Conditions: Head and Neck Squamous Cell Carcinoma With Inoperable Recurrent or Progressive Disease
Keywords: Head and Neck Recurrent Cure Unresectable Immunotherapy Oncolytic Virus SBRT Intratumoral injection
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
The purpose of this study is to test the effects, of the research study drug Telomelysin (OBP-301) in combination with pembrolizumab in subjects with inoperable, recurrent, or progressive squamous cell carcinoma of the head and neck. Telomelysin is an investigational treatment, while pembrolizumab and SBRT are approved standard treatments. The combination of these three treatments is also considered investigational.

Detailed description:
This is a phase II open label single arm study of OBP-301 in combination with pembrolizumab and SBRT in advanced HNSCC which is either recurrent and inoperable, or progressing after prior radiation with curative-intent for advanced disease (adjuvant or definitive with or without chemotherapy or cetuximab).

The efficacy of pembrolizumab monotherapy is modest in second or third line of treatment of advanced head and neck cancer (\~response rate 16-22%). SBRT reirradiation in patients that received prior surgery and chemoradiation for advanced disease is associated with a response rate (RR) of approximately 60% and approximately 50% 1-year survival. Recently, the results of the Keynote-048 study were published. The projected 1-year survival in the immunotherapy arms with pembrolizumab alone or pembrolizumab and chemotherapy was approximately 57%. So, at present, the benchmark RR for patients with head and neck squamous cell carcinoma with inoperable, recurrent or progressive disease treated with SBRT is approximately 60% and the 1 year survival for patients with head and neck squamous cell carcinoma (HNSCC) with inoperable, recurrent or progressive disease using the most effective contemporary treatments including immunotherapy is approximately 50-57%. Trying to improve the results of the current standard of care, this study will examine the effects of oncolytic virus, OBP-301, administered in addition to pembrolizumab and SBRT in this patient population. The goal of using this triple therapeutic combination is to enhance the chances of cure of the patients.

A total of 36 patients will be enrolled into a two-stage parallel cohort design: In the first stage, 12 patients will be enrolled.

All patients will receive intratumoral injection(s) with OBP-301. If tolerated and no progression is observed, up to twelve injections may be given in each patient.

If the targeted injected lesion(s) disappear, another lesion can be injected at the Investigator's discretion.

A minimum additional 3 doses of concurrent OBP-301 and pembrolizumab will be given if no toxicity, technical impediment to injection or progression is seen.

A maximum total of up to 9 doses of concurrent OBP-301 and pembrolizumab will be given.

Pembrolizumab alone will be continued after day 183 for a total treatment time up to 1 year.

Arms:
arm 1: All patients will receive intratumoral injection(s) with OBP-301. If tolerated and no progression is observed, up to twelve injections may be given in each patient.

Interventions: intervention 1: OBP-301 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Telomerase-specific Type 5 Adenovirus. OBP-301 OBP 301 will be injected intratumorally into tumor lesions. intervention 2: Standard dose pembrolizumab 200 mg IV every 3 weeks for up to one year

Protocol document:
Prot_SAP_000.pdf: 
                                    
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TITLE:   
Phase 2 study of OBP-301 (Telomelysin ™) in combination with Pembrolizumab and 
stereotactic body irradiation in patients with head and neck squamous cell carcinoma 
with inoperable, recurrent or progressive disease 
 
IRB Protocol #:  19-12021148 
IND #: 26377 
Version 3, Date:  5/7/21 
 
Principal Investigators:  
 
Doru Paul, MD, PhD 
 
 
Weill Cornell Medical Center 
 
 
1305 York Avenue, 12th Floor 
 
 
New York, NY 10021 
 
 
Phone 646-962-6200 
 
 
Fax 646-962-1607 
 
      dop9054@med.cornell.edu 
 
 
 
 
 
 
Statistician: 
                                 
                                                      Paul Christos, PhD, Healthcare Pol & Res                
                                                      Director of the Research Design and  
  
                                                      Biostatistics Core                                                         
 
                                                      402 E 67th St, Rm 234 
 
                                                      646-962-8018  
 
                                                      pac2001@med.cornell.edu   
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                    
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Participating Sites:  List all participating sites (include site name, PI, and contact 
information).  
Principal Investigator(s) 
Academic Center(s)  
Doru Paul 
Weill Cornell Medical College 
 
Maged Ghaly 
Northwell Health 
Doug Adkins 
Washington University 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.) 


                                    
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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. .  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
1 
STUDY SYNOPSIS ............................................................................................... 13 
2 
STUDY SCHEMA ................................................................................................. 21 


                                    
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3 
BACKGROUND .................................................................................................... 22 
1.1 The rationale for using a triple therapy combination in head and neck cancer ................. 22 
1.4.1 Non-Clinical Studies ....................................................................................................... 30 
1.4.2 Clinical Studies ....................................................................................................... 32 
3.5 
Summary of Potential Risks and Benefits ................................................................. 35 
3.6 
Dosage and Treatment Periods .................................................................................. 36 
3.7 
Patient Population ..................................................................................................... 36 
4 
OBJECTIVES ......................................................................................................... 37 
5 
STUDY DESIGN ................................................................................................... 37 
5.1 
Study Overview ......................................................................................................... 37 
6 
STUDY POPULATION ......................................................................................... 39 
6.1 
Selection of Study Population ................................................................................... 39 
6.2 
Inclusion Criteria ....................................................................................................... 39 
6.3 
Exclusion criteria....................................................................................................... 41 
 
6.3.1 Patient Registration – Part 1 (WCMC Only) ................................................... 42 
 
6.3.2 Patient Registration – Part 2 (All Sites) ........................................................... 42 
6.4 
Stopping Criteria ....................................................................................................... 42 
6.4.1 
Patient Withdrawal Criteria ................................................................................ 42 
6.4.2 
Termination or Suspension of the Study ............................................................ 43 
7 
STUDY TREATMENTS........................................................................................ 44 
7.1 
Investigational Product (IP) Identification ................................................................ 44 
7.2 
Dosage and Treatment ............................................................................................... 44 
7.3 
Investigational product .............................................................................................. 45 
5.3.1 Study Supplies OBP-301 ........................................................................................ 45 
7.3.2 
Selection and Timing and IT Administration for each Patient ........................... 47 
7.3.3 
Injection Procedures ........................................................................................... 48 
7.4 
Pembrolizumab.......................................................................................................... 51 
7.4.1 
General Concomitant Medication and Supportive Care Guidelines................... 53 
7.4.2 
Rescue Medications & Supportive Care ............................................................. 54 
7.5 
Radiation therapy ...................................................................................................... 58 
8 
STUDY PROCEDURES ........................................................................................ 62 
8.1 
Schedule of Events .................................................................................................... 63 
8.1.1 
Screening Visit ................................................................................................... 65 
8.1.2 
Treatment Phase ................................................................................................. 65 


                                    
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8.1.3 
Follow up Phase .................................................................................................. 65 
8.1.4 
Patient Withdrawal Criteria ................................................................................ 65 
8.2 
Informed Consent Form (see appendix) .................................................................... 67 
8.3 
Demographic Data and Baseline Characteristics ...................................................... 67 
8.4 
Medical History, Concomitant Disease, Previous and Ongoing Medications .......... 67 
8.5 
Safety Assessments ................................................................................................... 68 
8.5.1 
Adverse Events ................................................................................................... 68 
8.5.2 
Physical Examination ......................................................................................... 68 
8.5.3 
Vital Signs .......................................................................................................... 68 
8.5.4 
Electrocardiogram .............................................................................................. 68 
8.5.5 
Laboratory Assessments ..................................................................................... 69 
8.6 
Efficacy Assessments ................................................................................................ 70 
8.6.1 
Imaging Assessment for the Study ..................................................................... 70 
8.6.2 
Definitions of Measurable and Non-Measurable Disease .................................. 70 
8.6.3 
Response Criteria ................................................................................................ 70 
8.6.4 
Determination of Tumor Stage According to Tumor, Lymph Nodes, Metastasis 
(TNM) Classification .......................................................................................... 71 
8.7 
Biopsies and Immune Monitoring (optional) ............................................................ 72 
9 
ADVERSE EVENTS.............................................................................................. 72 
9.1 
Definitions ................................................................................................................. 72 
9.1.1 
Definition of an Adverse Event .......................................................................... 72 
9.1.2 
Severity of an Adverse Event ............................................................................. 73 
9.1.3 
Causal Relationship of an Adverse Event .......................................................... 73 
9.1.4 
Definition of a Serious Adverse Event ............................................................... 74 
9.1.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events and Serious Adverse Events ..................................................... 75 
9.2 
Documenting Adverse Events ................................................................................... 75 
9.2.1 
Recording of Adverse Events ............................................................................. 76 
9.2.2 
Reporting of AE to WCMC IRB ........................................................................ 76 
9.2.3 
Follow-up of Adverse Events and Serious Adverse Events ............................... 76 
9.2.4 
Reporting of SAE to IRB .................................................................................... 76 
d. For multicenter studies, the multicenter core within the Quality Assurance Unit 
(QAU) will distribute the IND Safety Report .................................................... 77 
9.2.5 
Notification of Serious Adverse Event to Oncolys ............................................ 77 
9.2.6 
Notification of Suspected Unexpected Adverse Reactions ................................ 78 


                                    
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9.2.7 
Notification of Pregnancies ................................................................................ 78 
9.3 
Multicenter Study Monitoring ................................................................................... 78 
10 
STATISTICAL ANALYSES ................................................................................. 78 
10.1 
General Considerations ............................................................................................. 78 
10.2 
Definitions for Statistical Data Analysis ................................................................... 79 
10.3 
Handling of Missing Values and of Values outside the Detection Limits ................ 79 
10.3.1 Data Collection ................................................................................................... 79 
10.3.2 REDCap .............................................................................................................. 79 
10.4 
Analysis Populations ................................................................................................. 79 
10.4.1 Safety Population ................................................................................................ 79 
10.4.2 Evaluable Population .......................................................................................... 80 
10.4.3 Intent-to-Treat (ITT) Population ........................................................................ 80 
10.4.4 Per-Protocol (PP) Population .............................................................................. 80 
10.5 
Efficacy Analysis ...................................................................................................... 80 
10.5.1 Primary Efficacy Endpoint ................................................................................. 80 
10.5.2 Secondary Efficacy Endpoints ............................................................................ 80 
10.5.3 Exploratory Analysis .......................................................................................... 81 
10.6 
Correlative Studies .................................................................................................... 81 
10.7 
Safety Analyses ......................................................................................................... 84 
10.7.1 Safety Endpoints ................................................................................................. 84 
10.7.2 Summary of Adverse Events .............................................................................. 84 
10.7.3 Summary of Laboratory Assessments ................................................................ 85 
10.7.4 Summary of Special Laboratory Assessments ................................................... 85 
10.7.5 Summary of Vital Signs ..................................................................................... 85 
10.7.6 Summary of Physical Examinations ................................................................... 85 
10.7.7 Summary of ECG Measurements ....................................................................... 85 
10.7.8 Concomitant Medications ................................................................................... 85 
10.7.9 Adverse Event Stopping Rule ............................................................................. 85 
10.8 
Determination of Sample Size................................................................................... 87 
11 
REGULATORY REQUIREMENTS ..................................................................... 89 
11.1 
Regulatory Approvals ............................................................................................... 89 
11.2 
Institutional Review Board/Ethics Committee Approval.......................................... 89 
11.3 
Ethical Conduct of the Study .................................................................................... 89 
11.4 
Participant Informed Consent.................................................................................... 90 


                                    
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11.5 
Compliance with Trial Registration and Results Posting Requirements .................. 90 
12 
Data and Safety Monitoring Plan (DSMP) ............................................................. 91 
13 
ADMINISTRATIVE PROCEDURES ................................................................... 91 
13.1 
Financing, Liability/Indemnity/Insurance ................................................................. 91 
13.2 
Recording of Data and Retention of Records............................................................ 91 
13.3 
Retention of Records ................................................................................................. 92 
13.4 
Disclosure and Data Confidentiality ......................................................................... 92 
13.5 
Publication of Results................................................................................................ 92 
14 
CLINICAL STUDY REPORT ............................................................................... 92 
15 
AppendixES ............................................................................................................ 93 
15.1 
ECOG performance status ......................................................................................... 93 
15.2 
Comparison of RECIST 1.1 and iRECIST ............................................................... 93 
15.3 
Appendix ................................................................................................................... 94 
 
 


                                    
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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 
CRAd 
Conditionally Replicative Adenovirus  
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 


                                    
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FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
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  
ICI 
Immunotherapy with Checkpoint Inhibitors 
IEC 
independent ethics committee 
IL 
interleukin 
IM 
intramuscular 
IMRT 
Intensity-modulated Radiation Therapy 
IND  
Investigational New Drug  
INR 
international normalized ratio 
IP 
investigational product 
irCR 
immune-related complete response 


                                    
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irPD 
immune related progressive disease 
irPR 
immune-related partial response 
irRC 
immune-related response criteria 
irSD 
immune-related stable disease 
IRB 
institutional review board 
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 
OBP-301 (Telomelysin ™) 
OBP-301 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 


                                    
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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 
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 
SBRT 
Stereotactic  Body Radiation Therapy 
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 
Treg 
regulatory T cell 
TTR 
time to treatment response 
T-VEC 
talimogene laherparepvec 
US 
United States 
USP 
United States Pharmacopoeia 


                                    
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ULN 
upper limit of normal 
VP 
viral particles 
WCM 
Weill Cornell Medicine 
WCMC 
Weill Cornell Medical College 
XTT 
cell viability assay 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                    
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1 
STUDY SYNOPSIS 
Protocol Title: 
Phase 2 study of OBP-301 (Telomelysin ™) in combination with 
Pembrolizumab and stereotactic body irradiation in patients 
with head and neck squamous cell carcinoma with inoperable, 
recurrent or progressive disease. 
Protocol Number: 
 
Study Sites: 
1. Weill Cornell Medical College 
2. Northwell Health 
3. Washington University 
4.  
Study Phase: 
Phase II 
Study 
Objective(s): 
Primary Objective: 
• To examine the ORR of OBP-301 in combination with 
pembrolizumab and SBRT in advanced head and neck 
squamous cell cancer as assessed by the RECIST 1.1 
response rate. 
• To evaluate the safety of the combination of multiple 
intratumoral injections of OBP-301 with SBRT and 
pembrolizumab. 
 
