adenovirus vectors. Signals of efficacy were seen even in patients 
treated with a single intratumoral injection. Most patients had stable disease after treatment 
(15/17); 2 patients reported progressive disease on Day 28. One additional patient who 
had stable disease on Day 28 reported progressive disease on Day 56. In patients followed 
for up to 5 years after study participation, there was no signal of a safety concern related 
to OBP-301 treatment. 
 
 
Retrospective analyses: 
o Biopsy samples were obtained from Case C-S, a 60-year-old black male patient 
enrolled in the Phase I study, who had a diagnosis of squamous cell carcinoma in 
mouth (Stage IVa). OBP-301 was injected in the tumor in submandibular area. 
Tumor shrinkage was observed within 7 weeks after injection. Biopsy samples 
were obtained from the injected site on Day 28 after injection and evaluated 
retrospectively for histopathological and immunological responses. Results 
demonstrated tumor cell degradation accompanied by increased numbers of antigen 
presenting cells (APC), CD8+ T cells, and a decreased regulatory T cell (TRregR) 


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population, suggesting treatment-induced oncolysis and immunological activation. 
In this patient, the anti-tumor effect of OBP-301 appeared to be mediated by direct 
cytopathic activity following immunological activation. 
o Five patients with melanoma were extracted from the total population of patients 
enrolled in the Phase I study for a retrospective analysis. Changes in tumor size in 
OBP-301 injected and non-injected lesions, and survival duration were calculated. 
As for the main study, the effect of treatment on tumor reduction was observed in 
distant non-injected lesions as well as injected lesions in patients with advanced 
melanoma. Furthermore, the median survival time was 31.3 months in 5 patients 
with melanoma 34. In other reports, the median overall survival of patients 
diagnosed with unresectable melanoma in Stage IV M1a, M1b, and M1c, are 22.3 
months, 11.2 months and 5.1 months, respectively 35. Survival in patients with 
other types of tumor who had been treated in the Phase I study was 8.0 months. 
The results of this retrospective analysis in a subpopulation of patients were 
suggestive of a positive anti-tumor effect and extended survival in patients with 
melanoma treated with OBP-301 compared to other types of tumor and other 
therapies 34. 
Ongoing studies 
• CT-OT-21 (OBP-301-002-B-H): a Phase I/II Study to Evaluate the Safety and Efficacy of 
OBP-301 at doses of 1 × 1010 VP/tumor and 1 × 1012 VP/tumor in patients with 
hepatocellular carcinoma. The study aims to recruit a maximum of 36 patients from 2 
clinical trial sites in two countries, Taiwan and Korea. A maximum of 36 patients with 
hepatocellular carcinoma meeting all inclusion criteria and none of the exclusion criteria 
will be recruited in the trial. For dosing cohorts of at least 3 patients each are planned to be 
sequentially accrued until study agent related DLT is met in equal or more than 2 patients 
at whichever dose level. Recruitment to this study commenced in November 2014. 
• In this study, the safety of more than 2 mL has been investigated. In single dose cohorts, 
3mL of 1x1012 VP/mL (3x1012 VP) was administered in 3 subjects and no DLT was 
observed. 
• OBP-301-003-C-V: a Phase I/II dose-escalation study to determine the safety and efficacy 
of OBP-301 at doses of 1 × 1010 VP/tumor and 1 × 1012 VP/tumor in patients with head 
and neck, esophagus and lung cancers with radiation therapy is being conducted in Japan 
under Ministry of Health, Labour and Welfare (MHLW) approval (granted on 13 July 
2012). The study was initiated on 29 November 2013 and aims to recruit a maximum of 
24 patients from Okayama University Hospital in Japan. The primary objectives are assess 
the clinical safety of OBP-301 in combination with radiotherapy in patients with head and 
neck, esophagus, and lung cancers; to determine the MTD/maximum feasible dose (MFD) 
of OBP-301 and to assess the DLT of OBP-301. Secondary objectives for this study 
include determination of the tumor response rate of OBP-301 and the duration of response 
and overall survival. 
o In OBP-301-003-CV (OBP-301 + Radiation phase I study, NCT0321305), the 
safety was monitored when OBP-301 were administered in the dosing levels of; 1 
mL of 1x1010 VP/mL(Level 1), I mL of 1x1011 VP/mL(Level 2), and 1mL of 
1x1012 VP/mL (Level 3), 3 times of the administration, with the dose escalation 
study design. The dose difference between the level was 10 times and 100 times of 
OBP-301 compared to Level 1 was tested in the Level 3, resulted in no DLT and 
no any intolerable adverse events. 


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o Thus far, no dose limiting toxicities have been observed. Specifically in esophageal 
cancer, 13 patients have been enrolled and have received OBP-301 with radiaiton, 
with no dose limiting adverse events. 
• TL03001: a Phase IIa Study to Evaluate the Efficacy, Safety, and Immunological Response 
of OBP-301, Telomerase Specific Replication-competent Oncolytic Adenovirus in Patients 
with Unresectable Metastatic Melanoma. This study aims to recruit a maximum of 50 
patients in the US. Recruitment to this study commenced in July 2017. 
• TL04001: a phase 1 study to evaluate the safety of OBP-301, OBP-301 in combination 
with radiation therapy in patients with esophageal cancer not applicable for standard 
therapy. The study aims to recruit a maximum of 12 patients in two sites in Japan. 
Recruitment to this study commenced in July 2017. 
o In addition, in TL04001, the cohort 2 (1mL of 1x1012 VP/mL, 3 times biweekly) 
is ongoing and no DLT was observed so far. 
• EPOC1505: a phase I study to evaluate the safety and potential efficacy of OBP-301 in 
combination with Pembrolizumab in patients with advanced or metastatic solid tumors. 
This study aims to recruit a maximum of 28 patients in two sites in Japan. Recruitment to 
this study commenced in December 2017. 
 
1.2 
Summary of Potential Risks and Benefits 
The side effects listed below are expected based on those seen with the same type of adenovirus- 
based oncolytic agents in human trials and are anticipated from non-clinical toxicological studies 
of OBP-301 treatment: 
 
Transient fever 
Chills 
Injection site pain 
Injection site inflammation 
Flu-like symptoms 
Fatigue 
Nausea 
Vomiting 
Headache 
Lymphopenia 
Myalgia 
Neutropenia 
Pneumonia 
Leukopenia 
Transaminitis 
In the Phase I study conducted in patients with advanced cancers (OBP-301-001), intratumoral 
injection with OBP-301 at dose of 1 × 1010 VP/tumor and 1 × 1012 VP/tumor was well tolerated 
with no DLTs reported 29. Five patients reported 9 serious adverse events (SAEs) of dysphagia 
and difficulty breathing, syncope, intractable pain, ECG T-wave abnormality, abdominal pain, 
ascites, hypotension, chills and pyrexia. Although only patients in the 2 highest dose cohorts 
reported SAEs, none of the events occurred in more than one patient. SAEs of chills and pyrexia 
were considered related to drug treatment whereas the causality of all other SAEs was assigned to 
tumor progression, prior medical conditions, and/or dehydration. Decreases in lymphocytes were 
noted at the time of treatment, but these changes were transient and returned to baseline levels by 
no later than Day 7. The changes were not considered to reflect drug toxicity. No consistent 
changes were observed in the hematological or biochemical laboratory parameters and there was 


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no indication of hepatic, renal or bone marrow toxicity. In summary, analysis of available safety 
data from this Phase I study demonstrated an acceptable safety profile for intratumoral injection 
of OBP-301, which exhibited similar events to those reported in patients receiving comparable 
adenovirus vectors. 
There are no known direct benefits to the participants in this study. 
1.3 
Dosage and Treatment Periods 
The OBP-301 NOAEL in a GLP rodent species toxicology study was 109 VP/animal 
(approximately 1010 VP/kg). Higher doses (>1011 VP/kg), administered IM, showed minimal-to- 
mild sporadic hepatocellular damage on histopathological evaluation but no animals experienced 
morbid changes, weight loss, or deaths when 1011 VP/animal (approximately 1012VP/kg) was 
administered either via the intravenous (IV) or IM route. Furthermore, administration of 3.6 × 109 
VP via intratumoral injection in a pre-clinical xenograft model achieved demonstrated oncolytic 
activity. The HED is calculated on a body weight-adjusted basis (to 1010 VP/kg × 70 kg, or 
7 × 1011 VP; the HED) with the highest proposed clinical dose in this study, 1 × 1012 VP 
(equivalent to ~1.4 × 1010 VP/kg), equivalent to the NOAEL dose in the animal studies. In the 
Phase I study in patients with advanced solid carcinoma, the starting dose was a single intratumoral 
injection of 1 × 1010 VP (1.4 × 108 VP/kg) per tumor. This was administered to an initial 3 cohorts 
(n = 3 each) and escalated to a maximum of 5 × 1012 VP/tumor. As DLT was not observed with 
single injections of the highest dose, a repeat dose (5 × 1 × 1012 VP), was administered. No DLTs 
were reported in this patient population with the dosing regimen described. 
1.4 
Patient Population 
Patients with advanced, metastatic gastric and gastroesophageal junction adenocarcinoma that has 
received at least 2 lines of therapy for advanced/metastatic disease. Patients must be PD-L1 
positive, as defined as CPS > 1, and have measurable disease for the primary study endpoint of 
overall response rate by iRECIST. 
2 
OBJECTIVES 
2.1 
Primary Objective 
• To examine the efficacy of OBP-301 with pembrolizumab in PD-L1 positive advanced gastric 
and gastroesophageal junction adenocarcinoma in the 3rd or 4th line setting, as assessed by the 
iRECIST response rate. 
 
• To examine the safety of multiple OBP-301 intratumoral injections in combination with 
pembrolizumab in advanced gastric and gastroesophageal junction adenocarcinoma. 
 
Secondary Objectives 
The secondary objectives of the study are: 
• To examine other measures of efficacy of the combination of OBP-301 with pembrolizumab 
in advanced gastric and gastroesophageal junction adenocarcinoma including the disease 
control rate, duration of response, overall survival and progression free survival. 


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2.2 
Exploratory Objective 
• To examine the tumor-immune microenvironment prior to and following OBP-301 and 
pembrolizumab therapy as assessed by bulk RNA sequencing and single-cell RNA 
sequencing. 
• To examine and characterize the immune infiltrate by multi-parameter flow cytometry. 
3 
STUDY DESIGN 
3.1 
Study Overview 
This is a phase II study of OBP-301 with pembrolizumab in advanced gastric and GEJ 
adenocarcinoma that has progressed on at least 2 lines of prior therapy for advanced disease. This 
study will examine the addition of OBP-301 with pembrolizumab in this exact patient population. 
 
 
Figure 4. Study Schema. Patients will be enrolled in the study in two stages. The first stage will 
be 18 patients. If 3 or more patients respond to the combination therapy, the study will move 
forward to stage 2, with 19 more patients enrolled. In the overall study population of 37 evaluable 
patients, 9 or more patients with an objective response would indicate a positive study. 
The study schema is provided in Fig 4. Patients will be enrolled in a two stage design, with 18 
patients in the first stage. If 3 or more patients respond to the combination therapy, the study will 
move forward to stage 2, with 19 more patients enrolled. Patients will receive 1x1012 VP/ tumor 
injection with Pembrolizumab (200 mg IV every 3 weeks). The tumor will be injected with OBP- 
301 four times (d1, d15, d29, d43). The preference is to inject the primary tumor endoscopically. 
Metastatic lesions may be injected on a case-by-case basis after discussion with the PI (Shah). All 
patients treated with OBP-301 will be eligible for the safety cohort. 
4 
STUDY POPULATION 
4.1 
Selection of Study Population 
Only those patients will be included in the study that meet inclusion and exclusion criteria as 
outlined below. 


