A Study to Assess Overall Response Rate by Inducing an Inflammatory Phenotype in Metastatic BReast cAnCEr With the Oncolytic Reovirus PeLareorEp in CombinaTion With Anti-PD-L1 Avelumab and Paclitaxel - BRACELET-1 Study
Phase: PHASE2
Conditions: Breast Cancer Metastatic
Sponsor: Oncolytics Biotech

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
 
PrECOG Protocol Number: PrE0113 
Oncolytics Biotech Inc. Protocol Number: REO 028 
 
A study to assess overall response rate by inducing an inflammatory 
phenotype in Metastatic BReast cAnCEr with the Oncolytic Reovirus 
PeLareorEp in CombinaTion with anti-PD-L1 Avelumab and Paclitaxel –  
BRACELET-1 Study 
 
STUDY CHAIR: 
Kathy D. Miller, MD 
STUDY CO-CHAIRS: 
Amy Clark, MD 
ECOG-ACRIN COMMITTEE CHAIR: 
Antonio Wolff, MD 
STATISTICIAN: 
Fengmin Zhao, PhD 
PRECOG STUDY SITE CONTACT: 
Carolyn Andrews, RN 
MEDICAL MONITOR: 
Ashok Srivastava, MD, PhD, MBA 
SPONSOR: Oncolytics US Ref. ID Number: REO 028 
 
 
IND #: 
12318 
Version Number: 
3.0 
Version Date: 
21 July 2022 
Release/Revision History 
Version 1.0: 10/30/2019 
Not Released to Sites: Administrative Changes Incorporated 
Version 1.1: 12/05/2019 
Released to Sites 
Version 1.2: 04/27/2020 
Released to Sites 
Version 2.0: 03/25/2021 
Released to Sites 
Version 3.0 07/21/2022 
Released to Sites 
 
This protocol contains information that is confidential and proprietary 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
2 
Table of Contents 
Brief Protocol Synopsis ...............................................................................................................................5 
List of Abbreviations ....................................................................................................................................6 
1. 
Introduction- Background and Rationale ........................................................................................ 10 
1.1 
Breast Cancer – Disease Overview ........................................................................................... 10 
1.2 
Reovirus ..................................................................................................................................... 10 
1.3 
Pelareorep ................................................................................................................................. 10 
1.4 
Pelareorep – Clinical Experience ............................................................................................... 11 
1.5 
Avelumab ................................................................................................................................... 12 
1.6 
Paclitaxel .................................................................................................................................... 13 
1.7 
Summary of Rationale for Proposed Study ............................................................................... 13 
2. 
Study Objectives ................................................................................................................................ 17 
2.1 
Primary Objective ....................................................................................................................... 17 
2.2 
Other Objectives (these objectives are all exploratory) ............................................................. 17 
3. 
Selection of Patients .......................................................................................................................... 18 
4. 
Registration Procedures .................................................................................................................... 22 
4.1 
Ethics ......................................................................................................................................... 22 
4.2 
Regulatory Requirements .......................................................................................................... 22 
4.3 
Patient Registration .................................................................................................................... 22 
4.4 
Research Tissue and Blood Samples ........................................................................................ 23 
5. 
Treatment Plan ................................................................................................................................... 24 
5.1 
Overview .................................................................................................................................... 24 
5.2 
Cohort 3 Safety Run-In .............................................................................................................. 24 
5.3 
Treatment and Administration Schedule .................................................................................... 25 
5.4 
Premedications .......................................................................................................................... 27 
6. 
Dose Modifications and Discontinuation of Therapy ..................................................................... 28 
6.1 
Dose Delays & Modifications ..................................................................................................... 28 
6.2 
Concurrent Therapies ................................................................................................................ 35 
7. 
Study Duration and Discontinuation of Therapy ............................................................................ 37 
7.1 
Study Duration – General Considerations ................................................................................. 37 
7.2 
End of Study .............................................................................................................................. 37 
7.3 
Duration of Follow-Up ................................................................................................................ 37 
7.4 
Criteria for Removal from Study Treatment ............................................................................... 37 
8. 
Adverse Event Reporting .................................................................................................................. 39 
8.1 
AE Definition .............................................................................................................................. 39 
8.2 
Assessment of Seriousness ...................................................................................................... 39 
8.3 
Assessment of Severity ............................................................................................................. 39 
8.4 
Assessment of Causality ............................................................................................................ 39 
8.5 
Unexpected Adverse Event ....................................................................................................... 40 
8.6 
Time Period for Collecting AEs and SAEs ................................................................................. 40 
8.7 
Documentation of AEs and SAEs .............................................................................................. 41 
8.8 
Follow-up of AEs and SAEs ....................................................................................................... 41 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
3 
8.9 
Reporting Serious Adverse Events ............................................................................................ 41 
8.10 Special Situation Reports........................................................................................................... 42 
8.11 Reporting of Other Second Primary Cancers ............................................................................ 43 
9. 
Measurement of Effect ....................................................................................................................... 44 
10. Study Parameters ............................................................................................................................... 45 
11. Drug Formulation and Procurement ................................................................................................ 49 
11.1 Pelareorep ................................................................................................................................. 49 
11.2 Avelumab ................................................................................................................................... 50 
11.3 Paclitaxel .................................................................................................................................... 51 
12. Statistical Considerations ................................................................................................................. 52 
12.1 Cohort 3 Safety Run-In .............................................................................................................. 52 
12.2 Analysis Populations .................................................................................................................. 52 
12.3 General Considerations ............................................................................................................. 53 
12.4 Efficacy Analyses ....................................................................................................................... 53 
12.5 Biomarker Analyses ................................................................................................................... 53 
12.6 Sample Size Considerations ...................................................................................................... 53 
12.7 Additional Analyses .................................................................................................................... 54 
13. Laboratory and Pathology Correlative Studies ............................................................................... 55 
13.1 Correlative Studies: Optional Tumor Samples........................................................................... 55 
13.2 Correlative Studies: Mandatory Peripheral Blood Samples ....................................................... 55 
14. Administrative .................................................................................................................................... 57 
14.1 Protocol Compliance .................................................................................................................. 57 
14.2 Institutional Review Board (IRB) ................................................................................................ 57 
14.3 Informed Consent Procedures ................................................................................................... 57 
14.4 Safety Communication ............................................................................................................... 58 
14.5 Monitoring .................................................................................................................................. 58 
14.6 Study Records ........................................................................................................................... 58 
14.7 Electronic Case Report Form (eCRF) Information .................................................................... 59 
14.8 Records Retention ..................................................................................................................... 59 
14.9 Publication Policy ....................................................................................................................... 59 
14.10 Study and Site Closure .............................................................................................................. 60 
15. References .......................................................................................................................................... 61 
Appendix I 
ECOG Performance Status ....................................................................................... 63 
Appendix II: 
RECIST Version 1.1 ................................................................................................... 64 
Appendix III: 
NYHA Classification .................................................................................................. 69 
Appendix IV: 
Investigator’s Statement ........................................................................................... 70 
 
 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
4 
PrECOG STUDY SITE CONTACT 
MEDICAL MONITOR 
Carolyn Andrews, RN 
Project Manager 
PrECOG, LLC 
1818 Market Street 
Suite 3000 
Philadelphia, PA 19103 
Phone: 215-789-7001 
Email: PrE0113@precogllc.org 
Ashok Srivastava, MD, PhD, MBA 
985 Old Eagle School Road 
Suite 510 
Wayne, PA 19087 
During normal business hours 
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Phone: 484-574-2367 
Email: asrivastava@precogllc.org 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
5 
Brief Protocol Synopsis 
See Protocol Document Sections for complete details 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Accrual Goal: 48 
Cycle Length = 28 days 
 
 
 
 
*SOPs = Standard Operating Procedures 
1. 
A three patient safety run-in will be conducted in Cohort 3 prior to beginning randomization to all three cohorts. Once these patients have completed one cycle 
of treatment or discontinued study treatment in the event of toxicity, a safety review of the combination will be conducted. Following the safety run-in, eligible 
patients will be randomized 1: 1: 1.Safety run-in complete 9/21/2020. 10/22/2020: Randomized part of the study opened to enrollment following Steering 
Committee review of the first cycle safety data. No modifications to the protocol were made. 
3 patients 
safety run-in1 
Cohort 1 (n= 15): 
● 
Paclitaxel 80 mg/m2 1-3 hour IV infusion (per site SOPs*) weekly days 1, 8, and 
15 
Cohort 2 (n= 15): 
● 
Paclitaxel 80 mg/m2 1-3 hour IV infusion (per site SOPs) weekly days 1, 8, and 
15; plus 
● 
Pelareorep 4.5 x 1010 TCID50 1-hour IV infusion days 1, 2, 8, 9, 15, and 16 
Stratification: 
• Visceral versus 
Non-Visceral 
Metastatic 
Disease 
Treatment until: 
 