Secondary Objectives: 
 
• To examine other measures of efficacy of the combination 
of OBP-301 intratumoral injections in combination with 
SBRT and pembrolizumab in recurrent, inoperable or 
progressive HNSCC including the disease control rate, 
duration of response, overall survival and progression free 
survival.  
 
Exploratory Objectives (optional): 
 
Patients undergoing treatment with OBP-301 will have standard fine 
needle tissue biopsies along with correlative blood samples. In order 
to observe a potential response in the non-injected lesions, if several 
tumors are present, biopsies will be taken both from an injected 
tumor and a non-injected tumor and a comparison will be done 
between them. 
• To determine viral related biomarkers in the tumor: i.e. 
proof of the presence of the replicating virus (i.e- 
Adenovirus Hexon Protein) in the tumoral tissue. 
• To examine the tumor-immune microenvironment prior to 
and following OBP-301, SBRT and pembrolizumab 
therapy.  


                                    
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• To examine treatment response to OBP-301 + SBRT + 
pembrolizumab by monitoring changes in plasma and 
tumor tissue-derived exosomes and circulating tumoral 
DNA.  
• To examine and characterize the intra-tumoral and 
systemic immune responses by multi-parameter flow 
cytometry. 
• To determine changes in circulating tumor cells as 
quantified by the TelomeScan, a liquid Biopsy diagnostic 
tool. The blood of 10 patients at a maximum of 4 time 
points will be analyzed. 
 
Study Design: 
This is a phase II study of OBP-301 in combination with 
pembrolizumab and SBRT (or equivalent) in advanced HNSCC 
which is either recurrent and inoperable, or progressing after prior 
radiation with curative-intent for advanced disease (adjuvant or 
definitive with or without chemotherapy or cetuximab). 
 
The efficacy of pembrolizumab monotherapy is modest in second or 
third line of treatment of advanced head and neck cancer (~response 
rate 16-22%). SBRT reirradiation in patients that received prior 
surgery and chemoradiation for advanced disease is associated with 
a RR of approximately 60% and approximately 50% 1-year 
survival. Recently, the results of the Keynote-048 study were 
published. The projected 1-year survival in the immunotherapy arms 
with pembrolizumab alone or pembrolizumab and chemotherapy 
was approximately 57%. So, at present, the benchmark RR for 
patients with head and neck squamous cell carcinoma with 
inoperable, recurrent or progressive disease treated with SBRT is 
approximately 60% and the 1 year survival for patients with head 
and neck squamous cell carcinoma with inoperable, recurrent or 
progressive disease using the most effective contemporary 
treatments including immunotherapy is approximately 50-57%. 
Trying to improve the results of the current standard of care, this 
study will examine the effects of oncolytic virus, OBP-301, 
administered in addition to pembrolizumab and SBRT in this patient 
population.  
A total of 36 patients will be enrolled into a two-stage parallel cohort 
design: In the first stage, 12 patients will be enrolled. 
 
All patients will receive intratumoral injection(s) with OBP-301 in a 
level 2 biohazard room by an experienced ENT surgeon. If tolerated 
and no progression is observed, up to twelve injections may be 
given in each patient.  
 
 


                                    
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The volume of  OBP-301/tumor will be dependent on the targeted 
tumor volume. The same concentration of OBP-301 will be used for 
all patients    (1 x1012 vp/ml). 
 
A maximum volume of 4 ml or 4  x1012 vp total OBP-301 dose 
per treatment day will be administered. This maximum volume 
will be divided among one or more injectable lesions with the 
largest lesion getting the largest dose portion. The OBP-301 dose 
distribution between tumors will be at the discretion of the 
Investigator. (please see detailed description Section 5.3.2 Table 1). 
 
If the targeted injected lesion(s) disappear, another lesion can be 
injected at the Investigator's discretion.  
 
Treatment schedule is as follows: 
• D1: Targeted tumor(s) will be injected with intratumoral 
OBP-301 alone. 
• D8: Patients will receive both intratumoral OBP-301 and 
systemic pembrolizumab.  
• D15- D29: Radiotherapy with SBRT (or equivalent) will be 
given for a total of 5 doses on days 15, 18, 22, 25, 29 
• D15-D29: Concurrent with radiation intratumoral OBP-301 
injections to targeted tumor(s) will be given on days 18 and 
25 
There will be no concurrent pembrolizumab given during 
SBRT. 
D31: Systemic pembrolizumab will be resumed on a standard every 
21-day schedule with concurrent intratumoral injections of OBP-301 
on the same treatment day. 
A minimum additional 3 doses of concurrent OBP-301 and 
pembrolizumab will be given [day 73] if no toxicity, technical 
impediment to injection or progression is seen. 
A maximum total of up to 9 doses of concurrent OBP-301 and 
pembrolizumab will be given [day 183]. 
Pembrolizumab alone will be continued after day 183 for a total 
treatment time up to 1 year.  
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. 
 
OBP-301 (1 × 1012 VP/mL) will be administered as intratumoral 
injection cutaneous, subcutaneous, and nodal tumoral lesions that are 
deemed safe for percutaneous or transmucosal injection therapy by 
the study Investigators. 
 
At least one measurable lesion will be designated as a targeted lesion 
for intratumoral injection with OBP-301 and will be monitored for 
response. ORR will take into consideration  all lesions injected or not.  


                                    
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Planned Patients: 
A maximum of 36 eligible patients will be enrolled in the study. 
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/assent 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 or 1. 
4. Have histologically or cytologically confirmed advanced 
head and neck squamous cell cancer with cutaneous, 
subcutaneous or nodal tumors deemed as injectable 
lesions [see definition below] and have measurable 
disease for the primary study endpoint of overall 
response rate by RECIST 1.1 and iRECIST.In addition 
they must have:  
4.1. A single measurable tumor at least 1 cm in size and 
amenable to intratumoral injection or 
4.2. Multiple measurable tumors that in aggregate have a 
longest diameter of ≥ 10 mm  
 
Note: Injectable lesion definitions: lesions amenable to 
percutaneous approach , if technically feasible 
 
5. Recurrent and inoperable tumor, progressing after prior 
radiation with curative-intent for advanced disease 
(adjuvant or definitive with or without chemotherapy or 
cetuximab). No prior treatment for local regional 
recurrence (LRR). 
6. Tumors may be either HPV+ or HPV-. 
7. Tumor must be PD-L1 positive,  defined as CPS ≥ 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 14 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 permissible for this serum test to be 
performed on the same day, within 14 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 


                                    
                                Page 17 of 99  
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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>=9.0 g/dL 
D) Serum total bilirubin<=2.0 mg/dL 
E) Aspartate aminotransferase (AST) (SGOT) and 
alanine aminotransferase (ALT) (SGPT) <= 2.5x 
Upper limit of normal (ULN). For subjects with 
liver metastases<= 5x ULN. 
F) Serum creatinine<= 1.5 mg/dL; or if serum 
creatinine >1.5 mg/dL, measured or calculated 
creatinine/clearance>=60 mL/min (Cockcroft-
Gault formula). 
11. Life expectancy of ≥ 6 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 2 weeks (chemotherapy, 
small molecule), or 3 weeks (antibody) 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 the equivalent of 
prednisone 20 mg/day) or any other form of 
immunosuppressive therapy within 7 days prior to study 
Day 1. Daily dose of maintenance prednisone 10mg or 
equivalent is allowable. 
4. Has a known additional malignancy that is progressing 
or requires active treatment, with the exception of 
stable/low grade tumors that are not expected to 
influence life-expectancy (e.g. skin SCC, basal cell, 
differentiated thyroid cancer, prostate cancer on 
hormonal therapy). 
5. Has received a live vaccine within 30 days of planned 
start of study therapy. 


                                    
                                Page 18 of 99  
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6. Has a known history of Human Immunodeficiency 
Virus. 
7. Has known active Hepatitis B or Hepatitis C. 
8. Has known history of, or any evidence of active, non-
infectious pneumonitis. 
9. Has an active infection requiring systemic therapy. 
10. Has known psychiatric or substance abuse disorders that 
would interfere with cooperation with the requirements 
of the trial. 
11. 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. 
12. Previous severe hypersensitivity to another monoclonal 
antibody. 
13. 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. 
14. Prior intolerance related to severe (>=grade 3) irAE to a 
prior anti-immune checkpoint inhibitor agent leading to 
discontinuation of anti-immune checkpoint inhibitor 
therapy. 
15. Any disorder or condition, or any medication that would 
put the patient at risk from bleeding after direct tumor 
injection. 
16. Not a candidate for SBRT (or equivalent) given for 
potentially curative intent. All tumors must receive 
SBRT. For example, patients with locoregional neck 
recurrence without significant overlap with the previous 
radiation field, and who do not warrant SBRT for re-
irradiation as per the treating radiation oncologist (e.g. 
out-of-field recurrence), will not be included in the 
study. 
17. Received prior immunotherapy with checkpoint 
inhibitors or other immunotherapy agents.  
18. Exclude injection of study agent adjacent to great vessels 
19. Exclude injection into tumor impinging tracheostomy 
sites 
20. Exclude subjects with history of bleeding diathesis 
21. Exclude patients with abnormal coagulation profile 
(PT/PTT).  
22. Exclude subjects that have been treated with two or more 
courses of radiation therapy to the head and neck, 
including patients who previously received palliative re-
irradiation for recurrence. 


                                    
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Study Procedures: 
1. OBP-301 1.0-4.0x1012 viral particle/treatment day delivered 
by intratumoral injection therapy into one or more tumors 
per study schedule. 
2. SBRT (or equivalent) 40-45 Gy divided over a total of 5 
treatments. 
3. Pembrolizumab 200 mg intravenous per study schedule. 
 
 
 
Study Endpoints: 
 
 
 
 
 
Primary Endpoint: 
• To examine the efficacy of OBP-301 in combination with 
pembrolizumab and SBRT in advanced head and neck 
squamous cell cancer as assessed by the RECIST 1.1 
response rate 
To examine the safety of multiple OBP-301 intratumoral 
injections in combination with pembrolizumab or/and SBRT 
• Secondary Endpoints: 
To determine the following additional measures of efficacy 
including: 
• Overall survival (OS) at 1 year 
• Progression free survival (PFS) 
• Disease control rate at 6 months 
• Immune related Response Rate (irRR) 
• Time to response in non-target lesions  
  
Exploratory Analysis (optional): 
Correlative endpoints include the following: 
• To examine the tumor-immune microenvironment prior to 
and following OBP-301, SBRT and pembrolizumab 
therapy both in injected and non-injected lesions. 
• To examine treatment response to OBP-301 + SBRT + 
pembrolizumab by monitoring changes in plasma 
exosomes and circulating tumoral DNA.  
• To examine and characterize the immune infiltrate by 
multi-parameter flow cytometry. 
• To determine viral related biomarkers in the tumor: i.e. 
proof of the presence of the replicating virus (i.e. 
Adenovirus Hexon Protein) in the tumoral tissue or/and 
presence of the receptor for Coxsackie Adenovirus 
Receptor (CAR). 
• To determine changes in circulating tumor cells as 
quantified by the TelomeScan, a liquid Biopsy diagnostic 
tool. 