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4.2 
Inclusion Criteria 
Patients who meet all of the following criteria will be considered for inclusion in the study: 
1. Be willing and able to provide written informed consent for the trial. 
2. Be >18 years of age on the day of signing the informed consent. 
3. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 
4. Have histologically or cytologically confirmed advanced or metastatic gastroesophageal 
adenocarcinoma amenable to intratumoral injection (i.e. at least 1 cm in size). 
5. Tumor must be PD-L1 positive, as defined by a combined positive score (CPS). 
6. Patient must have received at least 2 lines of systemic therapy for advanced disease 
7. Have one or more measurable lesions based on RECIST v1.1. 
8. Be willing to provide tissue; newly obtained biopsy specimens or formalin-fixed, paraffin- 
embedded (FFPE) block specimens. 
9. Female subjects of childbearing potential have a negative urine or serum pregnancy test within 
7 days prior to enrollment. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. It is allowed that the test at the same day at 7 days prior 
to enrollment. And male / female subjects of childbearing potential must agree to use an 
adequate method of contraception starting with signing the informed consent through 120 days 
after the last dose of study medication. 
10. Demonstrated adequate organ function as defined in following criteria. All screening labs 
should be performed within 14 days of enrollment. Note: Subject must not have taken 
transfusion, hematopoietic agent; granulocyte-colony stimulating factor (G-CSF) etc., and/or 
oxygen supplementation within 7 days before the screening labs. 
a. Absolute neutrophil count (ANC) >1,000 /mm3 
b. Platelets >100,000 /mm3 
c. Hemoglobin >8.0 g/dL 
d. Serum total bilirubin <2.0 mg/dL 
e. Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT)<3x 
Upper limit of normal (ULN). For subjects with liver metastases <5x ULN. 
f. Serum creatinine< 2.0 mg/dL; or if serum creatinine > 2.0 mg/dL, measured or calculated 
creatinine/clearance >45 mL/min (Cockcroft-Gault formula). 
11. Life expectancy of ≥ 4 months from the first OBP-301 treatment. 


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12. Understand the study requirements and the treatment procedures, and is willing to comply with 
all specified follow-up evaluations, and provides written informed consent before any study- 
specific tests or procedures are performed. 
4.3 
Exclusion Criteria 
The presence of any of the following criteria will constitute cause for the exclusion of the 
participant: 
1. 
Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy within 4 weeks of study Day 1. 
2. 
Has an active autoimmune disease that has required systemic treatment in past 2 years. 
3. 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (greater than 
equivalent of 20 mg/day) or any other form of immunosuppressive therapy within 7 days 
prior to study Day 1. 
4. 
Has known active central nervous system metastases and/or carcinomatous meningitis. 
5. 
Has had prior anti-cancer monoclonal antibody chemotherapy, targeted small molecule 
therapy, or radiation therapy within 2 weeks prior to study Day 1, who has not recovered 
from adverse events due to a previously administered agent. 
6. 
Has a known additional malignancy within 3 years before the first OBP-301 administration 
that is progressing or requires active treatment, with the exception of prostate cancer 
controlled with androgen deprivation therapy. 
7. 
Has received a live vaccine within 30 days of planned start of study therapy. 
8. 
Patients known to have acute or chronic active hepatitis B virus (HBV), hepatitis C virus 
(HCV) or human immunodeficiency virus (HIV). 
9. 
Has any evidence of active, non-infectious pneumonitis or interstitial lung disease requiring 
steroids. 
10. Has an active infection requiring systemic therapy within 2 weeks of Day 1. 
11. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the screening visit through 120 days after the last dose of 
trial treatment. 
13. Previous severe hypersensitivity to another monoclonal antibody 
14. Has 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. 
15. Uncontrolled intercurrent illness including, but not limited to, uncontrolled diabetes, ongoing 
or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/psychological incompetence, whereby in the opinion of the 
Investigator the patient is assessed as being unable to provide information, consent, or comply 
with the study requirements and procedures. 
16. Patients who are pregnant or breastfeeding, or expecting to conceive or father children within 
the projected timeframe of the study, starting from the time of the Screening Visit through 4 
months (120 days) after the last OBP-301 administration. Females of childbearing potential 
must have a negative serum or urine pregnancy test at screening. A female not of childbearing 


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potential is one who has undergone bilateral oophorectomy or who has had no menses for 12 
consecutive months. 
 
 
4.4 
Registration Procedures 
4.4.1 Patient Registration – Part 1 (WCMC Only) 
Patients will be centrally registered with the Office of Billing Compliance. To register 
a patient, submit the following documents via the JIRA Registration Process: 
• Legible copy of the HRBAF 
• First and last page of signed informed consent form 
Registration must be completed within 24 hours of the signing of informed consent. 
4.4.2 Patient Registration – Part 2 (All Sites) 
Study participants will be centrally registered Monday through Friday from 9:00am to 
4:00pm with the Weill Cornell Medicine Joint Clinical Trials Office (JCTO). To register a 
new study subject, email the following documents to 41TJCTOIIT@med.cornell.edu41T: 
 
• Completed WCM subject registration form 
• First and last page of the fully executed informed consent form, plus additional pages 
if checkboxes for correlative studies are required 
• Fully executed HIPAA research authorization form 
• Eligibility checklist signed and dated by investigator and research nurse 
• Documentation of any eligibility waivers granted 
• Redacted source documentation to verify eligibility 
 
Note that attachments larger than 4.5 MB are not accepted, so larger attachments should be 
split into more than one email. Central registration information is reviewed and entered into 
the REDCap database. 
4.5 
Stopping Criteria 
4.5.1 Patient Withdrawal Criteria 
In accordance with applicable regulations, a participant has the right to withdraw from the study, 
at any time and for any reason, without prejudice to his future medical care. 
Withdrawal from the study and therapeutic measures taken shall be at the discretion of the 
Investigator. A full explanation for the discontinuation from the study should be made in the 
participant’s medical records and in the eCRF. 
Premature discontinuation from active study participation may occur at any time due to any of the 
following reasons: 


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• Any situation where, in the opinion of the Investigator or the Medical Monitor, continued 
participation in the study would not be in the best interest of the patient. 
• Positive pregnancy test (see Section for procedures to be followed in case of a pregnancy). 
• Patient initiates other anti-cancer therapy. The anti-cancer therapy will be documented in 
the medical record and eCRF. 
• Patient is unable or unwilling to comply with study procedures. 
• Patient is lost to follow-up. 
• Patient withdraws consent. 
• Request by a Health Authority. 
• Termination of the study by the study investigator(s). 
• Progressive neoplastic disease, unless the Investigator feels this may be pseudo- 
progression, in which case the patient may remain on study until the next evaluation for 
extent of disease. 
The reason(s) for premature study discontinuation/withdrawal should be reported in the eCRF and 
within the source documents along with the date of withdrawal. AEs should be documented 
according to Section 7.0 Adverse Events. 
For all patients who discontinue, a Final Visit will be performed within 28 ± 5 days after the last 
IP administration. If a participant is withdrawn because of an AE, the Investigator must arrange 
for the participant to have appropriate follow-up care until the AE is resolved or has stabilized. 
Unresolved AEs will be followed until the last scheduled follow-up visit or until the Investigator 
determines that further follow-up is no longer indicated. Investigators should attempt to collect 
the survival information as dictated in section 6.1.3. 
Patients who discontinue the active study participation will not be replaced. 
Any enrolled patients who are discontinued before study dosing will be documented as screen 
failures in the eCRF and replaced. No follow-up is required for these patients. 
4.5.2 Termination or Suspension of the Study 
Investigator and the IEC/IRB reserve the right to terminate or suspend the study at any time for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and Good Clinical Practice (GCP); however, this should be discussed between the 
relevant parties beforehand and the reason for such decision recorded. Should this occur, all data 
available will also be recorded in the eCRFs. The Investigator should notify the IEC/IRB in 
writing of the study’s completion or early discontinuation. 
We have included adverse events stopping rule (see Section 8.7.9). 
In the event that the study is terminated early, the Investigator should make every effort to follow 
AEs and SAEs for all patients until the end of the defined follow-up period resolution, until the 
condition stabilizes, until the event is in the opinion of the Investigator stabilized or determined to 
be chronic, or until the participant dies or is lost to follow-up. SAEs that occur after the Final 
Visit, that are thought to be related to the administration of OBP-301, should be reported to 
Oncolys BioPharma Inc. or designee. 


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5 
STUDY MEDICATION 
5.1 
Investigational Product (IP) Identification 
The OBP-301 clinical study material and product is generated according to current Good 
Manufacturing Practice (cGMP). Table 1 shows an overview of OBP-301. OBP-301 will be 
provided by Oncolys BioPharma Inc. 
Table 1 
Investigational Product Information 
Investigational product 
code: 
OBP-301 
Content: 
2 mL/vial (1×1012 VP/mL) 
Dosage form: 
Solution; formulated in 20 mM Tris pH 8.0, 25 mM NaCl with 
2.5% glycerin, USP by volume, filled in each 5 mL glass vial 
Storage method for the 
investigational product: 
Store at ≤ -60°C 
 
5.2 
Dosage and Treatment 
1. OBP-301 2x1012 viral particles/ tumor injection every 2 weeks x 4 injection encounters. 
 
* Up to 1 additional tumor injection encounter may be considered in discussion 
with the PI (Dr. Shah) which may be given 2 weeks after the 4th injection of OBP- 
301. 
* OBP-301 will be administered as a fixed dose to the tumor. The target dose of 
OBP-301 injection will be 2x1012 VP (i.e. 1 vial), and a minimum of 1x1012 VP 
(i.e. 1 ml). Specifically, inject as much OBP-301 as possible, but within 1 - 2 mL. 
The maximal injection volume of 2.0 mL is preferred (2 x1012 VP per lesion) and 
should be injected as long as this is technically possible. At least 1 mL OBP-301 
should be injected to the same location as the 1st and 2nd injection even though the 
primary tumor mass may have decreased and may be hard to locate. 
 
* OBP-301 will be administered to one lesion. If the gastroesophageal tumor is 
multifocal, only the largest lesion will be targeted. 
* For patients with tumors not assessable by endoscopy, injection via 
interventional radiology procedure is permitted, applying the same dosing 
principles above. 
* Note that it is expected that some amount of material will be used to prime the 
injection device (i.e. 0.8 mL for a Carre-Locke injection needle). This will be 
discarded as per standard procedure. 
2. Pembrolizumab 200mg intravenous every 3 weeks until disease progression. 