 
● 
Disease Progression 
● 
Unacceptable Toxicity 
● 
Withdrawal of Consent 
● 
End of Study 
 
Cohort 3 (n= 18): 
● 
Paclitaxel 80 mg/m2 1- 3 hour IV infusion (per site SOPs) weekly days 1, 8, and 
15; plus 
● 
Pelareorep 4.5 x 1010 TCID50 1-hour IV infusion days 1, 2, 8, 9, 15, and 16 
● 
Avelumab 10 mg/kg (not more than 800 mg) 1-hour IV infusion days 3 and 17 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
6 
List of Abbreviations 
5-FU 
5-Fluorouracil 
ACTH 
Adrenocorticotropic Hormone 
ADL 
Activities of Daily Living 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
APC 
Antigen Presenting Cell 
ASCO-CAP 
American Society of Clinical Oncology – College of American 
Pathologists 
AST 
Aspartate Transaminase  
BNP 
B-Type Natriuretic Peptide 
BSC 
Biological Safety Cabinet 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CA 15-3 
Carcinoma Antigen 15-3 
CBC 
Complete Blood Count 
CBPF 
Central Biorepository Pathology Facility 
CCTG 
Canadian Cancer Trials Group 
CDK 
Cyclin-Dependent Kinase 
cfDNA 
Cell Free DNA 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIVI 
Continuous IV Infusion 
CK 
Creatine Kinase 
CNS 
Central Nervous System 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID 
Coronavirus Disease 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy and Evaluation Program 
DLT 
Dose-Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
dsRNA 
Double-Stranded RNA 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
7 
eDC 
Electronic Data Capture 
EDTA 
Ethylenediaminetetraacetic Acid 
EOS 
End of Study 
ER 
Estrogen Receptor 
EU 
European Union 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed, Paraffin Embedded 
FSH 
Follicle-Stimulating Hormone 
G 
Grams 
GCP 
Good Clinical Practice 
GH 
Growth Hormone 
GITR 
Glucocorticoid-Induced Tumor Necrosis Factor Receptor 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HER 
Human Epidermal Growth Factor Receptor 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
HR+ 
Hormone Receptor+ 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH GCP 
International Council for Harmonisation-Good Clinical Practice 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-Like Growth Factor 1 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
irAE 
Immune-Related Adverse Event 
IRB 
Institutional Review Board 
ITT 
Intent To Treat 
iTU 
Intratumoral(ly) 
IV 
Intravenous(ly) 
kg 
Kilogram 
L 
Liters 
LDH 
Lactate Dehydrogenase 
LH 
Luteinizing Hormone 
LV 
Leucovorin 
m2 
Square Meter 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
8 
mBC 
Metastatic Breast Cancer 
MDSC 
Myeloid Derived Suppressor Cells 
mg 
Milligrams 
MHC 
Major Histocompatibility Complex 
mL 
Milliliter 
MOA 
Mechanism of Action 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose  
mTOR 
Mammalian Target of Rapamycin 
n 
Number 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NCIC CTG 
National Cancer Institute of Canada Clinical Trials Group 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
NYHA 
New York Heart Association 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein 1 
PD-L1 
Programmed Death-Ligand 1 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PgR 
Progesterone Receptor 
PPM 
Parts Per Million 
PR 
Partial Response 
PRL 
Prolactin 
PTT 
Partial Thromboplastin Time 
PTX 
Paclitaxel 
RCF 
Relative Centrifugal Force 
RECIST 
Response Evaluation Criteria in Solid Tumors 
Reovirus 
Respiratory Enteric Orphan Virus 
RNA 
Ribonucleic Acid 
RSI 
Reference Safety Information 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SOC 
Standard of Care 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
9 
SOP 
Standard Operating Procedure 
SRS 
Stereotactic Radiosurgery 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TCID 
Median Tissue Culture Infective Dose 
TCID50 
50% Tissue Culture Infective Dose 
TEAE 
Treatment-Emergent Adverse Events 
TME 
Tumor Microenvironment 
TNBC 
Triple-Negative Breast Cancer 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
US 
United States 
vs 
Versus 
WBC 
White Blood Count 
WBXRT 
Whole-Brain Radiation Therapy 
WOCBP 
Women of Child Bearing Potential 
XRT 
Radiation Therapy 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
10 
1. 
Introduction- Background and Rationale 
1.1 
Breast Cancer – Disease Overview 
In women worldwide, breast cancer is the most common cancer and the leading cause of 
cancer mortality, with approximately 1.7 million new cases diagnosed each year and over 
half a million deaths per year (International Agency for Research on Cancer, 2012; Torre et 
al., 2015). In 2015, there were an estimated 560,000 deaths due to breast cancer globally 
(World Health Organization, Projections of mortality and causes of death 2015 and 2030, 
updated July 2013), and in the United States alone in 2016, 246,660 new cases of breast 
cancer were estimated as well as 40,450 deaths due to metastatic disease (Siegel et al., 
2016). 
Despite major advances in cancer treatment over the last decades, metastatic breast cancer 
(mBC) remains incurable, with a median overall survival (OS) of approximately 2-3 years 
and a 5-year survival of only 25% (National Cancer Institute, 2014; Sundquist et al., 2017). 
Up to 30% of women originally diagnosed with early breast cancer will eventually progress 
to mBC (Berman et al., 2013; Brockton et al., 2015; Herrinton et al., 2005; O'Shaughnessy, 
2005). 
The current treatment for mBC is palliative with the goals to manage or prevent symptoms, 
control disease progression and improve quality of life (Smith, 2006). Treatment options and 
protocols are varied and dependent upon tumor phenotypes and genotypes. 
1.2 
Reovirus 
Reovirus is a ubiquitous virus found in untreated sewage, stagnant water, and rivers.  As 
such, exposure to reovirus is common, with seropositivity displayed in nearly 100% of 
healthy human adults (Minuk et al., 1985; Minuk et al., 1987). 
The name “reovirus” was originally coined by Sabin in 1959 to reflect the fact that these 
viruses are typically derived from the respiratory and gastrointestinal tracts and are not 
associated with any known disease state, hence, they were described as “orphan” viruses. 
The term is an acronym for Respiratory Enteric Orphan virus (Sabin, 1959). The general 
structure of the reovirus particle is that of a non-enveloped virus: a double-shelled capsid, 
each with icosahedral symmetry, that contains 10 linear double-stranded ribonucleic acid 
(dsRNA) genome segments (Tyler and Fields, 1990). There are three distinct serotypes 
based upon antibody neutralisation and hemagglutination inhibition tests (Rosen et al., 
1960). 
Reovirus infections are mild and usually restricted to the respiratory and gastrointestinal 
tract, but on occasion, they cause flu-like upper respiratory tract symptoms and/or mild 
diarrhea (Jackson et al., 1963; Jackson, 1961; Jarudi et al., 1973; Lerner et al., 1962; Rosen 
et al., 1963; Rosen et al., 1960). 
1.3 
Pelareorep 
Pelareorep is a propriety formulation of a naturally occurring, non-genetically modified, non-
enveloped human Reovirus Serotype 3-Dearing Strain which contains live, replication-
competent virus. Pelareorep has demonstrated in vitro and in vivo activity in many cancers 
including breast cancer and has been delivered intratumorally and intravenously. 
Pelareorep’s anti-tumor activity is based on a dual mechanism of action, which is 
complementary, but not interdependent: 
● 
Direct oncolytic activity of tumor cells permissive to viral replication. 
● 
Induction of anti-tumor immunity through: 
• 
Activation of innate immunity against virally infected tumor cells and upregulation of 
inflammatory cytokines. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
11 
• 
Increased presentation of tumor and viral-associated epitopes by antigen-
presenting cells (APCs, e.g., dendritic cells), allowing for the generation of an 
adaptive antitumor immune response. 
Thus, in addition to functioning as an oncolytic agent, pelareorep overrides the absence of 
anti-tumor immunity present in cancer patients, activating innate and adaptive anti-tumor 
immune responses. Refer to the Investigator’s Brochure for a comprehensive list of 
references relevant to pelareorep’s mechanism of action (MOA). 
1.3.1 
Pre-Clinical Experience with Pelareorep 
In breast cancer, Norman et al. (2002) demonstrated efficient lysis of breast tumor-
derived cell lines by reovirus (pelareorep strain), whereas normal breast cells are 
resistant to infection in vitro. In vivo studies have revealed that pelareorep can 
induce the regression of human breast cancer and targets breast cancer stem cells 
in immunocompromised mice models (Marcato et al., 2009). In immunocompetent 
mouse models, pelareorep as a single agent has been shown to reduce tumor 
burden, enhance survival, and promote protective immunity against tumor re-
challenge. These anti-tumor activities are further enhanced by anti-PD-L1 
combination therapy (Mostafa et al., 2018). 
Pelareorep combination therapy has been shown to be synergistic with a variety of 
standard chemotherapeutic agents, such as taxanes (Heinemann et al., 2011; Sei 
et al., 2009). When used with taxanes, pelareorep is synergistic even in cells with 
a high level of drug resistance or limited sensitivity to the virus. Moreover, virus 
production or titer is increased in the presence of taxanes as viral replication 
complexes or inclusion bodies with cells grow in association with stabilized 
microtubules (Sei et al., 2009). Additionally, paclitaxel has immunomodulatory 
activities that may synergize with pelareorep, such as: inhibition of myeloid derived 
suppressor cells (MDSCs), upregulation of Programmed Death-Ligand 1 (PD-L1) 
and Major Histocompatibility Complex 1 (MHC1) molecules and increases in 
antigen presentation (Champiat et al., 2014). 
1.4 
Pelareorep – Clinical Experience 
As of 2019, over 1400 patients have been enrolled in clinical studies of pelareorep 
conducted in a variety of solid tumor and hematologic cancers in the United States (US), 
Canada, and European Union (EU). Of these, 1065 patients received pelareorep, 974 via 
intravenous (IV) administration and 91 by intratumoral injections (ITu). The remaining 
patients were randomized to control arms and received treatment (357) or were not treated. 
Pelareorep has been administered as single or multiple doses ITu or IV, either as a 
monotherapy or in combination with chemotherapy, immunotherapy (e.g., checkpoint 
inhibitors), and radiotherapy. 
No Maximum Tolerated Dose (MTD) for intravenous pelareorep as monotherapy was 
defined in two Phase 1 trials (REO 004 and 005). When combined with chemotherapeutic 
agents, according to standard of care, pelareorep does not appear to enhance either the 
frequency or severity of the adverse effects with the exception of transient, mainly grade 1/ 