                                    
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Statistical 
Analysis: 
The primary endpoint for this study will be the objective response 
rate (CR + PR).  Sample size recommendations for the phase II 
design are determined according to Simon’s two-stage design 
(Simon R, 1989).  We project an objective response proportion of 
61%, below which the response will be unacceptable, and an 
objective response proportion of 78%, above which the regimen will 
be considered worthy of further exploration.  The null hypothesis 
that the objective response proportion is less than or equal to 61% 
will be tested against the alternative hypothesis that the response 
proportion is greater than or equal to 78%. 
The sample size computations were performed assuming 10% level 
of significance and 80% power.  In the first stage, 12 patients will 
enter the study.  If 7 or fewer respond, the study will be terminated 
early and declared to have a negative result.  If 8 or more patients 
respond, enrollment will be extended to 36 patients.  At Stage 2, the 
treatment will be declared effective and worthy of further testing if 
26 or more patients respond among the 36 patients entered.  This 
two-stage design yields a ≥ 0.80 probability of a positive result if the 
true percentage of overall responders is ≥ 78%.  It yields a ≥ 0.90 
probability of a negative result if the true percentage of overall 
responders is ≤ 61%.  A 95% confidence interval constructed around 
the expected objective response proportion of 78% can be estimated 
to be within ± 16.0% of the observed response proportion.  
Assuming 10% are unevaluable/ineligible, we anticipate that a total 
of 14 patients will be enrolled in the first stage, 40 in both the first 
and second stage if the study proceeds to the second stage. 
 
Statistical Table. Numbers of observed responders required to 
accept or reject H0 at each stage.  Under this design, H0 will not be 
rejected at Stage 1. 
 
 
N 
Accept H0 
Reject H0 
Stage 1 
12 
 7 
--- 
Stage 2 
36 
25 
>26 
Study Duration: 
Approximately 30 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  30 months  following the first intratumoral injection of 
OBP-301.   


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2 
STUDY SCHEMA 
 


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3 
BACKGROUND  
1.1 The rationale for using a triple therapy combination in head and neck cancer 
The Programmed Death Ligand-1 (PD-L1) and its receptor (PD-1) are important regulators 
of T cell activity1, and their inhibitors have now demonstrated antitumor activity in several 
malignancies2,3 including melanoma4,5, lung6-9, renal10, and bladder cancers11. Despite a 
high level of PD-L1 expression in head and neck tumors (up to 80%), progress in checkpoint 
inhibitors treatment of cancers of head and neck have been limited.  The response rate of 
monotherapy with checkpoint inhibitors in second line recurrent or locally advanced head 
and neck cancers has been only13-18% across the different PD-1 inhibitors12-18,42. 
 
FIGURE 1 Change from baseline of head and neck cancer tumors with 
pembrolizumab (Ref 13)                                                                           
Although activity is relatively modest, some patients live longer and those that respond tend 
to have durable responses of 12 months or greater with few patients stopping therapy for an 
adverse event (Fig 1). In 2016 pembrolizumab and nivolumab have been approved for 
second line treatment of recurrent or locally advanced head and neck cancers 
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 immunity19. 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 cells20-23.  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 of systemic immune response with the development of a neutralizing 


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antibody (Ab) response in all tested patients, and up regulation of serum IL-6 and IL-10 
levels in 8/9 and 7/9 patients respectively24.  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 patients24.   
 
▪ There is preclinical and clinical evidence that OBP-502 (the murine version of OBP-
301) is synergistic with anti-PD-1 therapy providing rationale for this proposal. 
(Figs 2A and 2B). In vitro and in vivo studies have shown the potential of OBP-502 
to activate antitumor immunity, leading to sensitization of non-immunogenic 
gastrointestinal tumors to PD-1 antibody. The growth in vaccinated mice was 
significantly suppressed than control mice and there was induction of tumor-
infiltrating cells following the administration of OBP-502 with an anti-PD1 
antibody combination compared to pre injection. (Figures 2A and 2B and Ref 43). 
 
 
  
 
Figure 2A Synergistic effects of OBP-502 and Anti-PD1 Antibody 
 
▪ In addition, a Japanese Phase I study of OBP-301 in combination with Anti-PD-1 is 
ongoing. (NCT03172819). The study aims to evaluate safety and potential efficacy 
of combination of OBP-301 and pembrolizumab in patients with advanced or 
metastatic solid tumors. Preliminary safety data in 9 evaluable patients demonstrated 
that the combination of OBP-301 and pembrolizumab was well tolerated in the 
tested dose of 1x1012 vp/tumor. Most common adverse events included fever (grade 
1-2) hepatic disorder (grade 1-3) and pleural effusion (grade 1). There were early 
signs of efficacy 3/9 partial response (PR)s44. 
 
 


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Figure 2B Induction of tumor-infiltrating cells was significantly increased following 
combination of OBP-502 and Anti-PD-1Ab. 
 
Also, OBP-301 has a radiosensitizing effect. As shown in Figure 3, OBP-301 increases the 
effect of ionizing radiation in a dose dependent manner. OBP-301 sensitizes human cancer 
cells to ionizing radiation by inhibiting the radiation-induced DNA repair machinery, and 
also eliminates radio-resistant quiescent cancer stem-like cells by promoting cell cycle 
entry.  
 
 
 Figure 3 Radiosensitizing effect of OBP-301 and Anti-PD1 Antibody 
 
An Investigator-initiated phase I/II Study of OBP-301 with radiation therapy in Japanese 
head and neck or/and thoracic malignant cancers patients unfit for surgery has been 
completed. Thirteen patients with esophageal cancer have been treated (3 at the highest dose 
level of 1X1012vp/tumor). Toxicities have been manageable. The only observed grade ¾ 
toxicities have been leukopenia (8%) and lymphopenia (77%). Grade1/2 toxicities include 
transient fever without evidence of infection (62%), chills (15%), nausea (25%), esophagitis 
(31%), anorexia (39%) and pneumonitis (23%). Indication of reduction in area of treated 
tumor was observed in 11 (8 clinical CR and 3 PR) out of 12 evaluable patients (objective 
response rate: 91.7%). Pathological responses were also observed in 8 patients (66.7%)45.  


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Preclinical data in murine cancer models show improved tumor growth control and survival 
when radiation therapy (RT) is combined with a PD-1 inhibitor40.  
 
Given the excellent toxicity profile of both checkpoint inhibitors and Radiation therapy and 
OBP-301 there is a rationale to combine OBP-301 with Radiation therapy and a checkpoint 
inhibitors. 
 
1.2 Locally recurrent head and neck cancer (HNC) 
 
Recurrent HNC in a previously irradiated field has a poor prognosis. When 
a recurrence develops in a head and neck cancer in an area previously treated with radiation, 
the mainstay of treatment remains local control of disease. The recurrence can have an 
attempt at salvage by surgery but this is often not possible given the extent of disease and 
previous therapy. A common approach involves re-irradiation to provide survival benefit 
over chemotherapy alone however the median survival in most series remains only 9-12 
months with radiation only, depending upon patient and disease-related factors36. Treatment 
options are often limited. For unresectable disease, systemic therapy alone, the historical 
standard of care, results in 10–15% 1-year overall survival (OS) and virtually no long-term 
survivors36,37,38. In the EXTREME trial, only 3% (6/222) and 1% (2/220) of patients 
enrolled in the cetuximab and control arms, respectively, were known to still be alive after 
5 years.38 
 
For patients with recurrent or second primary HNC within a previously irradiated area, the 
only potentially curative option is a second course of radiation, with or without 
chemotherapy, termed reirradiation (RRT). Early experiences with RRT in selected patients 
demonstrated OS rates (30–50%) that compared favorably to chemotherapy alone39.  
 
More recently, concomitant chemotherapy and stereotactic body irradiation (SBRT) has been 
adopted by some as a treatment strategy of choice for this patient population. Two 
consecutive multi-institutional cooperative group studies that used concurrent 
chemotherapy and re-irradiation for SCCHN, demonstrated the feasibility of re-irradiation. 
Two prospective studies32,33 done by a French group have shown support for SBRT 
reirradiation. The first feasibility study32 included 40 patients, with an SBRT dose of 36 Gy 
in 6 fractions, given over 11 to 12 days. The median OS was 13.6 months. There was a 79% 
response rate, and minimal toxicity (only G3 toxicity in 4 patients). Subsequently, the same 
group (Lartigau33 et al.) published a multi-institutional phase II study of SBRT reirradiation 
(same dose/technique) with concurrent cetuximab in 56 patients and they found a response 
rate of 58.4%. The median OS was 11.8 months, the 1-year OS was 48%, and the median 
PFS was 7.1 months. Of 49 evaluable patients, 49% had a complete response and 20% had 
a partial response. Eighteen patients (32%) developed G3 or higher toxicity, and there was 
1 death from hemorrhage. Two other retrospective studies34,35 showed response rates 
ranging from 50% 34 to 80% 35 an OS at 1 year around 50% but higher severe late toxicity. 
A 2017 review of the most relevant SBRT studies showed that response rates to SBRT in 
the recurrent head and neck cancer setting are approximately 60%71. 
 


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Recently, the Keynote-048 study was completed and the results were published67. The 
follow-up was only 11.5 months but the 1 projected year survival in the immunotherapy 
arms with pembrolizumab alone or pembrolizumab and chemotherapy was approximately 
57%. So, the benchmark 1 year survival using the most effective treatments from the clinical 
studies completed so far is 50-57%. 
 
At ASCO 2019, Harrington, K. J. et al. reported the safety and preliminary results of a Phase 
1 B study46 investigating the efficacy of another adenoviral construct, talimogene 
laherparepvec (T-VEC) administered locally in the tumor in combination with systemic 
pembrolizumab in patients with recurrent or metastatic squamous cell carcinoma of the head 
and neck. The primary objective was to evaluate safety, as assessed by the incidence of dose 
limiting toxicity (DLT). Key secondary objectives were objective response rate (ORR), best 
overall response per immune-related RECIST, and long-term safety. 36 pts were enrolled 
and treated: The ORR was 16.7% (6/36 pts; 5 PD-L1-positive; 95% CI, 6.4–32.8), and the 
disease control rate (objective response/stable disease) was 38.9% (14/36 pts; 11 PD-L1-
positive; 95% CI, 23.1–56.5). The combination demonstrated a manageable safety profile. 
The same author suggested recently that radiotherapy approaches may add to this 
combination47.  
 
Unpublished experience: 
 
A retrospective chart review of 20 patients treated in Northwell Health Monter Cancer 
Center with chemotherapy + SBRT or Cetuximab + SBRT confirmed the guarded prognosis 
of the majority of these patients. 
 
 
In our cohort, median age of the patients was 71 years. 13 men and 7 women were treated 
with chemotherapy + SBRT or Cetuximab + SBRT. 5 patients received Cetuximab + SBRT 
and 15 patients received chemotherapy + SBRT. The maximum follow up time was 2 years. 
 
-35% (7/20) patients progressed very fast after the local ttx and lived an average of 3.5 
months after the chemotherapy + SBRT or cetuximab + SBRT. 
-(50%) 10/20 patients were still alive but progressed after an average duration of 5.4 
months. 
-15% (3/20) patients did not progress and were alive at a f/up of 7, 12, and respectively 14 
months. 
Similarly, the University of Chicago has shown in series of publication of re-irradiation (not 
SBRT, but hyper-fractionated radiation) of HNSCC that prognosis is guarded with only 15-
20% of patients alive at 2 years (e.g. Seiwert et al JCO). 
 
Clearly, there is an urgent need to improve the grim prognostic of patients with recurrent 
unresectable head and neck cancer that have been previously irradiated. 
 
Conclusion and study rationale Treatment of recurrent unresectable head and neck cancer 
is an unmet medical need, for which drug development is lacking and for which currently 


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there is no standard of care. In the NCCN guidelines version 2.2018 it is clearly stated: 
“Research opportunities for reirradiation should be strongly considered in patients with 
unresectable head and neck cancer”.   
 
Given the proven radiosensitizing effects of OBP-301 and the synergistic interaction of 
OBP-301 with Pembrolizumab42, and the recent SBRT data in recurrent head and neck 
cancer46,47 this is a clear opportunity for OBP-301 to be used together with SBRT and 
Pembrolizumab in the recurrent unresectable head and neck cancer setting. We believe that 
this triple local and systemic combined approach represents a powerful synergistic 
therapeutic modality to attack cancer both directly and, indirectly, by stimulating the 
immune system. 
 