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Please note that the Pharmacy manual, which is used for all OBP-301 studies globally, also 
indicates another OBP-301 dose administration option (plan B). This protocol will only use Plan 
A (i.e. fixed dose administration). 
5.2.1 Study Supplies 
Pembrolizumab will be supplied by commercial venders. 
Oncolys BioPharma Inc. will be responsible for the preparation and labelling of the Investigational 
Product in accordance with local regulatory requirements. Oncolys BioPharma Inc. will also 
provide details of batch numbers and all associated safety and stability data. 
Oncolys BioPharma Inc. will be responsible for packaging and shipment of the IP to the site(s). 
Due to product specific requirements, shipments of IP will be made on dry ice using a validated 
container and temperature monitoring. An official shipping form to be completed by the study 
Investigator or designee (e.g., pharmacist) will be included in each shipment. Specific ordering 
information will be provided to each participating site upon study activation. 
5.2.1.1 Storage Conditions 
The study Investigator or designee is responsible for receiving each shipment of IP. Upon receipt 
of the IPs at the investigational site, the receipt procedures should be completed and IPs stored 
appropriately ≤ -60°C. A record to account for all dispensing and return of unused IPs will be 
maintained by the investigational sites. At the end of the study the IPs will be reconciled. The 
Investigator will be fully responsible for the security, accessibility, and storage of the IPs while 
they are at the investigational facility. 
Vials must be stored in the original vial storage boxes to facilitate supply tracking. It is 
recommended to leave the vial storage boxes in the original leak-proof bag or in a substitute leak- 
proof container, particularly if the supplies are not segregated (i.e., in a separate section of the 
freezer) from other products or biological samples. 
The freezer should be in a locked or secured area, with limited access. Additionally, the freezer 
should have a temperature recorder and an alarm system. The temperature plot should be properly 
maintained and checked. Documentation for calibration of the freezer at installation and at each 
maintenance inspection should be available (at least annually or as per manufacturer’s 
recommendations). A biohazard symbol should be affixed to the outside of the storage 
compartment. 
5.2.1.2 Accountability and Compliance 
The Investigator, pharmacist, or designee, may only dispense clinical supplies in accordance with 
this protocol. 
The Investigator, pharmacist, or designee, is responsible for maintaining an accurate and current 
record of all clinical supplies received from Oncolys BioPharma Inc., dispensed to the Investigator 
or destroyed. Accountability records must be maintained throughout the course of the study, 
showing receipt and disposition of the clinical supplies. 
At the end of the study, it must be possible to reconcile delivery records with that of used, unused 
and destroyed clinical supplies. 


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The Investigator is also responsible for the education of study staff in the correct administration of 
the IP. 
Additional measures to ensure treatment compliance are not required because the IP will be 
prepared and administered by study personnel (see Section 5.2.1.3). 
5.2.1.3 Study Material Preparation 
OBP-301 should be prepared according to Biosafety Level 2 Guidelines, unless local regulations 
require a more rigorous containment level. An outline of Biosafety Level 2 precautions is located 
in the OBP-301 Pharmacy Brochure Appendix V: Handling Guidelines/Universal Precautions for 
Biosafety Level 2 Agents. Aseptic technique must be followed at all times during the preparation 
and transport of the IP to the treatment area. A disinfectant that has been qualified as an effective 
virucide for adenoviruses should be used for any decontamination procedure. The recommended 
exposure time should be at least 5 to 15 minutes. However, if the handling precautions 
recommended by the manufacturer differ, the manufacturer’s instructions should be followed. 
The duration that the IP remains at room temperature should be minimized and it is recommended 
that OBP-301 be administered as soon as possible (within 4 hours) after the OBP-301 is thawed. 
Immediately before injection, the IP may be warmed by rolling the syringe between the palms of 
the hands, which may facilitate comfort of administration to the patient. 
The Investigator is responsible for the education of study staff in the correct administration of the 
IP and a designated staff member experienced in the administration of investigational agents 
directly into tumor lesions will administer all treatments. 
5.2.1.4 Destruction of Used and Unused Investigational Product 
Immediately after use, the used vials should be placed in a biohazardous waste container. Empty 
or partially used vials should be destroyed, by the study pharmacy, in accordance with institutional 
biosafety policy and procedures for biohazardous waste management. Proper accounting of the 
vials must be performed immediately using the Drug Accountability Form. 
Written authorization must be obtained from Oncolys BioPharma Inc. before any destruction of 
unused clinical material supplies. This will occur at the completion of the clinical study or when 
the expiration date has been reached and could not be prolonged by Oncolys BioPharma Inc. based 
on updated stability information. In addition, destruction of unused supplies may only be 
performed after product reconciliation by the monitor. 
The unused vials must be destroyed by the study pharmacy, in accordance with institutional 
Biosafety policy and procedures for biohazardous waste management or returned to Oncolys 
BioPharma Inc. 
The Investigator or designee must fill in, sign, and date the appropriate section of Clinical Trial 
Material Destruction Certificate. Discrepancies in vial accountability must be explained in writing 
by the Investigator or designee. A copy will be retained for the site study file and the monitor will 
retrieve the original. 
Further information of the storage, preparation, and administration of IP will be provided in the 
OBP-301 Pharmacy Brochure. 


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5.2.2 Selection and Timing and IP Administration for each Patient 
OBP-301 (2×1012 VP/vial) is administered as intratumoral injection into a primary gastric or GEJ 
tumor mass that is suitable for injection, eg greater than 1 cm in size and in a location amenable 
for endoscopic injection. For patients with tumors not assessible by endoscopy, injection via 
interventional radiology procedure is permitted, applying the same dosing principles described 
herein. The largest diameter of the lesion will determine the volume of OBP-301 injected. The 
rationale for this is to ensure adequate penetration of the viral particals throughout the tumor. 
Safety Guidelines for Clinical Study Patients and Caregivers 
• Avoid direct contact with body fluids of patients who were injected with OBP-301. 
• Immunocompromised individuals or pregnant women should not come into direct contact with 
body fluids of treated patients. 
Safety Guidelines for Healthcare Staff when Handling OBP-301 
• Immunocompromised individuals or pregnant women should not prepare or administer OBP- 
301 and should not come into direct contact with OBP-301 injection sites, dressings, or body 
fluids of treated patients. 
• Staff must follow Biosafety Level 2 guidelines by avoiding accidental exposure to OBP-301 
and follow the instructions for preparation, administration, and handling of OBP-301. 
• Staff must wear personal protective equipment (protective gown or laboratory coat, safety 
glasses or face shield, and gloves) while preparing or administering OBP-301. 
• Cover any exposed wounds before handling OBP-301. 
• In the event of an accidental occupational exposure (e.g., through a splash to the eyes or 
mucous membranes), flush with clean water for at least 15 minutes. 
• In the event of exposure to broken skin or needle stick, clean the affected area thoroughly with 
soap and water and/or a disinfectant. 
• Clean all surfaces that may have come in contact with OBP-301 and treat all spills with a 
virucidal agent such as 1% sodium hypochlorite or 70% isopropyl alcohol and blot using 
absorbent materials. 
• Dispose of all materials that may have come in contact with OBP-301 (e.g., vial, syringe, 
needle, cotton gauze, gloves, masks, or dressings) as biohazardous waste. 
 
5.2.3 Injection Procedures 
The optimum technique for injection of a primary tumor is to inject the viral particles 
circumferentailly around the lesion in 4 quadrants, similar to the technique used in endoscopic 
submucosal disection (Gotoda T, et al. J Gastroenterol 2006;41:929-942.). This will ensure that 
the viral partical will be maximally penetrated into the lesion. 
Endoscopists who perform single polypectomies will be eligible to perform the procedure. A 
trianing video (prepared by Oncolys Biopharma) is available as well. 
The procedure will be performed in the Endoscopy Unit or interventional suite with standard 
sterilization procedures. A standard gastroscope and needle (eg. GIF-HQ190 Olympus gastroscope 
with 25 gauge Carr-Locke injection needel made by US Endoscopy) is used for the procedure. 
Guidelines for each injection procedure are provided below. 


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Pre-Injection 
• Confirmation of eligiiblity 
• Review of medications 
• Abbreviated physical exam and performance status 
• Vital signs 
Post-Injection 
• Monitor patient for 60-90 minutes for any symptoms of injection site pain, bleeding, 
nausea. 
• Vital signs (except weight) 
Standard sedation procedures used for endoscopy will be used, and consists of monitored 
anesthesia care with an anesthesiologist and the patient monitored at all times. OBP-301 may be 
associated with injection site pain if administered to dermal lesions. However, pain has not been 
observed for intralumenal injections previously. 
5.2.4 Dose Delay and Adjustment 
Pembrolizumab 
Pembrolizumab is given at a flat dose of 200 mg IV every 3 weeks, per institutional guidelines. 
There are no dose modifications to this treatment. 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug- 
related toxicities and severe or life-threatening AEs as per Table 2 below. See Section 5.2.2.6 
and Events of Clinical Interest Guidance Document for supportive care guidelines, including use 
of corticosteroids. 
Table 2. Dose Modification Guidelines for Pembrolizumab -Related Adverse Events (as per 
package insert). 
 
Toxicit 
y 
Hold 
Treatme 
nt For 
Grade 
Timing for Restarting 
Treatment 
Discontinue Subject from Study 
Treatment 
Diarrhe 
a/Coliti 
s 
2-3 
Toxicity resolves to Grade 0- 
1. 
Toxicity does not resolve within 12 
weeks of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks. 


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Toxicit 
y 
Hold 
Treatme 
nt For 
Grade 
Timing for Restarting 
Treatment 
Discontinue Subject from Study 
Treatment 
4 
Permanently discontinue 
Permanently discontinue 
AST, 
ALT, 
or 
Increas 
ed 
Bilirubi 
n 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 
diabete 
s 
mellitus 
(if new 
onset) 
or 
Hyperg 
lycemia 
T1DM or 
3-4 
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus 
or Grade 3-4 hyperglycemia 
associated with evidence of 
beta cell failure. 
Resume pembrolizumab when patients 
are clinically and metabolically stable. 
Hypoph 
ysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypert 
hyroidi 
sm 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypoth 
yroidis 
m 
2-4 
Therapy with pembrolizumab 
can be continued while 
treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted. 
Infusio 
n 
3-4 
Permanently discontinue 
Permanently discontinue 


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Toxicit 
y 
Hold 
Treatme 
nt For 
Grade 
Timing for Restarting 
Treatment 
Discontinue Subject from Study 
Treatment 
Reactio 
n 
Pneum 
onitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal 
Failure 
or 
Nephrit 
is 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All 
Other 
Drug- 
Related 
Toxicit 
y2 
3 or 
Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or 
any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or 
ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week 
then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at 
physician discretion. Permanently discontinue study drug for persistent Grade 2 adverse 
reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 
within 12 weeks of the last dose. 
 
OBP-301 
OBP-301 injection will be delayed for any ongoing Grade 3 toxicity attributable to OBP-301 at 
the time of the next scheduled injection. Patients who require a delay of OBP-301 injection of > 
4 weeks (i.e., approximately 6 weeks from the previous injection) due to lack of resolution to 


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Grade 1 toxicity will be discontinued from the study. In this circumstance, the patient will be 
evaluable for toxicity, but will be replaced (up to the maximum enrollment) for efficacy 
assessment. 
5.2.5 General Concomitant Medication and Supportive Care Guidelines 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this with 
the Principal Investigator. The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician. 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care. All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, 
over-the-counter (OTC), herbal supplements, and IV medications and fluids. If changes occur 
during the trial period, documentation of drug dosage, frequency, route, and date may also be 
included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded. 
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 OBP-301 
• 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 
Sponsor. 
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 describe other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 


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5.2.6 Rescue Medications & Supportive Care 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below and in greater detail in the ECI guidance 
document. 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 investigator determines the events to be related to pembrolizumab. 
Note: if after the evaluation, the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. Suggested conditional procedures, as appropriate, 
can be found in the ECI guidance document. 
• Pneumonitis: 
o 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. 
o For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
• 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). 
o 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. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 


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o 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. 
• Hypophysitis: 
o For Grade 2 events, treat with 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. 
o For Grade 3-4 events, 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. 
• 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. 
o 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. 
o 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. 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• 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. 


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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. 
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 
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). 