2 “flu-like syndrome” after pelareorep administration, including fatigue, chills, fever, nausea 
and diarrhea. Doses up to 9 x 1010 TCID50 have been well tolerated with similar safety profile. 
A randomized, controlled phase 2 study (Canadian Cancer Trials Group (CCTG) IND.213) 
in mBC compared pelareorep plus paclitaxel versus paclitaxel alone. Following a safety 
run-in of 7 patients, 74 women with previously treated mBC were randomized to either 
treatment arm. Prior to enrolment, these patients had received at least one chemotherapy 
regimen for advanced/metastatic breast cancer unless they had relapsed within 6 months 
of completion of adjuvant chemotherapy or had received taxane and/or anthracycline 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
12 
containing adjuvant chemotherapy. In this study, although no difference was seen in 
Progression-Free Survival (PFS) its primary endpoint of the Intent to Treat (ITT) patient 
population, it was found that in the test arm (pelareorep plus paclitaxel, n=36) the median 
OS (secondary endpoint) was 17.4 months vs. 10.4 months in the control arm (paclitaxel 
alone; number (n)=38; Hazard Ration (HR) 0.65; 80% Confidence Interval (CI) 0.46–0.91; 
p=0.1). In a post-hoc analysis in Estrogen Receptor+ (ER+) patients (n=57), the OS 
improved from 10.8 months on control arm to 21 months on the test arm [Cox model 
HR=0.60; p=0.1]. Similarly, in ER+/Progesterone Receptor + (PgR+) patients (n=47), the 
OS improved from 10.8 months on the control arm to 21.8 months on the test arm [Cox 
model HR=0.36; p=0.003] (Gutierrez et al., 2017). There were only 15 patients who were 
hormone receptor-negative across the groups (triple negative) and only one with HER2-
positive breast cancer in the control group, so the survival analysis in these groups was 
inconclusive. 
However, despite the small sample size, the OS results in particular in the taxane treatment 
naïve Hormone Receptor+ (HR+) patients are encouraging. The late benefit may explain an 
immune response for pelareorep and is one of the key rationales to study the combination 
with checkpoint inhibitor. 
Of note, with the exception of a trend indicating a higher incidence of Grade ≥ 3 fatigue and 
a statistically significant lower incidence of Grade ≥ 3 LDH in the pelareorep plus paclitaxel 
combination arm, Grade ≥ 3 toxicities observed with paclitaxel were similar with or without 
pelareorep in this study. 
1.4.1 
Clinical Experience with Pelareorep in Combination with Immune Checkpoint 
Inhibitors 
A Phase 1b study enrolled patients with metastatic adenocarcinoma of the pancreas 
who progressed after first line treatment. Eleven patients were treated on a 21-day 
cycle with 1 of 3 chemotherapy backbone regimens based on physician preference: 
(i) gemcitabine 1000 mg/m2 IV on day 1, (ii) irinotecan 125 mg/m2 IV on day 1, or 
(iii) leucovorin (LV) 200 mg/m2 and 5-Fluorouracil (5-FU) 200 mg/m2 IV bolus on 
day 1, followed by 5-FU 1200 mg/m2 continuous IV infusion (CIVI) over 22 hours on 
day 1. Pelareorep was administered at 4.5 x 1010 TCID50 (50% tissue culture 
infective dose) IV on days 1 and 2 after chemotherapy infusion. Pembrolizumab 
was administered at 2 mg/kg IV on day 8 (dosing based on the package insert at 
the time of the study design). Treatment was well tolerated with manageable 
toxicities. The most common grade 1 or 2 treatment-emergent adverse events 
(TEAEs) included fever (73%), headache (55%), chills (46%), dehydration (36%), 
fatigue (27%), abdominal pain (27%), vomiting (27%) and neutropenia (27%). Most 
events were brief and/or resolved with symptomatic treatment. One patient 
(gemcitabine arm) experienced transient grade 2 increased transaminases on two 
occasions. Grade 3 or 4 TEAEs were reported in 8 patients (45.5%), with one 
occurrence each of the following: abdominal pain, anemia, arthralgias, biliary 
obstruction, chills, deep vein thrombosis, diarrhea, fever, hyperglycemia, 
leukopenia, myalgias, nausea, neutropenia, pulmonary emboli, urinary tract 
infection, and vomiting. Disease control was achieved in 3 of 11 patients. One 
patient achieved partial response for 17.4 months. Two additional patients achieved 
stable disease, lasting 9 and 4 months, respectively. Tumor analysis from patients 
showed reovirus protein replication, T cell infiltration and upregulation of PD-L1. 
1.5 
Avelumab 
Avelumab is a programmed death ligand-1 (PD-L1) blocking antibody. In the United States, 
avelumab is approved for the treatment of Merkel cell carcinoma, metastatic urothelial 
carcinoma, and advanced renal cell carcinoma in combination with axitinib. Avelumab has 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
13 
been studied as a therapeutic agent in mBC in a Phase 1 trial (JAVELIN Solid Tumor; 
NCT01772004) (Dirix et al., 2018). Patients with mBC refractory to or progressing after 
standard of care therapy received avelumab IV 10 mg/kg every 2 weeks. A total of 168 
patients with mBC, including 58 patients with triple-negative breast cancer (TNBC), were 
treated with avelumab for 2–50 weeks and followed for 6–15 months. Patients were heavily 
pretreated with a median of three prior therapies for metastatic or locally advanced disease. 
Avelumab showed an acceptable safety profile and clinical activity in a subset of patients 
with mBC. The overall response rate (ORR) was 3.0% overall (one complete response and 
four partial responses) and 5.2% in patients with TNBC. A trend toward a higher ORR was 
seen in patients with PD-L1+ versus PD-L1− tumor-associated immune cells in the overall 
population (16.7% vs. 1.6% and 22.2% vs. 2.6% in the TNBC subgroup). 
In the avelumab mBC study (Dirix et al., 2018), treatment-related adverse events (AEs) of 
any grade occurred in 115 of 168 patients (68.5%), including a Grade ≥ 3 event in 23 
patients (13.7%). The most commonly occurring treatment-related AEs of any Grade (>10% 
of patients) were fatigue (19.0%), infusion-related reaction (14.3%), and nausea (13.1%). 
Treatment-related AEs of any grade classified as immune-related occurred in 17 patients 
(10.1%) and include: hypothyroidism (4.8%), autoimmune hepatitis and pneumonitis (1.8% 
each), thrombocytopenia (1.2%), and antinuclear antibody production, dry eye, elevated 
rheumatoid factor, hyperthyroidism, and pemphigoid skin reaction (0.6% each). Four 
patients (2.4%) had a Grade ≥ 3 immune-related, treatment-related AE, including three 
patients (1.8%) with Grade 3 autoimmune hepatitis and one patient each with Grade 3 
pneumonitis and Grade 4 thrombocytopenia (0.6% each). 
1.6 
Paclitaxel 
Taxanes are anti-microtubule agents with significant activity in breast cancer and are part 
of standard of care in breast cancer when chemotherapy is indicated. Treatment guidelines 
on the use of paclitaxel and other chemotherapy agents for mBC vary from institution to 
institution across the world. Herein is a summary of current guidelines (Cardoso et al., 2017; 
National Comprehensive Cancer Network (NCCN) Guidelines, 2017). The weekly paclitaxel 
treatment used is in line with these guidelines and commonly used for the target patient 
population for this protocol. 
1.7 
Summary of Rationale for Proposed Study 
1.7.1 
Rationale 
A previous randomized Phase 2 clinical study in advanced or mBC examining 
pelareorep in combination with paclitaxel showed an improvement in OS from 10.4 
months with paclitaxel alone to 17.4 months with pelareorep + paclitaxel (HR=0.65, 
80% CI 0.46–0.91, p=0.1). In a post hoc subgroup analysis, the median OS 
improved from 10.8 months with paclitaxel alone to 21.0 months with pelareorep + 
paclitaxel (p=0.1; Cox model HR=0.60; n=57) in ER+ patients. However, in the ITT 
population, pelareorep + paclitaxel did not improve PFS or overall response rate 
relative to paclitaxel alone, suggesting a late onset immune response. 
A study with avelumab in patients with mBC achieved an overall response rate of 
3% in the ITT population, however patients with PD-L1 positive tumor-associated 
immune cells achieved a higher ORR (16.7%) compared to patients with PD-L1 
negative tumor-associated immune cells (1.6%) (Dirix et al., 2018). A similar study 
in advanced TNBC found that in patients treated with atezolizumab and Nab-
paclitaxel, the ORR is greater in PD-L1 positive tumors (41.4%) relative to PD-L1 
negative tumors (33.3%) (Adams et al., 2018). 
Thus, pelareorep mediated immunological responses that upregulate PD-L1 
expression and prime the tumor microenvironment (TME) for treatment with 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
14 
checkpoint blockade may allow for enhanced objective responses when avelumab 
is added to pelareorep + paclitaxel. Both clinical and preclinical studies have 
demonstrated that pelareorep can promote an inflamed TME, increasing the 
number of tumor infiltrating lymphocytes and enhancing the expression of PD-1/PD-
L1 within tumors. Thus, we hypothesize that the addition of anti-PD-L1 therapy to 
pelareorep and paclitaxel in patients with mBC will be synergistic and improve 
efficacy in terms of ORR compared to paclitaxel monotherapy and paclitaxel + 
pelareorep combination therapy. 
1.7.2 
Study Design 
This is an open-label randomized Phase 2, 3-cohort study in Hormone Receptor+ 
(HR+)/Human Epidermal Growth Factor Receptor 2 negative (HER2-) with 
endocrine-refractory metastatic breast cancer. 
Endocrine-refractory is defined as progression while on endocrine therapy and 
CDK4/6 inhibitor therapy. Prior treatment with an mTOR inhibitor is allowed but is 
not required. Patients may have received several lines of anti-hormone therapies 
but should not have received chemotherapy for metastatic disease. 
Patients may have received chemotherapy in the (neo)adjuvant setting. Patients 
receiving (neo)adjuvant taxanes must have a disease-free interval of at least 12 
months. 
Patients will continue to receive study treatment until disease progression, 
unacceptable toxicity, withdrawal of consent, or End of Study (EOS). Any patients who 
remain on study treatment when EOS is reached will be eligible to continue that 
treatment through an expanded access protocol. 
Patients who discontinue study treatment will continue to be followed for survival 
until they have withdrawn consent, been lost to follow-up, died, or EOS is reached, 
whichever occurs first.  
End of Study will occur when all patients have reached at least 2 years of study 
participation (measured from the first day of study treatment; including treatment and 
follow up), withdrawn consent, been lost to follow up, or died.  
Reduced clinical data will be collected in study treatment cycles past week 16, per 
Section 10. Blood samples for biomarker analyses will be collected on Day 1 of every 
cycle of study treatment. 
 