1.3 Oncolytic viral therapy background and rationale  
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 PD1 inhibition. This involves selective replication within neoplastic cells, resulting in 
a direct lytic effect on tumor cells, and induction of systemic antitumor immunity19. 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 cells 20-23.  OBP-301 has been examined in a phase I study in solid tumor patients, 
with an established safe dose of Ix1012 viral particles/tumor injection. In this study, there 
was evidence of systemic immune response with the development of a neutralizing Ab 
response in all tested patients, and up regulation of serum IL-6 and IL-10 levels in 8/9 and 
7/9 patient’s respective24. 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 
patients24. There is preclinical evidence that OBP-301 is synergistic with anti-PD-I therapy 
(Figure 2), providing the rationale for this proposal. 
Specifically, in a murine model of pancreas and colon cancer, the combination of PD-I 
inhibition with the murine equivalent of OBP-301 (OBP-502), the combination therapy was 
associated with immunogenic cell death48. OBP-502 induced a significant accumulation of 
tumor infiltrating lymphocytes within the tumors compared with control. The combination 
of OBP-502 and PD-I Ab significantly suppressed CT26 colon cancer subcutaneous tumors 
and successfully eradicated 4/12 (33% of mice. When these 4 tumor-free mice were re-
challenged by inoculation with CT26 colon cancer cells, 2/4 (50%) remained tumor free, 
indicating continued immune surveillance48.  (Figure 4) 
 
 


                                                                                                                                Page 28 of 99 
___________________________________________________________________________ 
 
 
Figure 4 Antitumor activity of the combination of OBP-502 in combination with PD-I Ab inhibitor. (A) 
study schema, CT26 and PAN02 are murine colon and pancreatic tumor models. OBP-and PD Ab were 
administered 3 times as indicated. (B) Tumor growth curves with control PD-I Ab, OBP-502: or the 
combination 
 
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 antitumor 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 20%,  
  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 Surgery50   
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 disease51.  


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Conditionally replicative oncolytic viruses (CRAds)  are engineered for selective replication in 
cancer cells that express certain oncogenic phenotypes52-53   .  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 (Figure 5). 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 (EIA), immediate early (EIB, E2, E3, E4), intermediate (IX 
and IVa2), and late genes. In the construct of OBP-301, the normal transcriptional regulatory 
element of the EIA gene is 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". In the resulting 
replication-selective, tumor specific adenovirus vector OBP-301, the hTERT promoter element 
drives the expression of E1A and E1B genes linked with an internal ribosome entry site. 
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 
cell52  
 
AE I = delta El adenovirus vector, E IA, E 1B = transcriptional units, hTERT = human telomerase reverse transcriptase, RES = 
internal ribosomal entry Site, ITR = inverted terminal repeat 
       Figure 5 The construct of OBP-301  
OBP-301 construct is taken by the cells expressing the Coxackie Adenovirus Receptor (CAR). It 
has been shown by Oncolys researchers that radiotherapy upregulates the expression of this 
receptor on the surface of tumor cells. Once the virus reaches the nucleosome it remains episomal 


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because there is no homology between the virus genome and the host genome. Important note: 
After entering the nucleus, the DNA of the virus does not integrate in the host DNA: it always 
remains episomal. This is a safety feature of Adenoviruses as a class that makes them 
attractive therapeutic constructs 20, 66.   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 24, 53 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 54 
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-a) 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 
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 antitumor 
activity were supportive of the continuing clinical development of OBP-301 as an oncolytic 
therapeutic agent. 
 1.4 Summary of Non-Clinical and Clinical Studies 
1.4.1 Non-Clinical Studies 
The pre-clinical experience with OBP-301 is described in further detail in the Investigator's 
Brochure55. 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 


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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 m 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.  
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.  
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.   
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 


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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.   
In 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 Tumors).  IM compared to IV 
administration was shown to limit toxicity, and all toxicities were reflected in the biomarker 
surrogates of clinical pathology. 
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.   
1.4.2 Clinical Studies 
Clinical trials of OBP-301 administered by intratumoral injection have been conducted in patients 
with advanced cancer under the following protocols: 


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Completed studies 
OBP-301-001:  an open-label, Phase I, 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: 
A.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 (Treg) 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. 
B.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.  


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Furthermore, the median survival time was 31.3 months in 5 patients with melanoma56.  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, 
respectively57.  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 
therapies56. 
           Other studies: 
A.OBP-301-003-C-V (NCT0321305): a Phase I/II dose-escalation study to determine the 
safety and efficacy of OBP-301 at doses of 1 × 1010 VP/tumor, 1 × 1010 VP/tumor and 
1 × 1012 VP/tumor in patients with head and neck or/and thoracic malignant 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 or/and thoracic malignant 
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. Thirteen 
patients with esophageal cancer were enrolled in this study, 12 subjects’ histological type 
were squamous carcinoma and one was adenocarcinoma. 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. Multiple doses of OBP-301 were 
well tolerated (1 x1010 ~1 x1012 VP/ injection), and no DLT and no any intolerable adverse 
events was observed. Indication of reduction in area of treated tumor was observed in 11 
(8 clinical CR and 3 PR) out of 12 evaluable subjects (objective response rate: 91.7%). 
Pathological responses were also observed in 8 patients (66.7%). 
B.TL04001 (NCT03213054): 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. The dose of OBP-301 will be started from 3 x 1011 VP in Cohort 1, 
and if no any DLT is observed, dose will be escalated to 3 x 1012 VP. OBP-301 will be 
injected to primary tumor by endoscopy at Day 1, Day 18 and Day 32. From Day 4, 
patients receive 6 weeks radiotherapy (60 Gy total).6 patients were enrolled to the phase 
I clinical trial, 3 patients were treated with 3 x 1011 VP and 3 x 1012 VP of OBP-301 in 
the Cohort 1 and Cohort 2, respectively. No any DLT was observed in this study, thus 
MTD of OBP-301 was not determined, and MTD was over 1012 VP/mL. 4 of 6 patients 
experienced complete response (CR) in primary tumor and CR rate for primary tumor 
was 66.7%, and other 2 patients also experienced tumor shrinkage. 


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C.TL03001: a phase II study to evaluate the efficacy, safety, and immunological response 
of OBP-301, in patients with unresectable metastatic melanoma. The study aims to recruit 
a maximum of 50 subjects from 5 clinical sites in the US. The first subject was dosed in 
July 2017. Four subjects were enrolled into this study and subject enrollment of the study 
was prematurely discontinued in December 2018 due to poor enrollment. The result of 
this study is being summarized.  
Ongoing studies 
A. CT-OT-21 (NCT02293850): a Phase I Study to Evaluate the Safety and Efficacy of 
OBP-301 at doses of 1 × 1010 VP/subject and 6 × 1012 VP/subject 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.    
B. EPOC1505 (NCT03172819): 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. As of November 2019, 19 patients have been enrolled and the study is ongoing. 
 
C. 1807019403: a phase II study to evaluate the efficacy, safety and immunological 
response of OBP-301 in combination with Pembrolizumab in patients with advanced or 
metastatic gastric or gastroesophageal junction adenocarcinoma. This study is an 
investigator initiated clinical study. This study aims to recruit a maximum of 41 subjects 
at multiple sites in the US. As of November 2020, 8 patients have been enrolled and the 
study is ongoing.  
 
3.5 
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: 
Arthralgia 
Chills  
Dehydration   
Erythema  
Fatigue 
Headache  
Injection Site Reaction (Bruising, Erythema, Pain)  
Lymphocyte count decreased  
Malaise 
Musculoskeletal Pain 
Myalgia 
Nausea 
Oedema Peripheral 
Pain in Extremity 


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Pyrexia 
Skin Inflammation 
Tachycardia 
Tumor Haemorrhage 
Tumor Necrosis  
Tumor Related Complication  
Vomiting  
 
 
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 reported24.  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 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.  
3.6 
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.   
3.7 
Patient Population 
Patients with locally advanced head and neck cancer that are not eligible for salvage surgery will 
be included. Subjects must have already received chemoradiation in combination using a platinum-
based chemotherapy and are immunotherapy naïve. 


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4 
OBJECTIVES 
Primary Objective: 
• To examine the ORR of OBP-301 in combination with pembrolizumab and SBRT in 
advanced head and neck squamous cell cancer as assessed by the RECIST 1.1 
response rate. 
• To evaluate the safety of the combination of multiple intratumoral injections of OBP-
301 with SBRT and pembrolizumab. 
 
 
Secondary Objectives: 
To evaluate: 
• Overall survival (OS) at 1 year. 
• Progression free survival (PFS). 
• Disease control rate at 6 months. 
• Immune related Response Rate (irRR). 
• Time to response in non-target lesions. 
 
Exploratory Objectives (optional): 
• To determine viral related biomarkers in the tumor: i.e. proof of the presence of the 
replicating virus (i.e- Adenovirus Hexon Protein) in the tumoral tissue or/and presence 
of the receptor for Coxsackie Adenovirus Receptor (CAR). 
• To examine the tumor-immune microenvironment prior to and following OBP-301, 
SBRT and pembrolizumab therapy. 
• To examine treatment response to OBP-301 + SBRT + pembrolizumab by monitoring 
changes in plasma and tumor-tissue exosomes and circulating tumoral DNA.  
• To examine and characterize the intra-tumoral and systemic immune responses by 
multi-parameter flow cytometry. 
• To determine changes in circulating tumor cells as quantified by the TelomeScan, a 
liquid Biopsy diagnostic tool. The blood of 10 patients at a maximum of 4 time points 
will be analyzed. 
 
5 
STUDY DESIGN 
5.1 
Study Overview 
This is a phase II study of OBP-301 with pembrolizumab and SBRT in recurrent inoperable head 
and neck cancer that has progressed after initial surgery and/or chemoradiation for advanced 
disease. The efficacy of pembrolizumab monotherapy is modest in second or third line of treatment 
of advanced head and neck cancer (~response rate 22%). SBRT reirradiation in patients that 
received prior surgery and chemoradiation for advanced disease is associated with a response rate 


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of approximately 60% and with approximately 30-50% 1-year survival. This study will examine 
the addition of OBP-301 with pembrolizumab and SBRT in patients with recurrent inoperable head 
and neck cancer that has progressed after initial surgery and/or chemoradiation for advanced 
disease. 
 The study schema is provided in Fig 6. 
 
                                       Figure 6 Study Schema 
A total of up to 36 patients will be enrolled in a two stage parallel cohort design.  
Enrollment will proceed in two stages in each cohort:  
• In the first stage, 12 patients will enter the study, if 8 or more patients respond, 
enrollment will be extended to 36 patients. 
The plan is to inject the tumor(s) with OBP-301, if tolerated and no progression, up to twelve 
injections in each patient.  
• All patients will receive OBP-301 at a concentration of 1 × 1012 VP/mL.  
• Patients will be able to receive up to a total of 4 × 1012 VP depending on the size of the 
target tumors (see dosing section 5.2.2 below).  
• If the targeted injected lesion disappears, another lesion can be selected for injection.  
 
Study treatment schedule will consist of the following [refer to Figure 6]: 


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The tumor will be injected with OBP-301 alone at D1. At D8 patients will received intratumoral 
OBP-301 and systemic pembrolizumab.  Radiotherapy with SBRT and OBP-301 injections will 
start at D15. Intratumoral OBP-301 and systemic pembrolizumab will be started again one week 
after the 5th dose of SBRT at D36 initially for additional 9 doses of the combination OBP-301-
pembrolizumab (up to 12 doses of OBP-301 administered) then pembrolizumab alone will be 
administered systemically for up to 1 year. 
Of note:  
1. All the lesions will be irradiated. 
2.  In order to observe a potential response in the non-injected lesions, if several tumors are present, 
biopsies will be taken at baseline (Day 1) and on Day 18 both from an injected tumor and a non-
injected tumor and a comparison will be done between them. 
 
3. Standard fine needle biopsies will be taken on the following days:  
1) Day 1, prior to therapy. 
2) Day 8, prior to therapy (to see the effect of OBP-301 alone), 
3) Day 18, prior to therapy (to see the effect of OBP-301 together with pembrolizumab) 
Given the fact that three biopsies will be done within approximately 3 weeks and 
special attention will be given to potential side effects (i.e. bleeding, etc.) that can be 
associated with the biopsy procedures. 
4) Optional on Day 94 +/- 5 days (to see the effect of OBP-301 + pembrolizumab + SBRT). 
 
6 
STUDY POPULATION 
6.1 
Selection of Study Population 
Only those patients will be included in the study that meet inclusion and exclusion criteria as 
outlined below. 
6.2 
Inclusion Criteria 
Patients who meet all of the following criteria will be considered for inclusion in the study: 
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/assent 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 or 1. 