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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
from further trial treatment 
administration. 
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. 


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6 
STUDY PROCEDURES 
Study procedures should be completed as outlined in the Schedule of Events. Section 6.1 
summarizes the trial procedures to be performed at each visit. Individual trial procedures 
are described in detail below. 


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6.1 
Schedule of Events 
 
Screening Phase 
Treatment Phase 
Treatment Encounter 
Part 1 
Part 2 
Baseline 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Scheduling Window 
(-28 to -1) (-14 to -1) 
Day 0e 
Day 1 
Day 4 
Day 
11-14 
Day 
15 
Day 
25 
Day 
29 
Day 
39-42 
Day 
43 
Day 
46 
Week 
9 
Week 10 
onwardsg 
End of 
Studyh 
Informed Consent 
X 
Inclusion/Exclusion Criteria 
X 
Demographics and Medical History 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
Xg 
X 
Physical Examination 
X 
X 
X 
X 
X 
Xg 
X 
Vital Signs and Weight 
X 
X 
X 
X 
X 
Xg 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
Xg 
X 
Pregnancy Test – Urine or Serum β- 
HCG 
Xm 
PT/INR and aPTT 
X 
X 
CBC & Serum Chemistrya 
X 
Xk 
X 
X 
X 
Xg 
X 
Urinalysis, T3, FT4 and TSH 
X 
X 
Xf 
X 
ECG 
Xi 
As clinically indicated 
Tumor Imaging - CT preferredb 
X 
Xb 
X 
Tissue Biopsyj 
X 
X 
X 
X 
X 
Correlative Blood Collectionc 
X 
X 
Xc 
X 
OBP-301l,n 
X 
X 
X 
X 
Pembrolizumab Administrationd, o 
X 
X 
X 
Xd 
Review Adverse Events 
X 
X 
X 
X 
X 
Xg 
X 


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a. Serum chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, AST, ALT, Alk Phos, lactate 
dehydrogenase, bilirubin (total and direct), total protein, albumin, calcium, magnesium and phosphorous, may be drawn up to -2 days from schedule. b. 
Tumor imaging studies preferably CT scans of chest/abdomen/pelvis should be performed every three cycles of Pembrolizumab after week 10 until end 
of study. 
c. Correlative blood collection will be done at screening, day 25, day 46, at week 19 and at the end of study. Correlative blood draws will be done pre- 
dose if treatment is given on the same day. 
d. Pembrolizumab will be administered every 3 weeks ± 3 days. 
e. Baseline assessment should be performed within 5 days of administrating first dose of OBP-301. 
f. Urinalysis, T3, FT4 and TSH should be performed every 3rd cycle of Pembrolizumab thereafter until end of study. 
g. From week 10 and onwards, concomitant medication review, physical exam, vitals/weight, ECOG performance status, CBC, comprehensive serum 
chemistry and review of adverse events should be performed every 3 weeks until end of study. 
h. End of study will occur 28 days (+/- 5 days) following study removal, disease progression, or following 2 years on treatment. Patients may still be 
followed for survival for up to 96 weeks from study start. 
i 12-lead ECG will be recorded after the patient has rested for 5 minutes 
j. Tumor biopsy may be needed during screening phase for PD-L1 testing if there is no archival tissue available. 
k. Only needed, if screening CBC and chemistry done more than 7 days prior to first cycle of pembrolizumab. 
l. OBP-301 will be administered every 2 weeks (-2 business day/ +5 business day window). If the window is used, the following doses should be 
administered following the same window, ensuring at least 12 days between each OBP-301 administration. 
m. Pregnancy test for screening should be done within 7 days of Day 1. 
n. A CBC and CMP should be obtained within 10 days of OBP injection, if not already performed. 
o. OBP-301 and Pembrolizumab should not be administered on the same day. 


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6.1.1 Screening Visit 
• 
Informed consent 
• 
Demographics 
• Medical history 
• Concomitant Medications 
• Physical exam 
• Vital signs and weight 
• ECOG performance status (Appendix A: ECOG Performance 
Status Criteria) 
• Urine or Serum Pregnancy Test 
• PT/INR and aPTT 
• Complete Blood Count (CBC) with differential 
• Serum chemistry 
• Urinalysis 
• T3, FT4 and TSH 
• ECG 
• Tumor Imaging CT preferred 
• Tumor Biopsy/Archival biopsy (for PD-L1 status) 
• Correlative Blood Collection 
6.1.2 Treatment Phase 
Pembrolizumab infusions will be administered every 3 weeks ± 3 days until disease progression 
or patient is withdrawn for another reason. OBP-301 is to be administered prior to 
pembrolizumab in this patient population. All patients will receive OBP-301 at 2 x1012 viral 
particles/ tumor injection administered every two weeks x 4 injection encounters. The tumor 
will be injected with OBP-301 four times (day 1, day 15, day 29, day 43). However, there may 
be some exceptions for OBP-301 injections which are outlined below. 
A. Up to 1 additional tumor injection encounter may be considered in discussion with the 
PI (Shah), which may be given 2 weeks after the 4th injection of OBP-301. 
B. Patients who initially respond to combination therapy may be rechallenged with OBP- 
301 at the time of disease progression, after discussion with the principal investigator. 
Criteria for the additional single dose of OBP-301 is that the patient has not had disease 
progression and has had no grade 3 or 4 events related to OBP-301. 
6.1.3 Follow up Phase 
Patients with disease progression will be followed every 3 months for survival for up to 96 
weeks from study start. This assessment can occur by telephone or some other remote 
monitoring. 
6.1.4 Patient Withdrawal Criteria 
In accordance with applicable regulations, a participant has the right to withdraw from the 
study, at any time and for any reason, without prejudice to his future medical care. 


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Withdrawal from the study and therapeutic measures taken shall be at the discretion of the 
Investigator. A full explanation for the discontinuation from the study should be made in the 
participant’s medical records and in the eCRF. 
Premature discontinuation from active study participation may occur at any time due to any of 
the following reasons: 
• Any situation where, in the opinion of the Investigator or the Medical Monitor, 
continued participation in the study would not be in the best interest of the patient. 
• Positive pregnancy test 
• Patient initiates other anti-cancer therapy. The anti-cancer therapy will be documented 
in the medical record and eCRF. 
• Progressive neoplastic disease, unless the Investigator feels this may be pseudo- 
progression, in which case the patient may remain on study until the next evaluation for 
extent of disease. 
• An intercurrent illness or AE that requires concomitant medication that precludes 
further study participation 
• Patient is unable or unwilling to comply with study procedures. 
• Patient is lost to follow-up. 
• Patient withdraws consent. 
• Termination of the study by the Sponsor. 
• Request by a Health Authority. 
In addition, the Sponsor will discontinue a patient from active study treatment for any of the 
following criteria (subjects will continue to be followed as apprioprate for outcomes and 
toxicities: 
• Patients who experience a Grade 4 hematologic toxicity or a Grade 3 or greater non- 
hematologic toxicity attributable to OBP-301 or the endoscopic procedure that has not 
resolved to Grade 1 (or basline) within 2 weeks of onset. 
• OBP-301 injection will be delayed for any ongoing Grade 2 toxicity at the time of the 
next scheduled injection after consultation with the Principal Investigator. Patients who 
require a delay of OBP-301 injection of > 4 weeks (i.e., approximately 6 weeks from 
the previous injection) due to lack of resolution to Grade 1 toxicity will be discontinued 
from the study after consultation with Medical Monitor and Principal Investigator. 
After apparent disease progression (PD) is observed, administration of OBP-301 may be 
continued as per iRECIST. Immune-related disease progression (irPD) will be confirmed if 
the increase in tumor burden is ≥ 25% relative to nadir (minimum recorded tumor burden). The 
confirmation is completed by a repeat, consecutive assessment no less than 4 weeks from the 
date the disease progression was first documented. If in the opinion of the investigator, the 
disease progression is not clinically significant, then the patient may continue to receive OBP- 
301 treatment. 
The reason(s) for premature study discontinuation/withdrawal will be documented along with 
the date of withdrawal. AEs should be documented according to the study calendar. 
For all patients who discontinue, a Final Visit will be performed within 28 ± 5 days after the 
last IP administration (see study calendar). If a participant is withdrawn because of an AE, the 
Investigator must arrange for the participant to have appropriate follow-up care until the AE is 


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resolved or has stabilized. Unresolved AEs will be followed until the last scheduled follow-up 
visit or until the Investigator and Medical Monitor determine that further follow-up is no longer 
indicated. Investigators should attempt to collect the survival information as dictated by the 
Schedule of Events in the Study calendar. 
Patients who discontinue the active study participation will not be replaced. 
Any enrolled patients who are discontinued before study dosing will be documented as screen 
failures in the eCRF and replaced. No follow-up is required for these patients. 
6.2 
Informed Consent Form 
Each patient is required to provide informed consent before participating in the study. 
Before performance of any study procedures, potential patients will attend a screening session 
at which time they will be provided with full information concerning details of the study 
assessments and procedures. They will also be provided with the ICF. Before being asked to 
sign the ICF, patients will be given time to review the study information and ask any questions. 
A copy of the signed ICF must be provided to the patient. 
6.3 
Demographic Data and Baseline Characteristics 
Gender, date of birth, height, and weight, as well as race and ethnic origin will be recorded for 
each patient and age and body mass index calculated from these data. 
6.4 
Medical History, Concomitant Disease, Previous and Ongoing Medications 
A detailed medical history, including surgical and cancer history, will be recorded and will 
include any conditions reported by the patient or noted by the Investigator in each body system. 
Medical history is defined as any condition that started and ended before the Screening Visit. 
A concomitant disease is defined as any condition detected at the Screening Visit that started 
after ICF signature or was started before the Screening Visit and is still ongoing at the 
Screening Visit. 
Prior medication taken before the Screening Visit and any concomitant medication will be 
documented. Prior medication is defined as any medication taken within 4 weeks of screening 
visit. Concomitant medications are those medications which the patient is currently taking at 
any particular visit. 
Records should include the drug name (preferably both generic and trade name), route of 
administration (e.g., oral, intravenous), injection and frequency (expressed in metric units, for 
example, mg, mL, or IU), indication, and the start and, if applicable, the stop date (day, month, 
and year). Therapy changes (including changes of regimen) during the study have to be 
documented. All concomitant medications will be recorded in the eCRF. 
6.5 
Safety Assessments 
6.5.1 Adverse Events 
Definitions, management of, and special considerations for AEs are provided in Section 7. 
Adverse events will be collected at each contact with the patient. Questions regarding the 
presence of adverse events should be open-ended without leading the patient. 


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6.5.2 Physical Examination 
The physical examination is to be conducted by the Investigator or designated fully trained 
representative. Performance status will also be determined at screening as well as at each 
subsequent visit as oulined in the section study schedule. Patients will be graded according to 
the ECOG Performance Status Scale. 
 
Performance 
Status 
Definition 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work. 
2 
Ambulatory and capable of self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours. 
3 
Capable of limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair. 
 
6.5.3 Vital Signs 
Vital signs will include measurements of heart rate, systolic and diastolic blood pressures while 
the patient is in a seated position, and temperature. 
6.5.4 Electrocardiogram 
During screening of patients, a standard baseline 12-lead ECG will be recorded after the patient 
has rested for 5 minutes. The Investigator or designee will review all ECGs. The following 
parameters will be documented: rhythm, heart rate, PR interval, QRS interval, QT interval, and 
QTc. Every ECG must be assessed as normal, abnormal – clinically not significant, or abnormal 
– clinically significant. A diagnosis must be provided in the eCRF for all ECGs assessed as 
abnormal – clinically significant. If clinically indicated, additional ECGs may be obtained 
during the study. 
6.5.5 Laboratory Assessments 
6.5.5.1 Clinical Chemistry, Hematology, Coagulation Parameters, and Urine Analysis 
for Safety Panel 
Following table illustrates laboratory assessments, which will be performed at prescribed 
intervals as per schedule of events. 