Cohort 1: 
Control group with dosing of weekly paclitaxel (PTX) according to 
standard of care (SOC) 
Cohort 2: 
Investigative treatment with pelareorep added to SOC (PTX) 
Cohort 3: 
Investigative treatment with pelareorep in combination with 
avelumab added to SOC (PTX) 
 
 
 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
15 
 
 
 
 
 
 
1.7.3 
Safety Phase 
A three patient safety run-in will be conducted in Cohort 3 (pelareorep+avelumab+ 
paclitaxel) prior to beginning randomization into all three cohorts. A safety 
evaluation will be conducted after all 3 patients have completed one 28 day cycle 
of treatment (i.e., received all the doses for all the drugs per protocol) or 
discontinued the therapy before completion of Cycle 1 due to toxicity (i.e., 
permanently discontinued or dose held). Patients who discontinue the therapy 
before completion of Cycle 1 due to reasons other than toxicity will be replaced. 
During the safety review, a Steering Committee will review all the safety data 
captured during the first cycle of treatment and make recommendations to continue, 
alter, or permanently suspend the study based on this analysis. The Steering 
Committee may recommend amendments to explore alternate dosing schedules or 
lower doses based on the overall toxicity experience, even if the criteria for dose-
limiting toxicity (DLT) are not met (Section 5.2). 
During this review period, enrolled patients may continue to receive study treatment. 
1.7.3.1 
Safety Run-In Complete 
9/21/2020:  
Safety run-in completed. 
10/22/2020:  Randomized part of the study opened to enrollment 
following Steering Committee review of the first cycle 
safety data. No modifications to the protocol were made. 
1.7.4 
Patient randomization and stratification factors 
• 
Patients will be stratified for visceral versus non-visceral metastatic disease 
• 
Patients will be randomized as 1:1:1 (PTX vs. PTX + pelareorep vs. PTX + 
pelareorep + avelumab). 
1.7.5 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical 
study but are not subsequently enrolled in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal 
information includes demographics, eligibility criteria not met or rationale for not 
enrolling despite meeting all eligibility criteria, and any serious adverse events 
3 patients 
safety run-in 
Cohort 1 (n= 15): PTX 
Cohort 2 (n= 15): Pelareorep + PTX 
HR+/HER2-(HR+) 
Total of 48 patients 
Primary Objective: 
ORR at 16 weeks 
 
Exploratory 
Objectives: 
•
Biomarkers 
•
Safety 
•
PFS 
•
ORR and OS 
at EOS 
Cohort 3 (n= 18) 
Pelareorep + PTX + Avelumab 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
16 
(SAEs) that occurred due to screening procedures required for the study. This 
information can be maintained in a Screen Failures Log at the study site. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
17 
2. 
Study Objectives 
This is an exploratory Phase 2 study to inform the design of a subsequent registration study.  
2.1 
Primary Objective 
• 
Determine the efficacy in terms of overall response rate (ORR) at week 16 according to 
RECIST V1.1 
2.2 
Other Objectives (these objectives are all exploratory) 
• 
Examine efficacy in terms of OS and ORR at EOS according to RECIST V1.1. 
• 
Examine efficacy in terms of PFS. 
• 
Examine the safety of the combination: 
o 
To be assessed using serious and non-serious adverse events (clinical and 
laboratory), laboratory parameters, treatment exposure (total delivered dose and 
dose modifications) and reasons for treatment discontinuation. 
• 
Examine biomarkers to determine the immunological changes within the TME and 
peripheral blood in patients treated with paclitaxel alone, in combination with 
pelareorep, and in combination with pelareorep and avelumab. 
Key assays will: 
○ 
Examine the expression of immune-related biomarkers, such as PD-1 and PD-L1. 
○ 
Identify biological changes, as defined by changes in gene expression within the 
TME and Peripheral Blood Mononuclear Cells (PBMCs), between pre-treatment 
and on-therapy specimens. 
○ 
Compare changes in the T cell repertoire between pre-treatment and on-therapy 
tumor biopsies; examining common T cell clones between tumor tissue and 
peripheral blood samples. 
○ 
Compare changes in the T cell repertoire between pre-treatment and on-therapy 
peripheral blood samples. 
○ 
Examine tumor mutational burden and prevalent Deoxyribonucleic Acid (DNA) 
mutations in all patients from Cell Free Deoxyribonucleic Acid (cfDNA). 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
18 
3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be considered 
eligible for this study. Use the checklist to confirm a patient’s eligibility. For each patient, this 
checklist must be photocopied, completed and maintained in the patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test is done on a Monday, the Monday four weeks later 
would be considered Day 28. 
PrECOG Patient No. 
 