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4. Have histologically or cytologically confirmed advanced head and neck squamous cell 
cancer with cutaneous, subcutaneous or nodal tumors deemed as injectable lesions [see 
definition below] and have measurable disease for the primary study endpoint of 
overall response rate by RECIST 1.1 and iRECIST.In addition they must have:  
4.1. A single measurable tumor at least 1 cm in size and amenable to intratumoral 
injection or 
4.2. Multiple measurable tumors that in aggregate have a longest diameter of ≥ 10 mm  
 
Note: Injectable lesion definitions: lesions amenable to percutaneous approach, if 
technically feasible 
 
5. Recurrent and inoperable tumor, progressing after prior radiation with curative-intent 
for advanced disease (adjuvant or definitive with or without chemotherapy or 
cetuximab). No prior treatment for local regional recurrence (LRR). 
6. Tumor may be either HPV+ or HPV-. 
7. Tumor must be PD-L1 positive,  defined as CPS ≥ 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 14 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 permissable that this serum 
test be performed on the same day as the urine pregnancy test; no more than 14 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 ≥ 9.0 g/dL 
D) Serum total bilirubin ≤ 2.0 mg/dL 
E) Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) 
(SGPT) ≤ 2.5x Upper limit of normal (ULN). For subjects with liver metastases 
≤ 5x ULN. 
F) Serum creatinine ≤ 1.5 mg/dL; or if serum creatinine >1.5 mg/dL, measured or 
calculated creatinine/clearance ≥ 60 mL/min (Cockcroft-Gault formula). 
11. Life expectancy of ≥ 6 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 
 
 
 


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6.3 
Exclusion criteria 
The presence of any of the following criteria will exclude the patient from the study: 
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 2 weeks (chemotherapy, 
small molecule), or 3 weeks (antibody) 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 the equivalent of prednisone 20 mg/day) or any other form of immunosuppressive 
therapy within 7 days prior to study Day 1. Daily dose of maintenance prednisone 10mg 
or equivalent is allowable. 
4. Has a known additional malignancy that is progressing or requires active treatment, 
with the exception of stable/low grade tumors that are not expected to influence life-
expectancy (e.g. skin SCC, basal cell, differentiated thyroid cancer, prostate cancer on 
hormonal therapy). 
5. Has received a live vaccine within 30 days of planned start of study therapy. 
6. Has a known history of Human Immunodeficiency Virus. 
7. Has known active Hepatitis B or Hepatitis C. 
8. Has known history of, or any evidence of active, non-infectious pneumonitis. 
9. Has an active infection requiring systemic therapy. 
10. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
11. 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. 
12. Previous severe hypersensitivity to another monoclonal antibody 
13. 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. 
14. Prior intolerance related to severe (≥grade 3) irAE to a prior anti-immune checkpoint 
inhibitor agent leading to discontinuation of anti-immune checkpoint inhibitor therapy 
15. Any disorder or condition, or any medication that would put the patient at risk from 
bleeding after direct tumor injection. 
16. Not a candidate for SBRT (or equivalent) given for potentially curative intent. All 
tumors must receive SBRT (or equivalent). For example, patients with locoregional 
neck recurrence without significant overlap with the previous radiation field, and who 
do not warrant SBRT for re-irradiation as per the treating radiation oncologist (e.g. out-
of-field recurrence), will not be included in the study. 
17. Received prior immunotherapy with checkpoint inhibitors or other immunotherapy 
agents. 


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18. Exclude injection of study agent adjacent to great vessels 
19. Exclude injection into tumor impinging tracheostomy sites 
20. Exclude subjects with a history of bleeding diathesis 
21. Exclude patients with abnormal coagulation profile (PT/PTT). 
22. Exclude subjects that have been treated with two or more courses of radiation therapy 
to the head and neck, including patients who previously received palliative re-
irradiation for recurrence. 
6.3.1 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. 
6.3.2 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 JCTOIIT@med.cornell.edu: 
 
• 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.   
6.4 
Stopping Criteria 
6.4.1 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. 


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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 (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.   
6.4.2 Termination or Suspension of the Study  
The drug manufacture (Oncolys BioPharma), 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. 


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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. 
7 
STUDY TREATMENTS 
7.1 
 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 
 
 
7.2 
Dosage and Treatment 
1. OBP-301 1x1012 to 4 x1012 viral particles/treatment day/subject injection as outlined 
below: 
 
• Up to a total of 12 total tumor injections may be considered in discussion 
with the PI (Dr. Doru Paul) which may be given in combination with 
pembrolizumab after completion of SBRT treatment.  
• Primary tumors that are greater than 5 cm may be administered up to 4 x 
1012 viral particles/ subject during the same procedure.   
• For smaller tumors (1.0 -2.5cm and 2.5-5.0cm), 1 ml or 2ml  OBP-301 
will be injected, accordingly based on the safety as determined by the 


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ENT surgeon. OBP-301 can be administered to more than one lesion 
simultaneously.   
2. Pembrolizumab 200 mg intravenous as per study schedule day 8-36 and then every 3 weeks 
until disease progression as per study schedule. 
 
2. Radiation therapy in the form of Stereotactic Body Radiation Therapy [SBRT] will be 
 
given for a total of 5 doses over a period of ten days. 
 
7.3 
Investigational product 
73.1 Study Supplies OBP-301 
Pembrolizumab will be supplied by commercial vendors. 
Oncolys BioPharma Inc. will be responsible for the preparation and labelling of the Investigational 
Product (IP) 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. 
7.3.1.1 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.   


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7.3.1.2 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.   
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 7.3.1.3). 
7.3.1.3 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 reconstitution.  
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.   
7.3.1.4 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. 


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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. 
7.3.2 Selection and Timing and IT Administration for each Patient 
OBP-301 (1×1012 VP/mL) is administered as intratumoral injection into a head and neck cancer 
tumor mass that is suitable for injection, eg greater than 1 cm in size and in a location amenable 
for injection.  The largest diameter of the lesion will determine the volume of OBP-301 injected. 
Lesions 1-2.5  cm will be injected with up to  1 ml (1x1012 VP) , lesions between 2.6 cm to 5.0 cm 
in size will be injected with up to  2 ml (2x1012 VP) and lesions >5cm in size will be injected with 
up to 4ml (4 x 1012VP).  The rationale for this is to ensure adeqate penetration of the viral particles 
throughout the tumor.   
Pre-injection planning is the key to success; therefore, a sketch of the tumor and the planned 
injection sites should be made. The sketch will be helpful in determining the total quantity of study 
drug to inject. 
 
The tumor to be injected should be ≥1 cm in length and can be mapped into (preferably at least) 
12 sections. The dose (volume) delivered to the lesion(s) (if patient has 2 or more lesions several 
lesions can be injected) should be within the range of 1.0 to 2.0 mL (Table 1). 
 
For example, in a 3 cm tumor, a total volume of 2 ml (i.e. (2x1012 VP)) will be injected in the 
tumor. 
Table 1: IT administration Volume Guidelines 
 
Lesion Size 
Injection Volume 
> 5.0 cm 
Up to 4 mL  
> 2.5 cm to 5.0 cm 
 2 mL  


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Note: If lesion shrinks, adjust injection volume according to the lesion size in the table above. 
If the tumor disappears, and there are other lesion(s) amenable for injections they should be 
injected. 
 
 
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. 
 
7.3.3 Injection Procedures 
7.3.3.1 The optimum technique for injection of a primary tumor is to inject the viral particles 
circumferentailly around the lesion in 12 tracks.  This will ensure that the viral particles will be 
> 1.0 cm to 2.5 cm 
 1 mL  


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maximally penetrated into the lesion. More detailed administration instructions can be found in 
the Pharmacy Manual (Section 6.5). 
ENT surgeons will be eligible to perform the procedure in a level 2 biohazard room.  A training 
video (prepared by Oncolys Biopharma) is available as well.   
Procedure will take place in the ENT or Interventional Radiology procedure rooms. Standard 
sterilization procedures will be used. A standard laryngoscope and needle will be used for the 
procedure. Guidelines for each injection procedure are provided below. 
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. There should be a minimum of 1 hour between injection and pembro 
administration. 
• Vital signs (except weight) 
OBP-301 may be associated with injection site pain if administered to dermal lesions. However, 
pain has not been observed for intralumenal injections previously.   
OBP-301 
OBP-301 injection will be delayed for any ongoing Grade 3 toxicity 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 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.   
7.3.3.2 Patient selection for injection 
In order to receive intratumoral (IT) injections, patients must have relatively good performance 
status (ECOG 0-1) and disease in a site that is considered to be amenable to local injection. Suitable 
sites for injection include cutaneous and subcutaneous nodules over the scalp, face, neck and upper 
chest wall. In addition, cervical nodal masses in levels I-VI are frequently accessible to injection. 
Direct injection into mucosal lesions affecting the oral cavity (lip, buccal mucosa, oral tongue, 
floor of mouth, palate) and oropharynx (tonsil, base of tongue) is also relatively straightforward 


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and feasible in many patients. Injection of primary tumors of the larynx and hypopharynx present 
specific challenges and these sites will not be injected. Most patients with squamous cell cancers 
of the head and neck who are considered for studies of IT will have previously received relatively 
high-dose irradiation (in either the radical or adjuvant settings). Injection into irradiated sites is 
usually safe and feasible, but there are specific concerns around injection into sites that have been 
irradiated on more than one occasion (i.e. re-irradiated), especially if they lie in close proximity to 
major blood vessels in the neck. Certainly, it would appear sensible to advise caution when 
considering IT in sites adjacent to the great vessels of the neck that have received cumulative 
radiation doses >100 Gy. Such concerns will be amplified in patients with any prior history of 
bleeding from their tumor or in patients who are taking anti-platelet or anti-thrombotic 
medications. If such therapy cannot be discontinued safely, these patients should not be routinely 
considered for IT therapy. Many patients entering clinical trials of IT will have loco-regionally 
recurrent disease that is sufficiently advanced to require them to have undergone tracheostomy 
(permanent or temporary) and/or insertion of feeding (nasogastric or percutaneous 
gastrostomy/jejunostomy) tubes. Such interventions can be extremely beneficial for the patient and 
may extend opportunities for trial entry to patients who might otherwise not be considered suitable. 
In particular, in patients with bulky nodal masses and/or mucosal disease involving the oropharynx 
and laryngo-hypopharynx, the presence of a tracheostomy and/or a feeding tube can allay concerns 
that inflammation and swelling associated with IT might cause airway compromise or loss of the 
ability to take oral fluids/nutrition. Nevertheless, caution is advised in patients with disease at or 
around tracheostomy sites. Direct injection of IT into such sites can be associated with airway 
compromise if treatment-related inflammation narrows the aperture of the stoma. In addition, 
marked treatment response with disappearance of disease at the stoma can cause difficult problems 
with stoma care and can be associated with exposure of great vessels in the neck (with resulting 
risks of major hemorrhage) and fistula formation with the pharynx/upper esophagus. 
7.3.3.3 Technical considerations 
Intratumoral injections into head and neck sites can pose a number of technical challenges that 
must be recognized and addressed. Squamous cell cancers have a marked tendency to 
ulcerate/fungate onto the skin surface, which can result in leakage of injected material through the 
skin surface during drug administration. This can, in turn, result in variable and unpredictable 
dosing of injected lesions and has frequently been used as an exclusion criterion in clinical 
protocols. For larger lesions, however, it is often possible to direct the injection into deeper parts 
of the lesion and deliver the injected material sufficiently slowly to avoid leakage through the 
surface of the lesion. Similar concerns exist for lesions that demonstrate fistulation between 
mucosal and cutaneous surfaces in the head and neck. Again, if the lesions are sufficiently large, 
it is often possible successfully to inject the deeper aspects of the lesions away from the fistulous 
tract and avoid leakage and loss of the therapeutic agent.  
Similar considerations apply when treating patients with large neck masses that have a substantial 
cystic or necrotic component. Clearly, in such cases, there is a risk that the therapeutic agent might 
be delivered into a fluid-filled space within the tumor mass where it is unlikely to mediate the 


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desired biological effects. In such cases, it is possible to perform injections directly without image-
guidance if a definite solid component of the tumor can be identified clinically. If that is not the 
case, it is usually advisable to perform the injections under ultrasonic guidance to enable targeting 
of solid, viable parts of the tumor. 
Another feature of recurrent cancer in the head and neck region is its tendency to be associated 
with dense fibrosis. This is most frequently seen in patients who have undergone previous surgery 
and/or irradiation. In such cases, the precise boundaries of the disease can be difficult to define, 
even with imaging investigations, and injections may have to be delivered using considerable force 
to overcome the high interstitial pressure in the target tissues. This can lead to spread of the 
injection into adjacent tissues away from the tumor-bearing site. In such circumstances, injection 
under image-guidance (preferably ultrasound) at a slow rate is advised in order to retain the 
injected material at the desired site. 
The greatest challenge is presented by patients with disease close to or involving the great vessels 
in the neck. As discussed above, specific concerns should arise when patients have disease that 
encases the carotid artery or its branches to 50% or more of the circumference of the vessel or 
shows radiological signs of invasion of the media or intima of the vessels. In addition, patients 
with disease that bridges a tissue plane connecting a major vessel to the skin or a mucosal surface 
must be considered high-risk for a major hemorrhagic complication. In such cases, a major 
response can lead to the formation of a sinus tract or fistula to the vessel and this can be associated 
with catastrophic bleeding. Additional risk factors for bleeding include prior radiation therapy to 
cumulative doses >100 Gy (achieved in patients who have received re-irradiation) and the presence 
of active bacterial infection in the neck. 
7.4 
Pembrolizumab 
Pembrolizumab is given at a flat dose of 200 mg IV according to the study schedule. There are no 
dose modifications to this treatment other than temporary or permanent discontinuation of therapy 
as detailed below.   
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). 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject from Study Treatment 
Diarrhea/
Colitis 
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 
AST, 
ALT, or 
Increased 
Bilirubin 
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 
diabetes 
mellitus 
(if new 
onset) or 
Hypergly
cemia 
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. 
Hypophy
sitis 
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 
Hyperthy
roidism  
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 
Hypothyr
oidism 
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. 
Infusion 
Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumon
itis 
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 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject from Study Treatment 
Renal 
Failure 
or 
Nephritis 
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 
Toxicity2 
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.   
 