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Table 4 
Clinical Laboratory Parameters for Safety Panel 
 
Hematology 
Coagulation 
Serum Chemistry 
Urine Analysis 
• Hemoglobin 
• Hematocrit 
• Red blood cell 
count 
• White blood 
cell (WBC) 
count 
• Platelet count 
• WBC 
differentials 
• International 
normalized 
ratio 
• Prothrombin 
time 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Blood urea 
nitrogen 
• Creatinine 
• Glucose 
• Alanine 
transaminase 
• Aspartate 
transaminase 
• Alkaline 
phosphatase 
• Lactate 
dehydrogenase 
• Bilirubin (total 
and direct) 
• Total protein 
• Albumin 
• Calcium 
• Magnesium 
• Phosphorous 
• pH 
• Specific 
gravity 
• Glucose 
• Ketones 
• Bilirubin 
• Hemoglobin 
• Protein 
• Microsopic if 
any dipstick 
value 2+ or 
greater 
 
6.5.5.2 Pregnancy Testing and Post-Menopausal Status 
A serum or urine pregnancy test will be performed on all women of childbearing potential at 
Screening. 
The post-menopause is defined as the time after which a woman has experienced 
12 consecutive months of amenorrhea (lack of menstruation) without a period. If a woman 
claims she is post-menopausal, but has had her menses within 12 months, a follicle stimulating 
hormone (FSH) test must be performed and must be within acceptable limits of the post- 
menopausal status. If the post-menopausal status of a female is confirmed, the pregnancy tests 
will not be performed. 
All pregnancies detected during the study must be reported and handled as described in Section 
7.2. 


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6.6 
Efficacy Assessments 
6.6.1 Imaging Assessment for the Study 
All the patients who enrolled into study will undergo efficacy assessments for overall response 
rate, disease control rate, progression free survival and overall survival, as defined in Section 
8.5. A baseline imaging study preferably CT scan of chest/abdomen/pelvis with IV contrast 
(permitting no contraindication to contrast) will be performed followed by every nine weeks 
interval while the patient is on study. Efficacy end points will be assessed according to RECIST 
1.1 criteria. 
6.6.2 Definitions of Measurable and Non-Measurable Disease 
6.6.2.1 Measurable Disease 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of 10 mm by CT scan (CT 
scan slice thickness no greater than 5 mm). 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
6.6.2.2 Non-Measurable Disease 
 
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-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 
measurable by reproducible imaging techniques. 
 
6.6.3 Response Criteria 
All patients will undergo re-evaluation imaging scans every nine weeks from the start of 
treatment as per the study schedule to determine response to treatment. Following designations 
will be assigned according to iRECIST. (see appendix below for differences in RECIST 1.1 
and iRECIST), 
6.6.3.1 Complete Response (iCR)* 
 
Defined as disappearance of all target lesions. Any pathological lymph nodes (whether target 
or non-target) must have reduction in short axis to <10 mm. 
 
6.6.3.2 Partial Response (iPR)* 
 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 


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6.6.3.3 Progressive Disease (PD)* 
 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm. 
 
Unconfirmed PD (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 (ie, 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 tumor 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 confirmed progressive disease (iCPD) to be 
assigned. If no change in tumor size or extent from iUPD occurs, then the timepoint response 
would again be iUPD. 
 
6.6.3.4 Stable Disease (iSD)* 
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on study. 
 
* May have had unconfirmed progressive disease (iUPD) (1 or more instances), but not 
confirmed progressive disease (iCPD), prior to complete response (iCR), partial response 
(iPR) or stable disease (iSD). “i” indicates immune responses assigned using iRECIST. 
6.6.4 Tumor Determination of Stage by Tumor, Lymph Nodes, Metastasis (TNM) 
Classification 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before confirming the complete response 
status. 
6.7 
Biopsies and Immune Monitoring 
All patients undergoing treatment with OBP-301 will have tissue biopsies along with 
correlative blood samples. Tissue biopsies will be performed with every injection of OBP-301. 
Correlative blood samples will be taken before the start of study treatment, during treatment 
and post-treatment as described in the section of study schedule. Blood and biopsy samples 
will be retained for future research if informed consent has been obtained from the patient. 
7 
ADVERSE EVENTS 
7.1 
Definitions 
7.1.1 Definition of an Adverse Event 
An AE is any event, side effect, or other untoward medical occurrence that occurs in 
conjunction with the use of a medicinal product in humans, whether or not considered to have 


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a causal relationship to this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (that could include a clinically significant abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
Events meeting the definition of an AE include: 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after IP administration even though it may have 
been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either IP or a 
concomitant medication (overdose per se will not be reported as an AE/SAE). 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from 
lack of efficacy will be reported if they fulfil the definition of an AE or SAE. 
Events that do not meet the definition of an AE include: 
• Medical or surgical procedure (e.g., appendectomy). The condition that leads to the 
procedure is an AE. 
• Situations where an untoward medical occurrence did not occur (e.g., social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
If there is evidence of an AE through report or observation, the Investigator or designee will 
evaluate further and record the following information: 
• Date of onset and resolution 
• Classification of ‘serious’ or ‘non-serious’ 
• Severity 
• Causality/relation to study treatment 
• Action taken regarding IP (no action taken, study treatment interrupted, study treatment 
discontinued) 
• Medication or additional treatment (no medication additional treatment, concomitant 
medication, non-drug therapy, other) 
• Outcome /Status (recovered, recovered with sequelae, recovering, ongoing, fatal 
unknown) 
7.1.2 Severity of an Adverse Event 
The intensity of AEs/SAEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 (dated 14 June 2010) 36. 
Should an event be missing in the NCI-CTCAE, the following 5-point scale is to be used: 
• Mild: Discomfort noticed, but no disruption of normal daily activity 
• Moderate: Discomfort sufficient to affect normal daily activity 


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• Severe: Inability to work or perform normal daily activity 
• Life-threatening: Risk of death at the time of the event 
• Fatal: The patient died 
The correspondence between the 2 scales is as follows: 
 
NCI-CTCAE 
5 point scale 
1 
Mild 
2 
Moderate 
3 
Severe 
4 
Life-threatening 
5 
Fatal/Death 
NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events 
7.1.3 Causal Relationship of an Adverse Event 
Causal relationship of an adverse event to the IP will be assessed by the Investigator as follows: 
 
Not related: 
The event is clearly related to other factors such as the participant’s clinical 
state, therapeutic interventions or concomitant drugs administered to the 
participant. This is especially so when an event occurs before the 
commencement of treatment with the IPs. 
Unlikely: 
The experience was most likely produced by other factors such as the 
participant’s clinical state, therapeutic interventions or a concomitant drug 
administered to the participant and does not follow a known response to the 
trial IP. 
Possible: 
The experience follows a reasonable temporal sequence from the time of IP 
administration and/or follows a known response to the trial IP, but could have 
been produced by other factors such as the participant's clinical state or other 
therapeutic interventions or concomitant drugs administered to the 
participant. 
Probable: 
The experience follows a reasonable temporal sequence from the time of IP 
administration and follows a known response to the trial IP, and cannot be 
reasonably explained by other factors such as the participant's clinical state or 
other therapeutic interventions, or concomitant drugs administered to the 
participant. 
Definite: 
The experience follows a reasonable temporal sequence from the time of IP 
administration and follows a known response to the trial IP, and cannot be 
reasonably explained by other factors such as the participant's clinical state or 
other therapeutic interventions or concomitant drugs administered to the 
patient and in addition one or more of the following: 
o Occurs immediately following trial IP administration 
o Improves on stopping the trial IP 
o Reappears on repeat exposure 


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7.1.4 Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence regardless of the grade that: 
• results in death, 
• is life-threatening, 
• requires inpatient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, or, 
• is a congenital anomaly/birth defect. 
Important medical events that may not be one of the above may be considered an SAE by the 
Investigator when, based upon appropriate medical judgement, are considered clinically 
significant and may jeopardize the participant, or may require medical or surgical intervention 
to prevent one of the outcomes listed above. 
"Life-threatening" means that the participant was at immediate risk of death from the 
experience that, had it occurred in a more serious form might have caused death. 
A congenital anomaly in an infant born to a mother who was exposed to the IP during 
pregnancy is considered an SAE. However, a newly diagnosed pregnancy in a patient that has 
received the IP is not considered an SAE unless it is suspected that the IP interacted with a 
contraceptive method and led to the pregnancy. Procedures for notification of pregnancies and 
follow-up are described in Section. 
7.1.5 Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events and Serious Adverse Events 
Abnormal laboratory findings (e.g., clinical chemistry, hematology, and urinalysis) or other 
abnormal assessments (e.g., ECG, X-rays, and vital signs) per se are not reported as AEs. 
However, those abnormal findings that are deemed clinically significant or are associated with 
signs and/or symptoms must be recorded as AEs if they meet the definition of an AE (and 
recorded as an SAE if they meet the criteria of being serious) as described previously. 
Clinically significant abnormal laboratory or other abnormal findings that are detected after 
consent or that are present at the time of consent and worsen after consent are included as AEs 
(and SAEs if serious). 
The Investigator should exercise his or her medical and scientific judgment in deciding whether 
an abnormal laboratory finding or other abnormal assessment is clinically significant. Usually, 
the abnormality should be associated with a clinically evident sign or symptom, or be likely to 
result in an evident sign or symptom in the near term, to be considered clinically significant. 
A clinically significant laboratory abnormality in the absence of clinical symptoms may 
jeopardize the participant and may require intervention to prevent immediate consequences. 
For example, a markedly low serum glucose concentration may not be accompanied by coma 
or convulsions, yet be of a magnitude to require glucose administration to prevent such 
sequelae. 
7.2 
Documenting Adverse Events 
Any AE occurrence (spontaneously volunteered and enquired for, as well as observed AEs) 
during the study must be documented in the patient’s medical records in accordance with the 
Investigator’s normal clinical practice and on the AE page of the eCRF. SAEs that occur during 


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the study must be documented in the patient’s medical record, on the AE eCRF, and on the 
SAE form. 
The Investigator should attempt to establish a diagnosis of the event based on the signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE (and SAE if serious) and not the individual signs/symptoms. 
If a clinically significant abnormal laboratory finding or other abnormal assessment meets the 
definition of an AE, then the AE eCRF page in the REDCap database must be completed as 
appropriate. In addition, if the abnormal assessment meets the criteria for being serious, the 
SAE form must also be completed. A diagnosis, if known, or clinical signs or symptoms if the 
diagnosis is unknown, rather than the clinically significant laboratory finding or abnormal 
assessment, should be used to complete the AE/SAE page. If no diagnosis is known and 
clinical signs or symptoms are not present, then the abnormal finding should be recorded. If 
an SAE report is completed, pertinent laboratory data should be recorded on the SAE form, 
with baseline values and copies of laboratory reports. 
The SAE page should be completed as thoroughly as possible and signed by the Investigator 
before transmittal to Oncolys BioPharma Inc at safety@oncolys.com. 
It is very important that the Investigator provide an assessment of the causal relationship 
between the event and the IP at the time of the initial report, as this will be useful for 
submissions to regulatory authorities. 
7.2.1 Recording of Adverse Events 
All adverse events will be recorded on a patient specific AE log after W1D1 and 
entered onto REDCap. The AE log will be maintained by the research staff and kept in 
the patient’s research chart. 
7.2.2 Reporting of AE to WCMC IRB 
All adverse events will be recorded on a patient specific AE log after Day 1. The AE log 
will be maintained by the research staff and kept in the patient’s research chart. 
7.2.3 Follow-up of Adverse Events and Serious Adverse Events 
In this study, non-serious AEs will be reported in all participants from Treatmet 1. Non-serious 
AEs reported from the time of consent to injecting on Day 1 will be recorded as medical history. 
Serious adverse events (SAEs) will be reported in all patients (enrolled and not enrolled) from 
the time of consent. Study procedure-related AEs will be evaluated specifically from the time 
of consent until the administration of OBP-301. Treatment-emergent AEs will be evaluated 
from the time of injecting with IP until the Final Visit. The Investigator is responsible to ensure 
that follow-up includes any supplemental investigations as may be indicated to elucidate as 
completely as practical the nature and/or causality of the AE/SAE. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
All non-serious AEs that are ongoing at the Final Visit will be marked as ongoing on the AE 
eCRF page in the REDCap database. 