 
Patient’s Initials (F, M, L) 
 
 
Physician Signature and Date 
 
NOTE:  PrECOG does not allow waivers to any protocol specified criteria. Therefore, all eligibility 
criteria listed in Section 3 must be met, without exception. The registration of individuals 
who do not meet all criteria listed in Section 3 can result in the participant being censored 
from the analysis of the study, and a major protocol violation. All questions regarding 
clarification of eligibility criteria must be directed to PrECOG Study Contact. 
NOTE: Institutions may use the eligibility checklist as source documentation if it has been reviewed, 
signed, and dated prior to registration/randomization by the treating physician. 
Inclusion Criteria 
3.1 
Female patients ≥ 18 years of age at the time of signing the informed consent form (ICF). 
3.2 
Must have a histological/cytological diagnosis of breast cancer. Disease must be: 
• 
Positive for estrogen receptor (ER) and/or progesterone receptor (PgR) as defined by 
≥ 1% tumor cell nuclei immunoreactive. 
• 
Negative for HER2 amplification / overexpression as defined per the American Society 
of Clinical Oncology – College of American Pathologists (ASCO-CAP) guidelines. 
However, patients with HER2 equivocal disease for whom HER2 targeted therapy isn’t 
indicated are also eligible for enrollment. 
Date of Initial Diagnosis: _______________ 
3.3 
ECOG performance status of 0-1 (Appendix I). 
3.4 
Must have unresectable locally advanced or metastatic disease, for which no curative 
therapy exists and for which systemic chemotherapy is indicated. 
3.5 
Measurable disease as defined by RECIST Version 1.1 (Appendix II). 
3.6 
Prior Hormonal Therapy: 
• 
Patients must have progressed on at least 1 hormone-based therapy with a CDK4/6 
inhibitor. Patients who received a CDK4/6 inhibitor in the adjuvant setting and 
progressed while on or within 6 months of discontinuation of CDK4/6 inhibitor therapy 
are eligible. 
• 
Prior mTOR inhibitor therapy is allowed but is not required. 
Date of Last Therapy: _______________ 
3.7 
Ability to understand and willingness to sign IRB-approved informed consent. 
_____
_____
_____ 
_____
_____
_____
_____

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
19 
3.8 
Willing to provide blood samples for research (Section 13.0). 
3.9 
Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks prior to 
registration: 
Hematology: 
Neutrophils 
≥ 1.5 x 109/L 
Neutrophils: ________ 
Date of Test: __________ 
Platelets 
≥ 100 x 109/L 
Platelets: __________ 
Date of Test: __________ 
Lymphocytes 
≥ 0.8 x 109/L 
Lymphocytes: ______ 
Date of Test: __________ 
INR 
< 1.5x ULN 
INR: ________ (Unless on therapeutic anticoagulation) 
 
 
 
Date of Test: __________ 
PTT 
< 1.5x ULN 
PTT: ________ 
Date of Test: __________ 
Biochemistry: 
Serum Creatinine 
 