7.4.1 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.   


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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. 
7.4.2 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.  


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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) 
 
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. 


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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. 
o  
• 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. 
Table 3 Infusion Reaction Treatment Guidelines 


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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 from 
further trial treatment 
administration. 
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). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
No subsequent dosing 


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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
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. 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration. 
 
 
7.5 
Radiation therapy 
Radiation (SBRT) will begin on Day 8  
 
Radiation Therapy Guidelines 
 
1. Treatment approaches will use SBRT (or equivalent).  
 
2. Localization requirements: All patients will be immobilized and simulated in the 
treatment position prior to the start of OBP-301. Immobilization devices using an 
aquaplast mask is recommended. A contrast enhanced CT with immobilization is 
recommended for planning. Additional diagnostic imaging may be fused to the contrast 
enhanced CT simulation at the discretion of the treating physician. For patients who 
cannot receive a contrast enhanced CT simultation, non-contrast CT simulation images 
should be fused to diagnostic contrast CT, MRI or PET-CT imaging performed within 
30 days of the CT simulation.  Slice thickness should be optimally 1-3 mm for SBRT. 


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Patients must be reproducibly immobilized. Radio-opaque markers may be used 
whenever possible to delineate the surgical scars, extent of nodal disease, skin 
involvement, and any gross disease. For SBRT, prior to each treatment, socenter or 
reference point localization images (anterior/posterior and lateral) should be obtained 
using a cone beam CT or verification imaging.   
 
 
3. Target volumes: Appropriate target volumes will be determined at the time of simulation 
to treat gross disease and areas of potential microscopic disease as determined by the 
treating physician.  All gross disease above the clavicles should be targeted for SBRT in. 
Two target volumes will be defined on each CT slice: GTV and PTV. In cases of multiple 
tumor sites, the treating physician may designate individual GTV and respective PTV 
planning for each lesion. GTV will be all gross tumor identified by physical exam, 
additional clinical information and radiographic studies before induction chemotherapy. 
The GTV will be expanded by 3 to 5 mm to create PTV.  PTV can be modified at the 
discretion of the treating physician for the constraints of normal tissue tolerance and to 
avoid extension beyond the skin. 
 
 
4. Field Size: Appropriate field sizes will be determined at the time of simulation to treat 
gross disease and areas of potential microscopic disease. Field size and arrangement will 
be at the discretion of the attending radiation oncologist. The optimal field arrangement 
will be determined based on the treatment planning techniques employed. All fields must 
be treated during each treatment session. Only photon (x-ray) beams with photon 
energies 4-10 MV will be allowed. Because of uncertainties in beam commissioning 
resulting from electronic disequilibrium within small beam apertures, a minimum field 
dimension of 3.5 cm is required for any field used for treatment delivery. It is understood 
that this may exceed the technical requirements for small lesions (< 2.5 cm axial GTV 
dimension or < 1.5 cm craniocaudal GTV dimension). In such cases, the prescription 
dose is still prescribed to the edge of the defined PTV. This minimum field dimension 
does not apply to centers using tomotherapy or multiple pencil beam delivery systems. 
 
 
5. Treatment technique: Blocking will be individualized for each patient.  Either custom 
Cerrobend blocks, multileaf collimator or stereotactic cones will be acceptable. 
 
IMRT/VMAT: IMRT/VMAT planning is preferred for SABR. IMRT/VMAT planning 
will depend on the planning system employed.  We anticipate the optimal plan will use 7 
to 11 gantry positions.  Acceptable plans will encompass the PTV with the 95% isodose 
line.  No more than 1% of the PTV should receive less than 95% of the prescribed dose.  
Plans should be reviewed to ensure that any part of the PTV getting less than 93% of the 
prescribed dose is at the edge of the volume.  In no case should a central area of the PTV 
receive less than 95% of the prescribed dose.  No more than 20% of the PTV should 
receive more than 110% of the prescribed dose.  
 


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3D Conformal Radiotherapy: Three-dimensional coplanar or non-coplanar beam 
arrangements will be custom designed for each case to deliver highly conformal 
prescription dose distributions. Non-opposing, non-coplanar beams are preferable. 
Typically, ≥ 10 beams of radiation will be used with roughly equal weighting. Generally, 
more beams are used for larger lesion sizes. When static beams are used, a minimum of 
seven non-opposing beams should be used. For arc rotation techniques, approximate 
rotation of 340 degrees (cumulative for all beams) should be utilized. For this protocol, 
the isocenter is defined as the common point of gantry and couch rotation for the treatment 
unit. Field aperture size and shape should correspond nearly identically to the projection 
of the PTV along a beam’s eye view (i.e., no additional “margin” for dose buildup at the 
edges of the blocks or MLC jaws beyond the PTV). The only exception will be when 
observing the minimum field dimension of 3.5 cm when treating small lesions (see above). 
As such, prescription lines covering the PTV will typically be the 60-90% line (rather than 
95-100%); however, higher isodoses (hotspots) must be manipulated to occur within the 
target and not in adjacent normal tissue. The plan should be normalized to a defined point 
corresponding closely to the center of mass of the PTV.  For 3D techniques, acceptable 
plans will encompass the PTV within the 95% isodose line. The dose variation in the PTV 
will be +20% and -5% of the prescription point dose. 
 
Dose Fractionation: Isodose calculations in the axial, sagittal, or coronal planes are 
required. In addition, dose volume histograms for the GTV and the spinal cord are 
required. 
 
SBRT Radiation will be delivered in 800 to 880 cGy fractions to a total dose of 4000 to 
4400 cGy (5 fractions total). Tumors <25 cm3 should receive 800 cGy per fraction for 5 
fractions to 40 Gy; tumors ≥25 cm3 should recieve 880 cGy per fractions for 5 fractions 
to 44 Gy. Each fraction will be given > 40 hours from the prior fraction (i.e. at least every 
other day) over a 2.5 week period. Ideally, treatment should be completed within 10 days. 
However, in case of holidays or unforeseen circumstances, treatment can be completed 
within 2.5 weeks.  
The dose per fraction is to be prescribed to the prescription line at the edge of the PTV. 
 
Normal Tissue Constraints/Dose Volume Histograms: The dose limit to the spinal cord will 
vary depending upon the technique used.  All attempts should be made to limit the spinal cord dose 
to < 1000 cGy. The cumulative spinal cord dose should not exceed 5000 cGy at the equivalent 
dose of 2 Gy per fraction (EQD2) for all patients.  In cases where cumulative spinal cord doses 
exceeds 5000 cGy, the cumulative maximum spinal cord dose may be as high as 5500 cGy at the 
equivalent dose of 2 Gy per fraction (EQD2) ONLY for patients where the interval between initial 
radiotherapy and re-irradiation is ≥ 2 years. The cumulative brainstem dose should not exceed 
6000 cGy at the equivalent dose of 2 Gy per fraction (EQD2) for all patients. If prior radiotherapy 
plans are not available to assess the cumulative spinal cord dose, then the spinal cord dose from 
the initial radiotherapy plan should be assumed to be 5000 cGy. Equivalent doses will be estimated 
using the equation: Equivalent dose in 2Gy fractions (EQD2) = D x ({d + (α/β)}/{2 + (α/β)}). The 
α/β ratio will be assumed to be 1 for the cervical spinal cord and 2 for the brainstem. Isodose 
calculations in the axial, sagittal, or coronal planes are required. In addition, dose volume 


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histograms for the planning treatment volumes and the following OARs are brachial plexus, 
carotid artery, parotid, cochlea, optic nerves, optic chiasm, larynx, esophagus. No more than 5% 
of any OAR or any other normal tissue should receive doses in excess of 110% of the primary 
PTV dose. Ultimate inclusion of the normal structures and exceptions from the above guidelines 
will be made at the discretion of theattending Radiation Oncologist. 
 
The radiotherapy safety monitoring committee (RSMC): All radiation plans and dose 
statistics/dose volume histograms will be reviewed prior to initiating treatment by the RSMC. The 
RSMC is an independent safety monitoring committee formed by several radiation oncologists 
with expertise in the SBRT techniques and not involved in the study. 
Supportive Guidelines 
• Antiemetics will be ordered at the discretion of the attending physician. 
 
• Use of a feeding device is recommended for high-risk patients. Placement of a feeding 
device is left to the discretion of the treating physician/investigator. Commonly applied 
criteria for feeding device placement include 
i. Loss of > 10% of body weight from the start of therapy 
ii. Dehydration or inability to maintain adequate oral hydration 
iii. Inability to maintain intake of > 25 kcal/kg of ideal body weight 
 
• During radiotherapy patients may receive instructions for oral hygiene and prescriptions 
to include: 
i. Oral nystatin or fluconazole (100mg QD) 
ii. Viscous lidocaine HCl (Xylocaine) solution) and/or Grade I mouthwash 
10ml QID, swish and spit 
 
Table 5: Grade I mouthwash (Magic Mouthwash) 
Lidocaine, Viscous (2%) 
50 mL 
Diphenhydramine elixir (12.5 mg/5 mL) 50 mL 
Sodium bicarbonate injection 
100 mL 
Normal saline irrigation 
500 mL 
Total volume 
700 mL 
 
iii. Normal saline mouthwash 10ml QID swish and spit 
 
iv. Natural Care Gel (or similar product) BID during chemoradiotherapy and TID 
during rest week. 
 
v. Vigilon (or similar product) to be applied to open wounds during 
chemoradiotherapy. 
 


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vi. Silvadene cream to open wounds followed by zinc oxide cream and then Telfa 
dressings BID during rest week (N.B.: discontinue Silvadene and zinc oxide 
creams 1 day prior to radiotherapy). 
 
vii. Aquaphor (or similar brand) cream to lips PRN. 
 
viii. Adequate analgesia is essential to maintain oral intake and patient comfort. 
Narcotic analgesics are usually necessary and should be used at the 
physician/investigator discretion. 
 
ix. Therabite for trismus if appropriate. 
 
x. Replacement for electrolyte imbalances when applicable.   
 
• Prior to discharge of the patients after a cycle of chemoradiation, a CBC and platelet count, 
and determination of serum electrolytes, including creatinine will be done  
 
• Use of intravenous home hydration is strongly recommended in patients with inadequate 
oral intake: normal saline 1000ml IV QD during rest week (days 6-14). 
 
• If Hgb < 10, patients should generally be transfused an amount sufficient to increase Hgb 
to  10.  The Hgb level should be maintained > 11 mg/dl for the duration of 
chemoradiotherapy in all patients.  
 
8 
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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8.1 
Schedule of Events (SoE) 
Any treatment delays for less than five days will not be considered a study deviation. 
 