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All SAEs that are ongoing at the Final Visit must be followed until resolution, until the 
condition stabilizes, until the event is, in the opinion of the Investigator, stabilized or 
determined to be chronic, or until the participant dies or is lost to follow-up. SAEs that occur 
after the Final Visit, that are thought to be related to the administration of OBP-301, should be 
reported to Oncolys BioPharma Inc. or designee. 
If a participant is withdrawn because of an AE, the Investigator must arrange for the participant 
to have appropriate follow-up care until the AE is resolved or has stabilized. Unresolved AEs 
will be followed until the last scheduled follow-up visit or until the Investigator and Medical 
Monitor determine that further follow-up is no longer indicated. Oncolys BioPharma Inc. may 
request that the Investigator perform or arrange for the conduct of supplemental measurements 
and/or evaluations. If a participant dies during participation in the study or during a recognized 
Follow-up Period, Oncolys BioPharma Inc. should be provided with a copy of any post-mortem 
findings, including histopathology. 
7.2.4 Reporting of SAE to IRB 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy,. 
For WCM investigator-initiated studies, the following reporting guidelines apply: 
a. A Mandatory MedWatch Form 3500A must be completed and sent to the FDA. Specific 
instructions on how to complete the MedWatch Form 3500A can be found on the FDA 
website. 
b. If the protocol requires SAEs to be reported to an outside agency (i.e., to the supplier of the 
study drug), specific instructions will be stated in the protocol. 
c. If the study utilizes the WCM Data and Safety Monitoring Board (DSMB), a narrative of 
the event will be submitted to the Regulatory Coordinator on a modified SAE cover sheet. 
The completed form serves as acknowledgement of the SAE’s occurrence and will be used to 
complete the DSMB periodic report. A copy should be filed in the regulatory binder. 
d. For multicenter studies, the multicenter core within the Quality Assurance Unit (QAU) will 
distribute the IND Safety Report 
7.2.5 Notification of Serious Adverse Event to Oncolys 
An SAE must be reported by the Investigator within 24 hours of discovery if it occurs during 
the clinical study or within 28 days of receiving the IP, whether or not the SAE is considered 
to be related to the IP. An SAE report consists of the SAE form, the AE form, and the 
concomitant medication form. A copy of these forms must be e-mailed to the attention within 
24 hours of discovery: 
E-mail: safety@oncolys.com 
Please note: If the SAE can be categorized into one or more of the “Outcomes Attributed to 
the Adverse Event” outlined on the Mandatory Medwatch form 3500, the form and SAE 
Cover Sheet will be submitted to WCM Quality Assurance Unit (QAU) within 24 hours of PI 
notification. 
The primary site will submit the Mandatory Medwatch form 3500 to Oncolys, Inc within 72 
hours of receiving the form and to the FDA as specified by FDA guidelines. 


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The Investigator should not wait to receive additional information to document fully the event 
before notification of a SAE, though additional information may be requested. Where 
applicable, information from relevant laboratory results, hospital case records, and autopsy 
reports should be obtained. 
Instances of death, congenital abnormality, or an event that is of such clinical concern as to 
influence the overall assessment of safety, if brought to the attention of the Investigator at any 
time after cessation of IP administration and linked by the Investigator to this study, should be 
reported to. 
All SAEs must be reported to the investigational site’s IEC/IRB by the Investigator in 
accordance with their regulations. 
Reporting of any SAEs to applicable regulatory authorities will be the responsibility of Oncolys 
BioPharma Inc. in compliance with local regulations. 
Details of the procedures to be followed if a pregnancy occurs are provided in Section7.2.7. 
7.2.6 Notification of Suspected Unexpected Adverse Reactions 
An unexpected adverse reaction is any untoward and unintended response that is related to the 
administration of the IP at any concentration that is not consistent with the applicable version 
of the Investigator’s Brochure 33. 
All suspected unexpected serious adverse reactions (SUSARs) will be the subject of expedited 
reporting in accordance with local requirements. All Investigators should follow-up SUSARs 
until the event is resolved or until, in the opinion of the Investigator, the event is stabilized or 
determined to be chronic. Post study SAEs that are deemed to be related to IP that occur after 
the patient has completed the clinical study must be reported by the Investigator to Oncolys 
BioPharma Inc. 
7.2.7 Notification of Pregnancies 
All pregnancies in female patients and female partners of male patients receiving IP will be 
recorded from treatment until 90 days after the patient has completed therapy. 
Should a patient or male patient’s partner become pregnant or suspect she is pregnant while 
participating in this study, or in the 90 days following when the patient received the last 
injection of IP, the treating Investigator should be informed immediately. All pregnancies will 
be reported on a pregnancy report form and submitted to safety along the same timelines as an 
SAE. 
The IEC/IRB and Oncolys BioPharma Inc. will be informed. The patient will be asked to 
provide information on the outcome of the pregnancy, including premature termination should 
the case arise. For pregnancies in a female partner of a male patient consent to follow-up on 
the pregnancy will be obtained in agreement with the US Health Insurance Portability and 
Accountability Act (HIPAA) and other local laws and regulations as outlined in Section. 
Pregnancy outcomes will be reported on a pregnancy follow-up report form. 
Spontaneous miscarriage and congenital abnormalities will be reported as SAEs The 
Follow-up Period for any and all pregnancies will be deemed to have ended when the health 
status of the child has been determined on its birth and followed up for 8 weeks after the birth 
for any potential abnormalities. 


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Full details will be recorded on the withdrawal page of the eCRF. 
7.3 
Multicenter Study Monitoring 
The study will be monitored by the Weill Cornell Multicenter Study group, according to the 
Clinical Trial Monitoring Plan, which addresses site qualification, regulatory documentation, 
and site monitoring and auditing. 
8 
STATISTICAL ANALYSES 
8.1 
General Considerations 
Full details of the statistical analysis will be provided in a statistical analysis plan (SAP). Any 
changes to the planned statistical methods from the SAP will be documented in the clinical 
study report (CSR). The statistical evaluation will be performed using SAS®, version 9.4 or 
later. 
All data will be presented in listings, ordered by patient, unless otherwise specified. 
Descriptive statistics for continuous variables (number of patients [n], number of patients with 
missing data, mean, standard deviation, minimum and maximum) and categorical data (n, 
percent, number of patients with missing data, by category) will be presented. 
8.2 
Definitions for Statistical Data Analysis 
The following definitions were used in the assessments of safety and efficacy. 
All patients who receive at least one injection of OBP-301 will be included in the Safety 
Population and are analysed according to the actual treatment received. Any patient that has 
at least one radiographic assessment for response will be included in the Efficacy Population. 
8.3 
Handling of Missing Values and of Values outside the Detection Limits 
Missing values will not be imputed. All missing values will be reported in the listings as either 
“missing” or as the justification for the value being missing (e.g., “ND” [test not done] or 
“BQL” [below quantitation limit], where appropriate. 
While efforts will be made to avoid incomplete or missing data, in rare cases the AE date could 
be incomplete or missing. If this happens, incomplete or missing dates will be imputed. For 
the calculation of AE duration and AE onset from dosing, missing AE dates will be imputed 
using a conservative approach. This approach will assume that the AE is treatment emergent 
where insufficient date information exists to determine if the AE occurred before or after 
dosing, except where year is missing. If the year is also missing then it will be assumed that 
the start is before the start of the study. 
Imputed onset dates of AEs will be checked to ensure they occur after the first study day and 
before the resolution date. Imputed resolution dates will be checked to ensure they occur after 
the onset date and before date of last study visit (where AE is not flagged as ongoing). 
Descriptive statistics for demographics, body weight, vital signs, and ECG data will be 
calculated from actual data only, with the number of actual data points used for the calculation 
of the summary statistics reported. 


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For censored safety lab data (i.e., hematology, clinical chemistry and urinalysis results that are 
outside the limit of quantification) the actual values reported by the laboratory (e.g., “< 2” for 
bilirubin) will be presented in the data listings. For the calculation of summary statistics, safety 
laboratory data values below the lower limit of quantification (LLOQ) will be set to ½ the 
LLOQ. 
8.3.1 Data Collection 
The data collection plan for this study is to utilize REDCap to capture treatment, 
toxicity, efficacy, and adverse event data for all enrolled patients. 
8.3.2 REDCap 
REDCap (Research Electronic Data Capture) is a free data management software 
system that is fully supported by the Weill Cornell Medical Center CTSC. It is a 
tool for the creation of customized, secure data management systems that include 
Web-based data-entry forms, reporting tools, and a full array of security features 
including user and group based privileges, authentication using institution LDAP 
system, with a full audit trail of data manipulation and export procedures. 
REDCap is maintained on CTSC-owned servers that are backed up nightly and 
support encrypted (SSL-based) connections. Nationally, the software is 
developed, enhanced and supported through a multi-institutional consortium led 
by the Vanderbilt University CTSA. 
8.4 
Analysis Populations 
8.4.1 Safety Population 
All patients who receive at least one injection of OBP-301 will be included in the Safety 
Population and are analysed according to the actual treatment received. 
8.4.2 Evaluable Population 
Any patient that has at least one radiographic assessment for response will be included in the 
Efficacy Population. Imaging studies preferably CT scan of the chest/abdomen/pelvis will be 
performed every 9 weeks as per the study schedule. Patients will be evaluated according to 
RECIST v1.1 criteria. Definitions of response evaluation are detailed in section 6.6 for 
further explanation. Only those patients whose response can be measured according to 
RECIST v1.1 will be included in this population. 
 