≤ 1.5x ULN 
Serum Creatine: ________ Date of Test: __________ 
Total Bilirubin 
≤ 1.0x ULN (unless due to Gilbert’s Disease and direct bilirubin <ULN) 
Total Bilirubin: ________ 
ULN: ________ 
Date of Test: __________ 
ALT and AST 
≤ 3x ULN (Note: ≤ 5x ULN if documented liver metastasis) 
ALT: ________ 
ULN: ________ 
Date of Test: __________ 
AST: ________ 
ULN: ________ 
Date of Test: __________ 
Proteinuria 
≤ Grade 2* (using spot testing; if Grade 3 repeat with mid-stream urine; if 
still Grade 3 then urine collection for 24 hours to confirm Grade 0, 1 or 2) 
*as per National Cancer Institute Common Terminology Criteria for Adverse 
(NCI-CTCAE) 
Proteinuria: ________ 
Grade: ________ 
Date of Test: __________ 
3.10 
Women must not be pregnant or breastfeeding since we do not know the effects of the study 
drugs on the fetus or breastfeeding child. All sexually active females of childbearing potential 
(not surgically sterilized and between menarche and 1 year post menopause) must have a 
blood test to rule out pregnancy within 2 weeks prior to registration. 
Is the patient a woman of childbearing potential? _____________________ (yes/no) 
If yes, Date of Test: _______________ Results: ____________________________ 
3.11 
Sexually active women of child-bearing potential with a non-sterilized male partner must 
agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) 
OR abstinence prior to study entry, for the duration of study participation, and for 3 months 
following last dose of study drugs. Method of contraception must be documented. 
NOTE: If a woman become pregnant or suspect she is pregnant while participating in this 
study, she must inform her treating physician immediately. 
Exclusion Criteria 
3.12 
No major surgery within 21 days prior to beginning study treatment. Major surgery >21 days 
prior to beginning study treatment is permitted provided that the patient has recovered 
adequately to receive systemic chemotherapy. NOTE: Placement of a vascular access 
device is not considered major surgery. 
_____
_____ 
_____ 
_____
_____ 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
20 
3.13 
Patients who have received radiation treatment within 14 days of beginning study treatment 
are excluded. Patients who have received palliative radiation ≥ 14 days prior to beginning 
study treatment may enroll if they have recovered from all local and systemic side effects to 
≤ Grade 1 (NCI-CTCAE). 
3.14 
No prior chemotherapy in the advanced/metastatic setting is allowed. Patients may have 
received chemotherapy in the (neo)adjuvant setting. Patients receiving (neo)adjuvant 
taxanes must have a disease-free interval of at least 12 months. 
3.15 
No known active, uncontrolled or symptomatic Central Nervous System (CNS) metastases, 
carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, 
cerebral edema, and/or progressive growth. Patients with CNS metastases treated with 
radiation therapy (Whole-Brain Radiation Therapy [WBXRT] or Stereotactic Radiotherapy 
[SRS]) are eligible if, >28 days following completion of XRT, they show stable disease on 
post-treatment MRI/CT, are off corticosteroids, and are neurologically stable. 
3.16 
No known history of other malignancies, except for adequately treated non-melanoma skin 
cancer or solid tumors curatively treated with no evidence of disease for >3 years. 
3.17 
Not on chronic immunosuppressive therapy including, but not exclusively, steroids (≥ 10 mg 
prednisone a day or equivalent) or monoclonal antibodies, chronic methotrexate or 
cyclophosphamide, tacrolimus or sirolimus. 
3.18 
No known HIV infection. Testing not required in absence of clinical suspicion. 
3.19 
No known active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection or undergoing 
anti-viral treatment. Testing for HBV/HCV is not required in absence of clinical suspicion. 
3.20 
No concurrent disease or condition that would interfere with study participation or safety, 
such as any of the following: 
• 
Active, clinically significant infection either Grade >2 by CTCAE V5.0 or requiring the 
use of parenteral anti-microbial agents within 14 days before registration. 
3.21 
No active or history of any autoimmune disease (patients with diabetes Type 1, vitiligo, 
psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are 
eligible) or immunodeficiencies. 
3.22 
Patients may not have evidence of uncontrolled cardiovascular conditions, including 
uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart 
failure (New York Heart Association [NYHA] Class III or higher [Appendix III]), unstable 
angina, or myocardial infarction within the past 6 months prior to registration. NOTE: 
Patients with asymptomatic rate-controlled atrial fibrillation may participate. 
3.23 
Patients may not have other significant diseases (for example, inflammatory bowel disease), 
which, in the opinion of the Investigator, might impair the patient's tolerance of trial 
treatment. 
3.24 
Patients with a known allergy to any of the study medications, their analogues, or excipients 
in the various formulations of any agent are not eligible. 
3.25 
Patients who have contraindications to treatment with paclitaxel and/or neuropathy >Grade 
2 are not eligible. 
3.26 
Patients who have not recovered from clinically significant acute toxicities of previous 
therapy are not eligible, except treatment-related alopecia or stable sensory neuropathy 
≤ Grade 2. 
3.27 
No prior therapy with any investigational anti-cancer therapy within 30 days. Prior 
immunotherapies are prohibited (see 3.28). 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____
_____ 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
21 
3.28 
No prior therapy with checkpoint inhibitors (e.g., anti-PD-1/PD-L1 antibodies), checkpoint 
agonist 
agents 
(e.g., 
anti-GITR, 
anti-OX40 
antibodies) 
and/or 
another 
active 
immunotherapy in breast cancer such as cancer vaccines or oncolytic virsus. 
3.29 
Patients with any serious medical or psychiatric illness that could, in the Investigator’s 
opinion, potentially interfere with the completion of the treatment according to the protocol, 
are not eligible. 
3.30 
Patients with legal incapacity or limited legal capacity are not eligible. 
3.31 
Patients with known alcohol or drug abuse are not eligible. 
3.32 
Patients may not participate in any other therapeutic clinical trials, including those with other 
investigational agents not included in this trial, throughout the duration of this study. 
3.33 
 Patients may not have any vaccine, including against SARS-COV-2 (COVID-19) <14 days 
prior to C1D1 nor in the first cycle of study treatment. Inactivated vaccines (including against 
COVID-19 or seasonal influenza) are permitted after the first cycle of study treatment is 
complete. 
 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
22 
4. 
Registration Procedures 
4.1 
Ethics 
This study will be conducted in accordance with the ethical principles that have their origin 
in the current Declaration of Helsinki and will be consistent with applicable US regulatory 
requirements and International Conference on Harmonization/Good Clinical Practice 
(ICH/GCP). 
The study will be conducted in compliance with the protocol. The protocol and any 
amendments and the patient informed consent will receive Institutional Review Board (IRB) 
approval prior to initiation of the study. 
Freely given written informed consent must be obtained from every patient or their legally 
acceptable representative prior to clinical trial participation, including informed consent for 
any screening procedures conducted to establish patient eligibility for the trial. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s). This trial will not use the services of 
Investigators or study personnel where sanctions have been invoked or where there has 
been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
Investigators are responsible for the conduct of the study at their study site. 
4.2 
Regulatory Requirements 
Before a site may enroll patients, protocol-specific regulatory and other documents must be 
submitted to PrECOG as noted in study materials. Detailed information regarding document 
submission and control is provided to each site in separate study materials. 
Once required documents are received, reviewed, and approved by PrECOG or their 
representative, study materials will be forwarded to the site. Any changes to site regulatory 
documents must be submitted by the Investigator to the responsible party in a timely 
manner. Initial study drug shipment will not occur until the regulatory packet is complete. 
Once PrECOG activates a site, enrollment may occur. No patients will begin protocol 
therapy without formal registration as per the process below. 
4.3 
Patient Registration 
Patients must not start protocol treatment prior to registration. 
Patients must meet all of the eligibility requirements listed in Section 3 prior to registration. 
Treatment should begin ≤ 10 working days from date of registration. 
An eligibility checklist is included in Section 3. A confirmation of eligibility assessment by 
the Investigator and/or site will be performed during the registration process. 
A three patient safety run-in will be conducted in Cohort 3 prior to beginning randomization 
to all three cohorts. The first 3 patients enrolled will be registered into the study after 
confirmation of eligibility.  
Once these patients have completed one cycle of treatment or have discontinued study 
treatment in the event of toxicity, a safety review of the combination will be conducted. If the 
study continues after the safety review, all remaining patients will require randomization into 
Cohort 1 or Cohort 2 or Cohort 3. 
 After it is verified by the site that the patient meets all eligibility criteria, randomization will 
occur by entering the patient in the electronic Data Capture (eDC) system. 
Confirmation of randomization/registration will be displayed in the eDC system. 
Full information regarding registration procedures and guidelines can be found in the 
materials provided to your site. Documentation from the web randomization system 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
23 
including the treatment assignment will be placed in the patient record. Correspondence 
regarding patient registration must be kept in the study records. 
4.4 
Research Tissue and Blood Samples 
Time points for tissue and blood samples are outlined in the study parameters (Section 10) 
and specific requirements are outlined in the correlative section of this protocol (Section 13) 
and the lab manual. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
24 
5. 
Treatment Plan 
5.1 
Overview 
This is an open-label randomized Phase 2, 3-cohort study for patients with hormone 
receptor (HR)-positive (HR+)/ Human Epidermal Growth Factor Receptor 2 (HER2)-
negative (HER2-), endocrine-refractory metastatic breast cancer. A total of 48 patients will 
be enrolled and will be treated until progression, unacceptable toxicity, withdrawal of 
consent, or EOS. The study will be conducted at approximately 20 US-based study centers. 
A three patient safety run-in will be conducted in Cohort 3 (pelareorep+avelumab+ 
paclitaxel) prior to beginning randomization into all three cohorts. 
Following the safety run-in, eligible patients will be randomized 1: 1: 1. Each cohort will 
enroll 15 patients. 
Cohort 1: Paclitaxel (PTX) 
Cohort 2: PTX + pelareorep 
Cohort 3: PTX + pelareorep + avelumab 
Patients will be stratified for visceral versus non-visceral metastatic disease. 
5.2 
Cohort 3 Safety Run-In 
A three patient safety run-in will be conducted in Cohort 3 (pelareorep+avelumab+ 
paclitaxel) prior to beginning randomization into all three cohorts. A safety evaluation will be 
conducted after all 3 patients have completed one cycle of treatment (i.e., received all the 
doses for all the drugs per protocol) or discontinued the therapy before completion of Cycle 
1 due to toxicity (i.e., permanently discontinued or dose held). Patients who discontinue the 
therapy before completion of Cycle 1 due to reasons other than toxicity will be replaced. 
During the safety review, a Steering Committee will review all the safety data captured 
during the first cycle of treatment and make recommendations to continue, alter, or 
permanently suspend the study based on this analysis. The Steering Committee may 
recommend amendments to explore alternate dosing schedules or lower doses based on 
the overall toxicity experience, even if the criteria for dose-limiting toxicity (DLT) are not met. 
Events that occur after completion of the first cycle of study treatment will not be included 
in the safety review or evaluated as potential DLTs. 
During this review period, enrolled patients may continue to receive study treatment. 
5.2.1 
Dose-Limiting Toxicity (DLT) Evaluation for Safety Run-In 
 
Table 5-1: DLT Evaluation for Safety Run-In 
Toxicity Category 
Criteria Defining a DLT 
Hematological 
Grade 4 neutropenia lasting ≥ 7 days 
Febrile Neutropenia (any grade) 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
25 
Grade 4 thrombocytopenia lasting ≥ 7 days OR Grade 3 
thrombocytopenia associated with clinically significant 
bleeding 
Non-Hematological 
Grade ≥ 3 nausea and/or vomiting that persists for at 
least 72 hours and is unresponsive to adequate/maximal 
medical interventions and/or prophylaxis as dictated by 
local institutional clinical practices or the judgment of the 
Investigator. 
Other Grade ≥ 3 toxicity that persists for ≥ 7 days or 
recurs despite the use of adequate/maximal medical 
interventions and/or prophylaxis as dictated by local 
institutional clinical practices or the judgment of the 
Investigator. 
If baseline AST and ALT <2.5x ULN: DLT will be ALT or 
AST >5x ULN 
If baseline AST and ALT ≥ 2.5x ULN: DLT will be ALT or 
AST >8x ULN 
Any toxicity that results in a >14 day delay in treatment will be considered a DLT. 
Any death not clearly due to underlying disease or extraneous causes will be 
considered a DLT. 
 
5.3 
Treatment and Administration Schedule 
Following the safety run-in, eligible patients will be randomized 1: 1: 1. Each cohort will 
enroll 15 patients. 
Patients from each cohort will receive the following treatment during a 28-day cycle: 
Cohort 1: 
● 
Paclitaxel 80 mg/m2 1-3 hour IV infusion (per site SOPs) weekly days 1, 8, and 
15. 
 