Screening Phase 
 
Treatment Phase 
Treatment Encounter 
Part 1 
Part 2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Scheduling Window 
(-28 to 
1) 
(-14 to 
-1) 
Day 
1 
Day 
8 
Day 
15 
Day 
18 
Day 
22 
Day 
25 
Day 
29 
Day 
31 
Day 
52 
Day 
73 
Day 
94 
Day 
115 
Day 
136 
Day 
157 
Day 
178 
Week 26 
onwardsg 
End of 
Studyh 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication Reviewe 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
Physical Examinatione 
 
X 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
Vital Signs and Weighte 
 
X 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Xg 
X 
ECOG Performancee 
Status 
 
X 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Xg 
X 
Pregnancy Test- Urine 
or Serum β-HCG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR AND aPTT 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC & Serum 
Chemistrya 
 
X 
Xl 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Xf 
X 
T3, FT4 and TSH 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Xf 
X 
ECG 
 
Xi 
 
 
 
 
As clinically needed 
Tumor Imaging - CT 
Preferredb 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Xb 
X 
Tissue Biopsyj 
X 
 
Xk 
X 
 
X 
 
 
 
 
 
 
Xm 
 
 
 
 
 
 
Correlative Blood 
Collectionc 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
Xc 
 
 
 
 
 
Xc 
SBRT 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
OBP-301d 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pembrolizumab 
Administrationd 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
 
Review Adverse Events 
 
 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
 
 


                                                                                                                    Page 64 of 99  
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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. 
b. Tumor imaging studies preferably CT scans of chest/abdomen/pelvis should be performed every three cycles of pembrolizumab after week 26 
until end of study.  
c. Correlative blood collection will be done during screening phase (-14 to -1), on day 1 (prior to drug administration), day 8, day 18, day 22, day 
94 (optional), and at the end of study. Baseline correlative bloods can be collected on study Day 1 if missed during screening. Correlative blood 
draws will be done pre-dose if treatment is given on the same day.  
d. Pembrolizumab and OBP-301 can be administered with a ± 5 day window in accordance with the above treatment plan. Pembrolizumab will 
be administered on day 8 and then every 3 weeks ± 5 days starting on day 31.  
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 26 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 1 year 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. If there is no archival tissue 
available, tissue collection for PD-L1 testing and correlative studies will be performed during screening phase. If patient is determined to be PD-
L1 negative they are not eligible for the study and the additional tissue that was collected for correlative studies will be returned to pathology. 
k. If biopsy was performed  during screening  phase to confirm PD-L1 status, No biopsy should be performed on Day 1.  Day 1 biopsy only to be 
performed for correlative studies if a biopsy was not performed at baseline. 
l. Only needed, if screening CBC and chemistry done more than 7 days prior to first cycle of pembrolizumab.  
m. An optional biopsy will be done on Day 94 +/- 5 days.


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8.1.1  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 
8.1.2 Treatment Phase 
Pembrolizumab infusions will be administered on day 8 and then every 3 weeks ± 5 days 
starting on day 31 until disease progression or patient is withdrawn for another reason or up to 
one year if no progression.  
OBP-301 only, is to be administered on D1, then in combination with pembrolizumab on D8, 
then in combination with SBRT on D18 and D25, then again in combination with 
pembrolizumab every 3 weeks on days D31, D52, D73, D94, D115, D136, D157 and D178. 
On days that both Pembrolizumab and OBP-301 are administered, there is no specificity to 
which drug should be administered first.The target tumor will be injected with OBP-301 up to 
12 times during the entire study.  
All patients will receive OBP-301 at a concentration of 1x1012 viral particles/ml injection. 
Volume to be injected is up to 4ml and will depend on lesion size i.e. the longest diameter of 
the lesion) (see Table 1, section 5.2.2 above). 
8.1.3 Follow up Phase 
Patients with disease progression will be followed every 3 months for survival for up to 2 years 
after last treatment. If patient unable to come for follow up, the assessment can occur by 
telephone or some other remote monitoring. 
8.1.4 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 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. 
Psuedo-progression occurs very rarely in head and neck cancer. If the patient is 
asymptomatic, after apparent disease progression (PD) is observed as per iRECIST, a 
biopsy of the lesion should be done to evaluate response. If progression is documented by 
the biopsy, administration of OPBP-301 will be discontinued. If response is confirmed by 
the biopsy, administration of OBP-301 may be continued. 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, at the repeated scan, the 
disease progression is not clinically significant, then the patient may continue to receive 
OBP-301 treatment. 
 


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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 
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.   
8.2 
Informed Consent Form (see appendix) 
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. 
8.3 
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. 
8.4 
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, 


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and year).  Therapy changes (including changes of regimen) during the study have to be 
documented.  All concomitant medications will be recorded in the eCRF. 
8.5 
Safety Assessments 
8.5.1 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. 
8.5.2 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. 
 
8.5.3 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. 
8.5.4 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 


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abnormal – clinically significant. If clinically indicated, additional ECGs may be obtained 
during the study. 
8.5.5 Laboratory Assessments 
8.5.5.1 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. 
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 
 
8.5.5.2 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 


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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. 
8.6 
Efficacy Assessments  
8.6.1 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 CT scans at regular 
intervals at the treating physician discretion. The first CT scan will be performed at 9 weeks 
after the initial CT scan. While the patient is on study CT scans should be performed every 9 
weeks (-1 week/+3 week window).. Efficacy end points will be assessed according to RECIST 
1.1 and iRECIST criteria.  
8.6.2 Definitions of Measurable and Non-Measurable Disease 
8.6.2.1 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. 
 
8.6.2.2 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.  
8.6.3 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. Intervals between scans 
should not exceed 12 weeks. Following designations will be assigned according to RECIST 
1.1 and iRECIST (see appendix below for differences in RECIST 1.1 and iRECIST). The 


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primary end point-response criteria is RECIST 1.1 in both injected and uninjected target 
lesions. iRECIST is only a secondary end point response criteria. 
8.6.3.1 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.  
8.6.3.2 Partial Response (iPR)* 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters.  
8.6.3.3 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 (i.e., target or non-target disease), or progression 
(defined by RECIST 1.1) in lesion categories that had not previously met RECIST 1.1 
progression criteria. However, if progression is not confirmed, but instead 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. 
8.6.3.4 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. 
 
8.6.4 Determination of Tumor Stage According to 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 assessment, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before confirming the complete response 
status. 


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8.7 
Biopsies and Immune Monitoring (optional) 
In order to observe a potential response in the non-injected lesions, if several tumors are 
present, biopsies will be taken at baseline (Day 1) and on Day 18 both from an injected tumor 
and a non-injected tumor and a comparison will be done between them. 
 
Standard fine needle biopsies will be taken on the following days: 
1. Day 1, prior to therapy, 
2. Day 8, prior to therapy (to see the effect of OBP-301 alone), 
3. Day 18, prior to therapy (to see the effect of OBP-301 together with 
pembrolizumab).  Given the fact that three biopsies will be done within approximately 
3 weeks, special attention will be given to potential side effects (i.e. bleeding, etc.) that 
can be associated with the biopsy procedures. 
4. Optional on Day 94 +/- 5 days (to see the effect of OBP-301 + pembrolizumab + 
SBRT). 
  
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. 
 
9 
ADVERSE EVENTS 
9.1 
Definitions  
9.1.1 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 
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: 


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• 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) 
9.1.2 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 5.0 (dated 27 Nov 2017) 65. 
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 
• 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 
9.1.3 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 


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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 
9.1.4 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.    Procedures for notification of pregnancies and follow-up 
are described in Section.  


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9.1.5 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. 
9.2 
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 
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. 


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9.2.1 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.     
 
9.2.2 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.    
9.2.3 Follow-up of Adverse Events and Serious Adverse Events 
In this study, non-serious AEs will be reported in all participants from Treatment 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.   
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. 
9.2.4 Reporting of SAE to IRB 
All SAEs occurring after study treatment on this study will be reported to the IRB according 
to the IRB policy, which can be accessed via the following link:   
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Po
licy.pdf.  
 
 For WCM investigator-initiated studies, the following reporting guidelines apply:  


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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 
9.2.5 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  
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. 
Investigator should report applicable adverse events to FDA per 21 CFR 312.32. The applicable 
form, such CIMOS or Medwatch that Investigator reported to FDA must also be provided to 
Oncolys BioPharma Inc (safety@oncolys.com) when SAE was considered OBP-301 related. 
In the case of unexpected fatal or life-threatening suspected adverse reaction, Investigator 
should provide the FDA report form to Oncolys no later than 3 days following Oncolys’ initial 
receipt of the information. Additionally, in the case of other SAE must be reported to FDA 
within 15 days of learning of the adverse event, investigator should provide the FDA report 
form to Oncolys no later than 7 days following Oncolys’ initial receipt of the information. 
Reporting of any SAEs to applicable regulatory authorities will be the responsibility of Oncolys 
BioPharma Inc. in compliance with local regulations. 


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9.2.6 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 [32]. 
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. 
9.2.7 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. 
Full details will be recorded on the withdrawal page of the eCRF. 
 
9.3 
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.  
10 STATISTICAL ANALYSES 
10.1 General Considerations 
The statistical evaluation will be performed using SAS®, version 9.4 or later.   


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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.  
10.2 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.  
10.3 Handling of Missing Values and of Values outside the Detection Limits  
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. 
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. 
10.3.1 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.  
 
10.3.2 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. 
10.4 Analysis Populations 
10.4.1 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. 


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10.4.2 Evaluable Population 
Any patient that has at least one radiographic assessment on study 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. Inevaluable patients will be replaced. 
 
10.4.3 Intent-to-Treat (ITT) Population 
All patients who are enrolled and allocated to treatment are included in the intent-to-treat 
population analysis. 
 
10.4.4 Per-Protocol (PP) Population 
Per-Protocol population will only include individuals who completed all twelve doses of OBP-
301 and followed the study protocol. 
10.5 Efficacy Analysis 
10.5.1 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 (PR) plus complete responses 
(CR) as defined by RECIST v1.1 criteria. 
 
10.5.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the disease control rate (DCR), duration of response 
(DoR), progression-free survival (PFS), and overall survival (OS). A secondary efficacy 
endpoint will also be the objective response rate (ORR), as measured by RECIST 1.1 and 
iRECIST 1.1 criteria.  
 
DOR is defined as the duration that subjects who have responded to combination therapy 
remain without disease progression.  
 
DCR is defined as the percentage of patients who have achieved complete response, partial 
response and stable disease. 
 
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. 
 
OS is defined as the time from registration until death from any cause, 


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10.5.3 Exploratory Analysis  
Correlative endpoints include the following: 
• To monitor viral replication post-treatment, viral protein expression in biopsies will be 
examined by immunostaining (Hexon) or FACS (CAR).  
• To examine the tumor-immune microenvironment prior to and following OBP-301 and 
pembrolizumab therapy as assessed by immunohistochemistry. 
• To examine and characterize the immune infiltrate by multi-parameter flow cytometry. 
• To identify possible biomarkers (i.e. exosomes, ctDNA) for response and mechanism of 
resistance by longitudinal profiling of patients before and after immunotherapy + OBP-301 + 
SBRT.  
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). 
10.6 Correlative Studies 
The purpose of our correlative studies is to identify potential associations between 
biomarkers and certain outcomes and not to for identifying predictive biomarkers. All 
patients undergoing treatment with OBP-301 will have tissue biopsies along with correlative 
blood samples. In order to observe a potential response in the non-injected lesions, if several 
tumors are present, biopsies will be taken both from an injected tumor and a non-injected 
tumor and a comparison will be done between them. Tissue biopsies will be performed at: 
-At screening (day -14 to -1)  
-Day 1 BEFORE administering the first dose,  
-then Day 8 to see the effect of OBP-301 alone,  
-then Day 18, to see the effect of OBP-301 together with pembrolizumab, 
-then at Day 94 to see the effect of OBP-301 + pembrolizumab + SBRT.   
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 detect viral replication in the tumor environment. To examine the tumor-immune 
microenvironment prior to and following OBP-301 and pembrolizumab therapy  
In order to detect viral replication in the tumors, post-treatment with OBP-301, biopsies will 
be immunostained for adenovirus proteins (Hexon AB1056; Millipore, Burlington, M) 65. In 
patients that the presence of the virus is not detected we will perform Coxackie Adenovirus 
Receptor (CAR) expression analysis by FACS68. 
Also, we will perform detailed cellular characterization of head and neck 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 will correlate the response to the oncolytic virus with the presence/absence of the virus 
using a Fisher exact test. 
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 analysis: Identify and quantify the cellular composition of tumor and 
adjacent normal tissues from head and neck cancer patients. In order to observe a potential 
response in the non-injected lesions, if several tumors are present, biopsies will be taken both 
from an injected tumor and a non-injected tumor and a comparison will be done between them. 
We will generate a patient-specific profile of tumor microenvironment. We will identify the 
cell types that are present in each patient at onset of treatment and how cellular composition 
changes in response to treatment. By immunostaining, flow cytometry or RNA sequencing 
using computational approaches we will cluster the cells from each sample by their expression 
profile to distinct groups representing specific cell types (e.g. tumor cells, lymphocytes, 
CD45+, squamous epithelium). Similarly, we will identify various immune cells such as but 
not limited at, CD8+ and CD4+, effector T cells, Treg and others immune subtypes and correlate 
with microbiome composition. Using this data, we will try to find correlates between different 
tumor-immune microenvironment components and clinical outcome. In addition, we will 
survey levels of PD-1, PD-L1/2, CD28 and other known marker of checkpoint inhibitor 
response.  
We will correlate the responses to the oncolytic virus with the presence/absence of the stromal 
changes using a Fisher exact test. 
B. Longitudinal profiling of patients before and after immunotherapy + OBP-301 + 
SBRT to identify possible biomarkers for response and mechanism of resistance 
We will do longitudinal profiling of patients before and after immunotherapy + OBP-301 to 
identify possible biomarkers for response and mechanism of resistance.  
We plan to investigate different biomarkers i.e. circulating tumor DNA (ctDNA) and tumor 
and plasma exosomes.  