8.4.3 Intent-to-Treat (ITT) Population 
All patients who are enrolled and allocated to treatment are included in the intent-to-treat 
population analysis. 
8.4.4 Per-Protocol (PP) Population 
Per-Protocol population will only include individuals who completed all four doses of OBP- 
301 and followed the study protocol 


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8.5 
Efficacy Analysis 
8.5.1 Primary Efficacy Endpoint 
The primary efficacy endpoint will be the objective response rate (RR), as measured by 
RECIST 1.1 criteria. 
Objective response rate is defined as the sum of partial responses plus complete responses as 
defined by RECIST v1.1 criteria. 
8.5.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the disease control rate, duration of response, 
progression-free survival (PFS), and overall survival (OS). 
Duration of response is defined as the duration that subjects who have responded to 
combination therapy remain without disease progression. 
Disease control rate is defined as the percentage of patients who have achieved complete 
response, partial response and stable disease. 
Progression-free survival (PFS) is defined as time from registration to progression or death 
due to any cause. Progression is defined as radiologic progression of disease by RECIST v1.1 
criteria. 
Overall survival (OS) is defined as the time from registration until death from any cause, 
8.5.3 Exploratory Analysis 
Correlative endpoints include the following: 
• To examine the tumor-immune microenvironment prior to and following OBP-301 and 
pembrolizumab therapy as assessed by bulk RNA sequencing and single-cell RNA sequencing. 
• To examine and characterize the immune infiltrate by multi-parameter flow cytometry. 
8.5.4 Methods for Analysis 
Endpoints involving response rates will be analysed by tabulating the response rates along with 
95% confidence interval and number of patients with data for each time point that the endpoint 
is collected. Waterfall plots for tumor response (CR, PR, and ORR) will be provided. 
Endpoints involving time to event or time to response will be analysed using survival analysis, 
including Kaplan-Meier plots. Median survival time with 95% confidence interval, 25th-75th 
percentiles will be provided. 
Exploratory subgroup analyses for tumor response will be defined in the statistical analysis 
plan (SAP). 
8.6 
Correlative Study 
All patients undergoing treatment with OBP-301 will have tissue biopsies along with 
correlative blood samples. Tissue biopsies will be performed with every injection of OBP-301. 
Correlative blood samples will be taken before the start of study treatment, during treatment 
and post-treatment as described in the section of study schedule. Correlative studies are focused 
on a detailed and comprehensive evaluation of the tumor immune microenvironment as it 


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relates to induction of the anti-tumor immune response. Specific procurement and shipping 
instructions will be provided to participating sites upon study activation. Our specific 
correlative studies include the following: 
A) To examine the tumor-immune microenvironment prior to and following OBP-301 
and pembrolizumab therapy as assessed by bulk RNA sequencing and single-cell RNA 
sequencing. 
The focus in this application is to perform detailed cellular characterization of gastric and GEJ 
tumors and their microbial environment towards better understanding of the factors that shape 
the response to immunotherapies and mechanism of resistance. To address this, we propose to 
perform single cell expression analysis and microbiome profiling of tissue samples collected 
from patients with esophageal/gastric tumors. 
We hypothesize that surveying the immune infiltration in the context of immunotherapy and 
OBP-301 will provide important biomarker for response to treatment. To address this, we 
propose the following studies: Sub-aim (1) Identify and quantify the cellular composition of 
tumor and adjacent normal tissues from esophageal and gastric cancer patients. Single cell 
profiling will be performed on each sample collected from patient recruited to the study at 
Weill Cornell and microbiome detection by whole genome sequencing at baseline (prior to 
treatment). Sub-aim (2) Generate a patient-specific profile of tumor microenvironment. In this 
aim the data collected in Aim1 will be analyzed to identify the cell types that are present in 
each patient at onset of treatment and how cellular composition changes in response to 
treatment. By computational approaches we will cluster the cells from each sample by their 
expression profile to distinct groups representing specific cell types (e.g. mucosa layer, 
lymphocytes, CD45+, squamous epithelium). Similarly, we will identify various immune cells 
such as CD8+ and CD4+, effector T cells, TRregR and others immune subtypes and correlate with 
microbiome composition. In addition, we will survey levels of PD-1, PD-L1/2, CD28 and other 
known marker of checkpoint inhibitor response. Sub-aim (3) Longitudinal profiling of patients 
before and after immunotherapy + OBP-301 to identify possible biomarkers for response and 
mechanism of resistance. In this aim we will summarize the results from all patient data to 
assess what are the consistent changes observed in cellular composition in response to 
immunotherapy and we will investigate how these changes impact response to treatment. 
B) To examine the T-cell response in responding and resistant individuals by TCR- 
sequencing on pre- and post- treatment tumor biopsies. 
The primary aim of this proposal is to overcome inherent resistance to immunotherapy in 
foregut tumors with the addition of a replication-selective oncolytic virus. This project will be 
focused on analyzing the immune landscape of individual tumors from tumor biopsies taken at 
baseline and on therapy. We will analyze changes associated with relapse and differences 
between refractory and sensitive patients. Our proposed analysis will take as input somatic 
mutations, raw WES reads, and raw RNA-Seq reads. In addition we will perform direct TCR- 
seq. We will run our existing pipeline for neoepitope prediction, expression, and TCRseq 
analysis. The output will be an immune landscape per tumor, including (1) mutation burden 
and high-affinity predicted neoepitopes, (2) checkpoint expression and immune composition, 
and (3) TCR-seq estimated profiles together with infiltration and diversity values. 
Comprehensive analysis of entire cohorts will reveal tumor type specific patterns such as 
correlation specific mutations and immune infiltration and repertoires as well as over- 
representation of specific T cell clones and signature of neoepitope burden. 


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For sub-aim (1) we will perform whole exome sequencing via the Englander Institute pipeline 
and apply state of the art neoantigen discovery tools. We will validate high affinity neoantigens 
using in vitro assay involving synthetic peptides and a patient’s own T cell where we measure 
T cell clonal expansion using TCR-seq from Archer DX (test already available in Weill 
Cornell’s genomics core). We will explore evolution of neoantigen in relapse biopsies. For sub- 
aim (2), we will perform RNAseq and TCR-seq using ArcherDX, then deconvolute using 
Cibersort and another in-house approach that takes into account lineage relationship between 
reference cell types. As needed we will perform single cell RNAseq to obtain orthogonal 
validation data. We will correlate immune cell type abundance and TCR repertoires with 
clinical outcomes. In sub-aim (3) we will develop an immunoscore that uses features defined 
by immune landscape analysis to build a predictive model of who will respond to 
immunotherapy. We will pre-train the model using genome profiling results from two recent 
studies of melanoma datasets treated with anti CTLA4 antibodies, then fine tune via transfer 
learning using the data from the trials. A variety of machine learning models such as logistic 
regression, random forest and deep learning will be tested and evaluated using cross-validation. 
We note that we have extensive experience building such models and that machine learning 
models we built have shown clinical value. We will determine how the immunoscore correlates 
with clinical outcome such as progression free survival (PFS) in prospective future trials. We 
will evaluate the immunoediting patterns of these cohorts, that is, identify variants whose 
presence is inversely correlated with T cell infiltration. The results will be presented as 
heatmaps and tables. 
C) 
To examine and characterize the immune infiltrate by multi-parameter flow- 
cytometry. 
In this application, innovative multi-parameter flow cytometry will be utilized that will provide 
single-cell high resolution of immune cell suppression or activation. Our collaborator, Dr. 
Gregory Sonnenberg has developed technologies to cryopreserve viable immune cells from 
primary human tissues and tumor biopsies or resections for side-by-side analyses of immune 
cells from multiple patients, thus reducing sample variation and allowing direct single-cell 
comparisons of cytokine production. This powerful approach will be utilized to characterize 
tumor immune cell infiltrates at baseline, following the induction of combination therapy and 
at the time of resection. This will be one of the first longitudinal analyses of tumor immune 
cell infiltrates by multi-parameter flow cytometry following immunotherapy. 
8.7 
Safety Analyses 
8.7.1 Safety Endpoints 
The primary safety endpoint is to examine the safety of multiple OBP-301 intratumoral 
injections in combination with pembrolizumab in advanced esophagogastric cancer. 
8.7.2 Summary of Adverse Events 
All adverse events, as defined in Section 7, will be recorded for each patient. Adverse events 
will be tabulated for all patients by: first occurrence of each adverse event, maximum severity, 
and relationship to treatment. Treatment-related AEs and serious AEs will be tabulated 
separately, by first occurrence, maximum severity, and strongest relationship to treatment. A 
listing of all AEs will also be included, per patient, including onset/resolution date, severity, 
relationship to study treatment, and action regarding IP. A listing of all discontinuations, 
injection delays, and deaths due to adverse events in the study will be included. 


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8.7.3 Summary of Laboratory Assessments 
Summary statistics will be presented for all blood chemistry, hematology, coagulation, and 
urinalysis results by study visit, where data are collected. 
In addition, all laboratory values will be flagged as low (L1, L2, L3, or L4), high (H1, H2, H3, 
or H4) or normal (N) based on the investigational site laboratory normal range and/or the NCI 
toxicity criteria. Shifts in assessments from baseline to all post-baseline visits will be presented 
(shift tables). 
8.7.4 Summary of Special Laboratory Assessments 
Summary statistics and shift tables will be presented for all special laboratories results 
including cytokines, and immune cell phenotypes by study visit, where data are collected. 
8.7.5 Summary of Vital Signs 
Summary statistics will be presented for all vital signs including temperature, blood pressure 
(systolic and diastolic), pulse, respiration rate, and body weight by study visit, where data are 
collected. Graphs of vital signs at each visit may also be provided. 
8.7.6 Summary of Physical Examinations 
The physical examination results will be evaluated by shift tables that compare baseline 
examination results to other study visit results in each exam. Frequency counts and percentages 
will be displayed. All abnormal results will be provided in a listing with a description of the 
abnormality. 
8.7.7 
Summary of ECG Measurements 
The results of the ECG will be evaluated by transition tables that compare Screening exam 
results to Final Visit results. Frequency counts and percentages will be displayed. All 
abnormal results will be provided in a listing with a description of the abnormality. 
8.7.8 Concomitant Medications 
Concomitant medications will be tabulated for all patients by: the first occurrence of 
medication classes, the first occurrence of concomitant medications, and all concomitant 
medications. A listing of all concomitant medications will also be provided. 
8.7.9 Adverse Event Stopping Rule 
The stopping rule specified below is based on the knowledge available at study development. 
We note that the Adverse Event Stopping Rule may be adjusted in the event of either (1) the 
study re-opening to accrual or (2) at any time during the conduct of the trial and in consideration 
of newly acquired information regarding the adverse event profile of the treatment(s) under 
investigation. The study team may choose to suspend accrual because of unexpected adverse 
event profiles that have not crossed the specified rule below. 
Accrual will be temporarily suspended to the study to allow for a full review of data 
according to the following AE stopping rule: 


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• If at any time more than 3 of the first 12 patients enrolled (or > 33% of all 
patients enrolled after 12 patients) have experience at least one grade 3 or worse 
immune related adverse event or adverse event related (possibly, probably, or 
definitely) to OBP-301 injection. 
o Immune related adverse events for the purposes of this adverse event 
stopping rule, will include diarrhea/colitis, pneumonitis, renal 
failure/nephritis, or increased LFTS (bilirubin, AST, ALT). Rash, joint 
aches, fatigue, thyroid abnormalities, or other immune related events 
that are not life threatening will not be included for the purposes of this 
Adverse Event Stopping Rule. 
• If grade 5 (death) event at least possibly, probably or definitely related to OBP- 
301 injection, the study will be halted. 
• If 3 or more grade 4 adverse events that are possibly, probably, or definitely 
attributed to OBP-301 occur, that do not resolve back to grade 1 within 30 days, 
the study will be halted. 
 