 
 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
26 
Cohort 2: 
● 
Paclitaxel 80 mg/m2 1-3 hour IV infusion (per site SOPs) weekly days 1, 8, and 
15; plus 
● 
Pelareorep 4.5 x 1010 TCID50 1-hour IV infusion days 1, 2, 8, 9, and 15, 16. 
On days that require treatment with both pelareorep and paclitaxel, pelareorep must be 
given at least 30 minutes after the completion of the paclitaxel infusion. 
Patients in Cohort 2 who discontinue paclitaxel for toxicity can continue with pelareorep 
monotherapy if, in the Investigator’s opinion, they may be experiencing therapeutic benefit, 
their disease has not progressed, and written approval has been obtained from PrECOG. 
 
Cohort 3: 
● 
Paclitaxel 80 mg/m2 1-3 hour IV infusion (per site SOPs) weekly days 1, 8, and 
15; plus 
● 
Pelareorep 4.5 x 1010 TCID50 1-hour IV infusion days 1, 2, 8, 9, and 15, 16. 
● 
Avelumab 10 mg/kg (not more than 800 mg) 1-hour IV infusion days 3 and 17. 
On days that require treatment with both pelareorep and paclitaxel, pelareorep must be 
given at least 30 minutes after the completion of the paclitaxel infusion. 
Patients in Cohort 3 who discontinue paclitaxel for toxicity can continue with pelareorep 
and/or avelumab monotherapy or combination therapy if, in the Investigator’s opinion, they 
may be experiencing therapeutic benefit, their disease has not progressed, and written 
approval has been obtained from PrECOG. 
 