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B1. The Cancer Genome Atlas demonstrated that specific genes and pathways are commonly 
altered in head and neck cancer, namely TP53, NOTCH1, PIK3CA, among other genes69. 
Also, predictable genetic alterations underlie HPV positive HNSCCs, such as the presence of 
HPV-16 viral DNA, p16INK4A overexpression. Researchers have found HPV DNA present in 
blood70, offering the possibility of a simple blood draw or saliva swab to detect cancer.  
We will investigate the utility of using ctDNA and exosomes both in HPV positive and HPV 
negative tumors to monitor response after immunotherapy + OBP-301 + SBRT. 
We will correlate the responses to the oncolytic virus with the presence/absence of the ctDNA 
changes using a Fisher exact test. 
B2. Another potentially interesting biomarkers are exosomes. The cargo of plasma exosomes 
from head and neck patients may contain valuable biomarkers with predictive value for head 
and neck cancer progression and response to therapies. Blood and tissue will be obtained from 
patients. Tissue will be obtained from prior surgeries. Tissue will be examined for extracellular 
matrix composition and cellular infiltrate using immunofluorescence (IF, classical or Hyperion 
mass cytometry based), immuno-histochemistry (IHC) or flow cytometry. Blood will be placed 
into EDTA coated tubes and centrifuged at 500 x g for 10 minutes at 4°C, followed by a second 
centrifugation step at 3000 x g for 20 minutes at 4°C and plasma will be stored at -80oC until 
the time of analysis. Tissues will be embedded in paraffin as well as O.C.T. and frozen.  
At the time of analysis, which will be performed in the lab of Dr. David Lyden at Weill Cornell 
Medical College/Cornell University, exosomes will be isolated from plasma, media from tumor 
biopsy tissue cultures by serially ultracentrifugation. Exosome size and number will be 
quantified using nanoparticle tracking analysis (Nanosight®, Malvern), and exosome cargo 
will be characterized using genomic and proteomic approaches (DNA/RNA sequencing, real-
time PCR and mass spectrometry, Western blot or Elisa).  
We will correlate the responses to the oncolytic virus with exosome number, size and cargo 
changes using a Fisher exact test. 
We will summarize the results from all patient data to assess what are the consistent changes 
observed in biomarkers in response to immunotherapy and we will investigate how these 
biomarkers are related to response to treatment.  
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. Investigators in Weill 
Cornell have 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 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. To examine and characterize 
the phenotype of immune infiltrates.  


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We will correlate the responses to the oncolytic virus with the presence/absence of immune 
infiltrates changes using a Fisher exact test. 
D. To investigate the presence of circulating tumor cells before, after treatment and at 
recurrence/progression in the blood using TelomeScan Telomescan. 
TelomeScan TelomeScan (OBP-401) a new telomerase-based liquid biopsy biomarker, will be 
used to detect the presence of circulating tumor cells in the blood. This technique allows the 
specific staining of circulating blood will be drawn before beginning of treatment, after 
completion of SBRT and at recurrence/progression.  
The blood sample processing for sequential monitoring of circulating tumor cells 
(CTCs)analysis using TelomeScan is described in the Standard Operation Procedure is 
included as appendix A. 
Specimen type 
Timepoint 
ACD tube x1 
8.5ml  
Screening 
Day 1 
Day 8 
Day 18 
Day 22 
Day 94 
Upon progression or end of study 
 
We will correlate the responses to the oncolytic virus with the presence/absence of CTCs in 
the peripheral blood using a Fisher exact test. 
 
10.7 Safety Analyses 
10.7.1 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. 
 
10.7.2 Summary of Adverse Events 
All adverse events, 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 


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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. 
10.7.3 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). 
10.7.4 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.   
10.7.5 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. 
10.7.6 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. 
10.7.7  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. 
10.7.8 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.  
10.7.9 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. 


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Accrual will be temporarily suspended to the study to allow for a full review of data 
according to the following AE stopping rule:  
(1)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.   
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.  
 (2) If grade 5 (death) event at least possibly, probably or definitely related to OBP-
301 injection, the study will be halted.  
(3) 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.  
 
10.7.10 Adverse Event Dose De-escalation 
If, after the first injection of OBP-301, 3 of the first 12 patients enrolled have experienced at 
least one grade 3 or worse immune related adverse event or adverse event related (possibly, 
probably, or definitely) to OBP-301 injection i.e. rash, joint aches, fatigue, thyroid 
abnormalities, or other immune related events that are not life threatening the concentration of 
OBP-301 will be reduced from 1 × 1012 VP/mL to 1 × 1011 VP/mL. Further de-escalation will be 
considered (i.e decrease of the number of OBP-301 injections by 25%) if more patients develop after 
the first injection at least one grade 3 or worse immune related adverse event or adverse event 
related (possibly, probably, or definitely) to OBP-301 injection i.e. rash, joint aches, fatigue, 
thyroid abnormalities, or other immune related events. 
If needed, OBP-301 dose level will be DE-ESCALATED to 1×1011 viral particles (vp)/mL 
(up to 4 mL of OBP-301 should be injected based on the tumor volume)) per intra-tumoral 
injection.   
 The following dilution instructions will be used:  
10.7.11 OBP-301 10x Dilution Procedure: 
1. Preparation Step: Use injection syringe to suck the 1 ml from 1x10^12 vp/mL vial. 
and use diluted solution syringe to suck the 9 mL D5W (Dextrose 5% in Water). 
2. Dilution Step: Slowly push 1 mL OBP-301 to Diluted solution syringe, and vertically 
mix in gentle motion for 20 times (The concentration of diluted solution syringe 
would be 1 x 10^11 vp/mL). 


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Injection syringe      T shape stopcock Or luer lock connector  Diluted solution (D5W) syringe  
                        1 mL                                                                                                     9 mL 
 
10.8 Determination of Sample Size 
Phase II study: 
Statistical Considerations: 
 
The primary endpoint for this study will be the objective response rate (CR + PR).  Sample size 
recommendations for the phase II design are determined according to Simon’s two-stage design 
(Simon R, 1989).  We project an objective response proportion of 61%, below which the 
response will be unacceptable, and an objective response proportion of 78%, above which the 
regimen will be considered worthy of further exploration.  The null hypothesis that the 
objective response proportion is less than or equal to 61% will be tested against the alternative 
hypothesis that the response proportion is greater than or equal to 78%. 
The sample size computations were performed assuming 10% level of significance and 80% 
power.  In the first stage, 12 patients will enter the study.  If 7 or fewer respond, the study will 
be terminated early and declared to have a negative result.  If 8 or more patients respond, 
enrollment will be extended to 36 patients.  At Stage 2, the treatment will be declared effective 
and worthy of further testing if 26 or more patients respond among the 36 patients entered.  
This two-stage design yields a ≥ 0.80 probability of a positive result if the true percentage of 
overall responders is ≥ 78%.  It yields a ≥ 0.90 probability of a negative result if the true 
percentage of overall responders is ≤ 61%. A 95% confidence interval constructed around the 
expected objective response proportion of 78% can be estimated to be within ± 16.0% of the 
observed response proportion.   
 
Assuming 10% are unevaluable/ineligible, we anticipate that a total of 14 patients will be 
enrolled in the first stage, 40 in both the first and second stage if the study proceeds to the 
second stage. 
 
Table 1. Numbers of observed responders required to accept or reject H0 at each stage. Under 
this design, H0 will not be rejected at Stage 1. 
 
 
 
 
N 
Accept H0 
Reject H0 
Stage 1 
12 
 7 
--- 
Stage 2 
36 
 25 
>26 


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Analysis Plan for Endpoints: 
 
Primary Endpoint: 
The primary endpoint of objective response rate (CR + PR) will be estimated and a 95% 
confidence interval will be estimated via binomial proportions. 
 
Secondary Clinical Endpoints: 
With adequate follow-up time, secondary endpoints of progression-free survival (PFS) and 
overall survival (OS) will be assessed by Kaplan-Meier survival analysis and 95% confidence 
intervals will be calculated using Greenwood’s formulae.  PFS will be defined as the time 
from first treatment day until objective or symptomatic progression or death.  OS will be 
defined as the time from first treatment day until death. 
The frequency of subjects experiencing toxicities in each treatment arm will be tabulated. 
Toxicities will be assessed and graded according to CTCAE v. 5.0 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). For Reference 
of the Phase 2 design see 41. 
 
Analysis Plan for Endpoints: 
 
Primary Endpoint: 
The primary end point is the objective response rate (ORR) according to RECIST v. 1.1 of 
multiple OBP-301 intratumoral injections in combination with pembrolizumab in recurrent 
locally advanced head and neck cancer. The frequency of subjects experiencing toxicities will 
be tabulated. Toxicities will be assessed and graded according to CTCAE v 5.0 terminology.   
 
Secondary endpoints: 
Secondary endpoints include the OS proportion at 1 year, the Kaplan-Meier progression free 
survival (PFS) and the toxicity profile of this three treatments combination. Median 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. 
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). 
 


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11 REGULATORY REQUIREMENTS 
11.1 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. 
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. 
11.2 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. 
11.3 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. 


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11.4 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. 
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. 
11.5 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 


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participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information. 
12 DATA AND SAFETY MONITORING PLAN (DSMP) 
12.1  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.  
 
12.2 The radiotherapy safety monitoring committee (RSMC) 
 
In order to avoid radiation toxicities, an independent safety monitoring committee formed by 
several radiation oncologists with expertise in the SBRT techniques and not involved in the 
study will review all radiotherapy treatment plans. 
 
13 ADMINISTRATIVE PROCEDURES 
13.1 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.  
13.2 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.   
13.2.1 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, 


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enhanced and supported through a multi-institutional consortium led by the Vanderbilt 
University CTSA. 
13.3 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.   
13.4 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. 
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 HIPAA64, applicable to national and/or local laws and 
regulations on personal data protection. 
13.5 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.  
14 CLINICAL STUDY REPORT 
 
We will provide the clinical study report to Oncolys Biopharma within 1 year of study 
completion.  
 


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15 APPENDICES 
15.1 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. 
 
 
15.2 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-
randomized 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 


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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—i.e., 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  
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. 
 
15.3 Appendix  
See attached Informed Consent and Clinical Trials Monitoring Plan including the SBRT Safety 
form.  
 
 
14. REFERENCES: 
1.  
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
Cancer. 2012;12(4):252-264. 
2.  
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in 
patients with advanced cancer. N Engl J Med. 2012;366(26):2455-2465. 
3.  
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, al. e. Safety, activity, and 
immunecorrelates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-
2454. 
4.  
Robert C, Long GV, Brady B, Dutriaux C, Maio M, al. e. Nivolumab in previously 
untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330. 
5.  
Robert C, Schachter J, Long GV, et al. pembrolizumab versus ipilumumab in advanced 
melanoma. N Engl J Med. 2015;372(26):2521-2532. 
6.  
Brahmer J, Reckamp KL, Bass P, Crino L, Eberhardt WE, al. e. Nivolumab versus 
docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 
2015;373(2):123-135. 


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7.  
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, al. e. Nivolumab versus 
docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 
2015;373(17):1627-1639. 
8.  
Garon EB, Rizvi NA, Hui R, Leighl N, Balmonoukian AS, al. e. pembrolizumab for 
the treatmnt of non-small cell lung cancer. N Engl J Med. 2015;372(21):2018-2028. 
9.  
Reck M, Rodriquez-Abreu D, Robinson AG, et al. pembrolizumab versus 
chemothreapy for PD-L1 positive non-small cell lung cancer. N Engl J Med. 
2016;375(19):1823-1833. 
10.  
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in 
advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. 
13.  
Chow LQM, et al. Antitumor Activity of pembrolizumab in Biomarker-Unselected 
Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: 
Results From the Phase Ib KEYNOTE-012 Expansion Cohort. J Clin Oncol 34 (32) 
(November 2016) 3838-3845. 
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