8.8 
Determination of Sample Size 
Sample size is determined according to Simon’s two-stage Minimax design. We project a RR 
of 15% (historical RR for pembrolizumab alone), below which the combination regimen will 
be unacceptable, and a RR of 30% (expected RR rate for OBP-301 + pembrolizumab), above 
which the combination regimen will be considered worthy of further exploration. The null 
hypothesis that the RR is less than or equal to 15% will be tested against the alternative 
hypothesis that the RR is greater than or equal to 30%. 
The sample size computations were performed assuming a 10% level of significance and 80% 
power. If 2 or fewer patients respond out of the first 18 evaluable patients, the study arm will 
be terminated and declared to have a negative result. If 3 or more patients respond out of the 
first 18 evaluable patients, enrollment will be extended to 37 patients. The treatment will be 
declared effective and worthy of further testing if 9 or more patients respond among the 37 
patients entered. This two-stage design yields a ≥ 0.80 probability of a positive result if the 
true RR is ≥ 30%. It yields a ≥ 0.90 probability of a negative result if the true RR is ≤ 15%. A 
95% confidence interval constructed around the expected RR of 30% can be estimated to be 
within ± 14.8% of the observed RR proportion. Assuming 10% are unevaluable/ineligible, we 
anticipate that a total of 41 patients will be enrolled in the study (assuming the study proceeds 
to the second stage). 
9 
REGULATORY REQUIREMENTS 
9.1 
Regulatory Approvals 
Once protocol amendments or consent form modifications are implemented at the lead site, 
Weill Cornell Medicine, updated documents will be provided to participating sites. Weill 
Cornell Medicine must approve all consent form changes prior to local IRB submission. 
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and approval 
before the beginning of the study. On completion of the study, the regulatory authorities will 
be notified that the study has ended. 


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As required by local regulations, the Investigator will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, before study initiation. 
9.2 
Institutional Review Board/Ethics Committee Approval 
Before initiation of the study at each study center, the protocol, the ICF, other written material 
given to the patients, and any other relevant study documentation will be submitted to the 
appropriate Ethics Committee. Written approval of the study and all relevant study information 
must be obtained before the study center can be initiated or the IP is released to the Investigator. 
Any necessary extensions or renewals of IEC/IRB approval must be obtained for changes to 
the study, such as amendments to the protocol, the ICF, or other study documentation. The 
written approval of the IEC/IRB together with the approved ICF must be filed in the study files. 
The Investigator will report promptly to the IEC/IRB any new information that may adversely 
affect the safety of the patients or the conduct of the study. The Investigator will submit written 
summaries of the study status to the IEC/IRB as required. On completion of the study, the 
IEC/IRB will be notified that the study has ended. 
Neither the Investigator nor Oncolys BioPharma Inc. will modify or alter this protocol without 
the agreement of the other. All agreed protocol amendments will be clearly recorded on a 
protocol amendment form and will be signed and dated by the original protocol approving 
signatories. All protocol amendments will be submitted to the relevant institutional IEC/IRB 
for approval before implementation, as required by local regulations. The only exception will 
be when the amendment is necessary to eliminate an immediate hazard to the trial participants. 
In this case, the necessary action will be taken first, with the relevant protocol amendment 
following shortly thereafter. 
9.3 
Ethical Conduct of the Study 
The Investigators and all parties involved should conduct this study in adherence to the ethical 
principles based on the Declaration of Helsinki, GCP, ICH guidelines and the applicable 
national and local laws and regulatory requirements. 
This study will be conducted under a protocol reviewed and approved by the applicable ethics 
committees and investigations will be undertaken by scientifically and medically qualified 
persons, where the benefits of the study are in proportion to the risks. 
9.4 
Participant Informed Consent 
The Investigator is responsible for ensuring that no subject undergoes any study-related 
examination or activity before that subject has given written informed consent to participate in 
the study. 
It is the Investigator's responsibility to ensure that each participant gives informed consent to 
participate in the study. The Investigator will explain the nature of the study, its purpose, 
procedures, expected duration, and the potential benefits, risks and inconveniences in 
participation. In addition, a participant information sheet/consent form containing relevant 
information will be prepared by Oncolys BioPharma Inc. in conjunction with the 
investigational site and will be provided to all participants. 
Participants must be informed that their participation is voluntary and that they have the right 
to withdraw from the study at any time without prejudice. 


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The participants will be informed of their rights to privacy but will be made aware that the 
study data will be submitted to Oncolys BioPharma Inc. and possibly to drug regulatory 
authorities for review and evaluation. They will be informed also that the study monitor may 
inspect their medical records to verify the accuracy and completeness of the study records and 
results. 
The ICF will contain a separate section that addresses the use of remaining blood and tissue 
samples for future research. Participants will be informed that they are free to refuse to these 
additional tests being carried out and may request at any time for the samples to be destroyed. 
The participants will be given an opportunity to ask questions and allowed sufficient time to 
decide whether they wish to participate. If the participant decides to participate in the study, 
they will voluntarily sign the written ICF. 
The acquisition of informed consent should be documented in the participant’s medical records, 
and should meet the requirements of GCP. The ICF will be signed and personally dated by the 
participant and by the person who conducted the informed consent discussion (not necessarily 
an Investigator). The original signed ICF will be retained in accordance with institutional 
policy, and a copy of the signed consent form will be provided to the participant or legal 
representative. The date that informed consent was signed will be recorded on the eCRF. 
If new information becomes available that may be relevant to the patient’s willingness to 
continue participation in the study, the ICF will be updated and approved by the IEC(s)/IRB(s) 
(and regulatory authorities, if required). The study participants will be informed about this new 
information and reconsent will be obtained. 
Participants who are rescreened are required to sign a new ICF. 
9.5 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to http://www.clinicaltrials.gov. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information. 
10 DATA AND SAFETY MONITORING PLAN (DSMP) 
The study will be reviewed by the Weill Cornell Medical College Data and Safety Monitoring 
Board (DSMB) as an independent means of data and safety monitoring. Enrollment 
information, adverse event and safety information, protocol changes, and other interim data 
will be evaluated by the DSMB. After each evaluation, the Board will provide the principal 
investigator with recommendations for protocol modification, continuation, or termination. 
 
DSMB reports will be made to the DSMB every 6 months. 


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11 ADMINISTRATIVE PROCEDURES 
11.1 Financing, Liability/Indemnity/Insurance 
Investigators are required to follow financial disclosure policies at their respective institutions. 
Any investigator with a conflict of interest with this study must report the conflict to the 
Sponsor-investigator. 
The study contract will govern all provisions relating to liability, indemnity and insurance. 
11.2 Recording of Data and Retention of Records 
Essential documents are those documents that individually and collectively permit evaluation 
of the study and quality of the data produced. After completion of the study (end of study 
defined as the date of the last follow-up contact at Week 48 with the last patient), all documents 
and data relating to the study will be kept in an orderly manner by the Investigator in a secure 
study file. Essential documents should be retained for 2 years after the final marketing approval 
in an ICH region or for at least 2 years since the discontinuation of clinical development of the 
IP. In addition, all patient medical records and other source documentation will be kept for the 
maximum time permitted by the hospital, institution, or medical practice. 
11.2.1 REDCap 
REDCap (Research Electronic Data Capture) is a free data management software system that 
is fully supported by the Weill Cornell Medical Center CTSC. It is a tool for the creation of 
customized, secure data management systems that include Web-based data-entry forms, 
reporting tools, and a full array of security features including user and group based privileges, 
authentication using institution LDAP system, with a full audit trail of data manipulation and 
export procedures. REDCap is maintained on CTSC-owned servers that are backed up nightly 
and support encrypted (SSL-based) connections. Nationally, the software is developed, 
enhanced and supported through a multi-institutional consortium led by the Vanderbilt 
University CTSA. 
11.3 Retention of Records 
Essential documents are those documents that individually and collectively permit evaluation 
of the study and quality of the data produced. After completion of the study (end of study 
defined as the date of the last follow-up contact at Week 48 with the last patient), all documents 
and data relating to the study will be kept in an orderly manner by the Investigator in a secure 
study file. Essential documents should be retained for 2 years after the final marketing approval 
in an ICH region or for at least 2 years since the discontinuation of clinical development of the 
IP. In addition, all patient medical records and other source documentation will be kept for the 
maximum time permitted by the hospital, institution, or medical practice. 
11.4 Disclosure and Data Confidentiality 
The Investigator must ensure that the participant’s anonymity is maintained. Participants 
should only be identified by their initials and a participant identification number on the eCRFs 
and other source documents. Other study-related documents (e.g., signed ICFs) should be kept 
in strict confidence by the Investigator. 


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Data is captured using database REDCap. Participants will be informed that data will be held 
on file by Oncolys BioPharma Inc. and that these data may be viewed by staff including the 
study monitor and by external auditors on behalf of Oncolys BioPharma Inc. and appropriate 
regulatory authorities. Participants will also be informed that a study report will be prepared 
and may be submitted to regulatory authorities and for publication. However, participants will 
be identified in such reports only by study identification number, gender, and age. All 
participant data will be held in strict confidence. 
Auditors, the IEC(s)/IRB(s) approving this research, and the US FDA, as well as that of any 
other applicable agency(ies), will be granted direct access to the study patients’ original 
medical records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the patients to the extent permitted by the law and regulations. In any 
presentations of the results of this study or in publications, the patients’ identity will remain 
confidential. 
All personal data collected and processed for the purposes of this study should be managed by 
the Investigator and his/her staff with adequate precautions to ensure confidentiality of those 
data, and in accordance with the HIPAA 37, applicable to national and/or local laws and 
regulations on personal data protection. 
11.5 Publication of Results 
Study results will be reported at appropriate international congresses and meetings as data are 
available, and the final study will be reported in a peer-reviewed oncology journal. 
12 CLINICAL STUDY REPORT 
We will provide the clinical study report within 1 year of study completion. 
13 APPENDIX 
13.1 ECOG performance status 
 
Performance 
Status 
Definition 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work. 
2 
Ambulatory and capable of self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours. 
3 
Capable of limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair. 


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13.2 Comparison of RECIST 1.1 and iRECIST 
 
RECIST 1.1 
iRECIST 
Definitions of 
measurable and 
non-measurable 
disease; numbers 
and site of target 
disease 
Measurable lesions are ≥10 
mm in diameter (≥15 mm for 
nodal lesions); maximum of 
five lesions (two per organ); 
all other disease is considered 
non-target (must be ≥10 mm 
in short axis for nodal 
disease) 
No change from RECIST 1.1; 
however, new lesions are assessed 
as per RECIST 1.1 but are recorded 
separately on the case report form 
(but not included in the sum of 
lesions for target lesions identified at 
baseline) 
Complete 
response, partial 
response, or stable 
disease 
Cannot have met criteria for 
progression before complete 
response, partial response, or 
stable disease 
Can have had iUPD (one or more 
instances), but not iCPD, before 
iCR, iPR, or iSD 
Confirmation of 
complete response 
or partial response 
Only required for non- 
randomised trials 
As per RECIST 1.1 
Confirmation of 
stable disease 
Not required 
As per RECIST 1.1 
New lesions 
Result in progression; 
recorded but not measured 
Results in iUPD but iCPD is only 
assigned on the basis of this 
category if at next assessment 
additional new lesions appear or an 
increase in size of new lesions is 
seen (≥5 mm for sum of new lesion 
target or any increase in new lesion 
non-target); the appearance of new 
lesions when none have previously 
been recorded, can also confirm 
iCPD 
Independent 
blinded review and 
central collection 
of scans 
Recommended in some 
circumstances—eg, in some 
trials with progression-based 
endpoints planned for 
marketing approval 
Collection of scans (but not 
independent review) recommended 
for all trials 
Confirmation of 
progression 
Not required (unless 
equivocal) 
Required 


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Consideration of 
clinical status 
Not included in assessment 
Clinical stability is considered when 
deciding whether treatment is 
continued after iUPD 
“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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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