Study treatment in all cohorts will continue until disease progression, unacceptable toxicity, 
withdrawal of consent, or EOS. Cross-over between cohorts is not permitted. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
27 
5.4 
Premedications 
Premedication for Paclitaxel 
Prophylactic dexamethasone, diphenhydramine, and ranitidine prior to each paclitaxel 
infusion. The suggested premedication regimen is: dexamethasone 10 mg IV, 
diphenhydramine 50 mg IV, and ranitidine 50 mg IV all given 30 minutes before paclitaxel 
infusion. Adjustments to this suggested premedication regimen to be consistent with local 
standards is allowed. 
Premedication for Avelumab 
Premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions 
of avelumab. Premedication should be administered for subsequent avelumab doses based 
upon clinical judgment and presence/severity of prior infusion reactions (see Warnings and 
Precautions of Avelumab Investigator’s Brochure). Refer to Premedication for Pelareorep, 
below, for maximum daily permitted dose of acetaminophen. 
Premedication for Pelareorep 
Acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) may be used for the 
prophylaxis or treatment of the flu-like signs and symptoms, especially fever, that are 
commonly associated with pelareorep. Guidelines for the use of acetaminophen and 
NSAIDs are as follows: 
Acetaminophen: 
● 
The decision about using acetaminophen should be considered for each individual 
patient, with particular attention to the patient’s hepatic status at the time of entry into 
the trial. Extra caution should be used if there is a history of viral hepatitis (HBV or HCV) 
and/or a pre-entry elevation of bilirubin above normal. If the patient has metastatic 
cancer in the liver, the impact of the metastases on overall liver function should be 
considered. If the values for AST and ALT are less than twice the upper limit of normal, 
acetaminophen may still be used, but careful monitoring of hepatic function should be 
done. 
● 
Given the usual timing of fever and other “flu-like” adverse events associated with 
pelareorep, treatment with acetaminophen should be limited to the days on which 
pelareorep is administered and the day following the last dose of each cycle. If used for 
prophylaxis, it is recommended that the first dose be given 1 to 3 hours following 
completion of pelareorep infusion on Day 1 of the cycle. 
● 
Dosing of acetaminophen: The recommended dose is 500 or 1000 mg every 6 to 8 
hours. The MAXIMUM daily (24-hour) dose must NOT exceed 3000 mg. 
NSAIDs: 
• 
The decision to use oral NSAID should be made for each individual patient, with 
attention to the patient's renal and hydration status at the time of pelareorep 
administration or the time of imaging scans with contrast. 
• 
Dose should not exceed ibuprofen 800 mg or equivalent per dose (ibuprofen 3200 
mg/day or equivalent). 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
28 
6. 
Dose Modifications and Discontinuation of Therapy 
6.1 
Dose Delays & Modifications 
All toxicities should be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE V5.0). A copy 
of 
the 
CTCAE 
V5.0 
can 
be 
downloaded 
from 
the 
CTEP 
website 
(http://www.ctep.cancer.gov). 
A +/-2 day window is allowed for scheduled therapy, required tests and/or visits except as 
otherwise noted. If the first day of paclitaxel/pelareorep treatment is delayed (in Cohorts 2 
and 3), the following day of treatment must also be delayed, as two pelareorep doses cannot 
be delivered on the same day. For cohort 3, pelareorep and avelumab cannot be delivered 
on the same day. Dose delays >2 days will be considered missed and will not be replaced. 
Delays due to holidays, weekends, bad weather or other unforeseen circumstances will be 
permitted. 
For Cohort 3 Safety Run-In for Cycle 1 please refer to Table 5-1 for criteria for defining 
DLT. 
NOTE: 
Response evaluation must be performed every 8 weeks until week 16, then every 
12 weeks even if cycles are delayed. When treatment is held for >4 weeks and 
<8 weeks, authorization from PrECOG must be obtained before restarting 
therapy. If study treatment is held for 8 weeks or more, the patient will discontinue 
study therapy permanently. 
Dose interruptions for ≤ 4 weeks for non-drug-related reasons (e.g., surgery, radiotherapy, 
holiday break, etc.) may be allowed after patients complete the response assessment at 
Week 16, and with the agreement of the Investigator and PrECOG. 
Patients in Cohort 2 who discontinue paclitaxel for toxicity can continue with pelareorep 
monotherapy if in the Investigator’s opinion, they may be experiencing therapeutic benefit, 
their disease has not progressed, and approval has been obtained from PrECOG. Similarly, 
patients in Cohort 3 who discontinue paclitaxel for toxicity can continue with pelareorep 
and/or avelumab monotherapy or combination therapy if in the Investigator’s opinion, they 
may be experiencing therapeutic benefit, their disease has not progressed, and approval 
has been obtained from PrECOG. 
NOTE: 
Patients who continue treatment with pelareorep alone (Cohort 2) or pelareorep 
and/or avelumab (Cohort 3) are considered on study and evaluations and data 
submission is required until study closure as outlined in Section 10. 
6.1.1 
Pelareorep 
In the event of toxicity ≥ Grade 2 considered reasonably related to pelareorep, the 
Investigator may choose to hold the dose of pelareorep until the toxicity resolves to 
Grade 0 or 1 or baseline, per the recommendations below. Dose delays >2 days 
will be considered missed and will not be replaced. 
Non-Hematologic Toxicity: 
In the event a ≥ Grade 2 non-hematologic toxicity occurs which is considered 
reasonably related to pelareorep, the Investigator may choose to hold the dose of 
pelareorep until achieving a complete or partial resolution (Grade 0 to 1) of the 
toxicity, or return to baseline. Pelareorep should not be restarted until the laboratory 
requirements defined below have been met or have returned to baseline values: 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
29 
Table 6-1: Criteria for Pelareorep Administration for Serum Creatinine, 
Total Bilirubin and ALT/AST 
Serum Creatinine 
≤ 1.5x ULN 
Total Bilirubin 
≤ 1.0x ULN (unless elevated secondary to conditions 
such as Gilbert’s Disease) 
ALT and AST 
≤ 3x ULN (Note: ≤ 5x ULN if documented liver metastasis) 
If the non-hematologic toxicity resolves to Grade 1 or baseline within 4 weeks, 
patients can continue therapy at the same dose and as per the original schedule. 
Table 6-2: Criteria for Pelareorep Administration for Proteinuria 
Degree of Proteinuria 
Pelareorep Dosing 
Grade 1 
Administer pelareorep dose as scheduled. 
Grade 2 
Hold dose. 
Urine microscopy and collect 24-hour urine for protein 
- 
If protein <1.0 g/24 hours AND no evidence 
glomerulonephritis on microscopy, restart 
pelareorep at same dose. 
- 
If protein ≥ 1.0 g/24 hours OR active sediment 
(suggestive of glomerulonephritis), investigate 
further (nephrology consultant). 
May restart at scheduled dose when protein <1.0 g/24 
hours AND no evidence of glomerulonephritis. 
Grade 3 
Grade 4 
Hold dose. 
Obtain urine microscopy and collect 24-hour urine for 
protein at noted above. 
May restart once toxicity resolves to ≤ Grade 1 or 
baseline. 
Hematologic Toxicity: 
Patients with Grade 1-2 neutropenia, lymphopenia or thrombocytopenia can be 
treated with pelareorep as scheduled. Pelareorep dose must be held for patients 
with Grade 3-4 neutropenia, lymphopenia or thrombocytopenia. These patients can 
restart therapy when values have returned to baseline or the following laboratory 
requirements are met: 
Table 6-3: Criteria for Pelareorep Administration for 
Hematologic Toxicity 
Platelets 
≥ 75 x 109/L 
Neutrophils 
≥ 1.0 x 109/L 
Lymphocytes 
≥ 0.8 x 109/L 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
30 
6.1.2 
Paclitaxel 
Dose adjustments of paclitaxel for hematological, non-hematological, and hepatic 
toxicities can be made according to the study site’s standard procedures. Patients 
should be monitored closely for the development of profound myelosuppression. 
6.1.3 
Avelumab 
Dose modifications of avelumab for immune-related adverse reactions are provided 
in the table below. Refer to the avelumab IB for further information and guidance on 
the management of infusion related reactions. 
Table 6-4: Avelumab – Management of Immune-Related Adverse Events (irAEs) 
NCI CTCAE V5 (modified)* 
Gastrointestinal irAEs 
Severity of Diarrhoea/Colitis 
Initial Management 
Follow-Up Management 
Grade 1 
Diarrhoea: <4 stools/day over 
Baseline 
Colitis: Asymptomatic 
Continue avelumab therapy. 
Symptomatic treatment (e.g., 
loperamide). 
Close monitoring for worsening 
symptoms. 
Educate subject to report worsening 
immediately. 
If worsens: Treat as Grade 2, 3 or 4. 
Grade 2 
Diarrhoea: 4 to 6 stools per day 
over Baseline; IV fluids 
indicated <24 hours; not 
interfering with activities of daily 
living (ADL) 
Colitis: Abdominal pain; blood 
in stool 
Withhold avelumab therapy. 
Symptomatic treatment. 
If improves to Grade ≤ 1: 
Resume avelumab therapy. 
If persists >5-7 days or recurs: Treat as 
Grade 3 or 4. 
Grade 3 to 4 
Diarrhoea (Grade 3): ≥ 7 stools 
per day over Baseline; IV fluids 
≥ 24 h; interfering with ADL 
Colitis (Grade 3): Severe 
abdominal pain, peritoneal 
signs 
Grade 4: Life-threatening 
consequence including 
perforation 
Withhold avelumab for Grade 
3. Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3. 
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections. 
Consider lower endoscopy. 
If improves: Continue steroids until 
Grade ≤ 1, then taper over at least 1 
month; resume avelumab therapy 
following steroids taper (for initial Grade 
3). 
If worsens, persists >3 to 5 days, or 
recurs after improvement: Add infliximab 
5 mg/kg (if no contraindication). 
Note: Infliximab should not be used in 
cases of perforation or sepsis. 
Dermatological irAEs 
Grade of Rash 
Initial Management 
Follow-Up Management 
Grade 1 to 2 
Covering ≤ 30% body surface 
area 
Continue avelumab therapy. 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids). 
If Grade 2 persists >1 to 2 weeks or 
recurs: Withhold avelumab therapy. 
Consider skin biopsy. 
Consider 0.5-1.0 mg/kg/day prednisone 
or equivalent. Once improving, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy 
following steroids taper. 
If worsens: Treat as Grade 3 to 4. 
Grade 3 to 4 
Grade 3: Covering >30% body 
surface area; 
Withhold avelumab for Grade 
3. 
If improves to Grade ≤ 1: 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
31 
Grade 4: Life-threatening 
consequences 
Permanently discontinue for 
Grade 4 or recurrent Grade 3. 
Consider skin biopsy. 
Dermatology consult. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections. 
Taper steroids over at least 1 month; 
resume avelumab therapy following 
steroids taper (for initial Grade 3). 
Pulmonary irAEs 
Grade of Pneumonitis 
Initial Management 
Follow-Up Management 
Grade 1 
Radiographic changes only 
Consider withholding 
avelumab therapy. 
Monitor for symptoms every 2 
to 3 days. 
Consider Pulmonary and 
Infectious Disease consults. 
Re-assess at least every 3 weeks. 
If worsens: 
Treat as Grade 2 or Grade 3 to 4. 
Grade 2 
Mild to moderate new 
symptoms 
Withhold avelumab therapy. 
Pulmonary and Infectious 
Disease consults. 
Monitor symptoms daily; 
consider hospitalization. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections. 
Consider bronchoscopy, lung 
biopsy. 
Re-assess every 1 to 3 days. 
If improves: When symptoms return to 
Grade ≤ 1, taper steroids over at least 1 
month, and then resume avelumab 
therapy following steroids taper. 
If not improving after 2 weeks or 
worsening or for recurrent Grade 2: 
Treat as Grade 3 to 4. 
Grade 3 to 4 
Grade 3: Severe new 
symptoms; New/worsening 
hypoxia; 
Grade 4: Life-threatening 
Permanently discontinue 
avelumab therapy. 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections. 
Consider bronchoscopy, lung 
biopsy. 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month. 
If not improving after 48 hours or 
worsening: 
Add additional immunosuppression (for 
example: infliximab, cyclophosphamide, 
IV immunoglobulin, or mycophenolate 
mofetil). 
Hepatic irAEs 
Grade of Liver Test Elevation 
Initial Management 
Follow-Up Management 
Grade 1  
Grade 1 AST or ALT >ULN to 
3.0x ULN and/or total bilirubin 
>ULN to 1.5x ULN 
Continue avelumab therapy. 
Continue liver function monitoring. 
If worsens: Treat as Grade 2 or 3 to 4. 
Grade 2 
AST or ALT >3.0 to ≤ 5x ULN 
and/or total bilirubin >1.5 to 
≤ 3x ULN 
Withhold avelumab therapy. 
Increase frequency of 
monitoring to every 3 days. 
If returns to Grade ≤ 1: Resume routine 
monitoring; resume avelumab therapy. 
If elevation persists >5 to 7 days or 
worsens: Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT >5x ULN and/or 
total bilirubin >3x ULN 
Permanently discontinue 
avelumab therapy. 
Increase frequency of 
monitoring to every 1 to 2 
days. 
If returns to Grade ≤ 1: 
Taper steroids over at least 1 month. 
If does not improve in >3 to 5 days, 
worsens or rebounds: Add 
mycophenolate mofetil 1 gram (g) twice 
daily. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
32 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections. 
Consult Gastroenterologist/ 
Hepatologist. 
Consider obtaining MRI/CT 
scan of liver and liver biopsy if 
clinically warranted. 
If no response within an additional 3 to 5 
days, consider other 
immunosuppressants per local 
guidelines. 
Renal irAEs 
Grade of Creatinine 
Increased 
Initial Management 
Follow-Up Management 
Grade 1 
Creatinine increased >ULN to 
1.5x ULN 
Continue avelumab therapy. 
Continue renal function monitoring. 
If worsens: Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased >1.5 and 
≤ 6x ULN 
Withhold avelumab therapy. 
Increase frequency of 
monitoring to every 3 days. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections. 
Consider renal biopsy. 
If returns to Grade ≤ 1: Taper steroids 
over at least 1 month, and resume 
avelumab therapy following steroids 
taper. 
If worsens: Treat as Grade 4. 
Grade 4 
Creatinine increased >6x ULN 
Permanently discontinue 
avelumab therapy. 
Monitor creatinine daily. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections. 
Consider renal biopsy. 
Nephrology consult. 
If returns to Grade ≤ 1: 
Taper steroids over at least 1 month. 
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-Up Management 
New onset of cardiac signs or 
symptoms and/or new 
laboratory cardiac biomarker 
elevations (e.g., troponin, CK- 
muscle/brain, BNP) or 
cardiac imaging 
abnormalities suggestive of 
myocarditis. 
Withhold avelumab therapy. 
Hospitalize. 
In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility 
experienced in advanced heart 
failure and arrhythmia 
management. 
Cardiology consult to establish 
etiology and rule out immune-
related myocarditis. 
Guideline based supportive 
treatment as per cardiology 
consult.** 
Consider myocardial biopsy if 
recommended per cardiology 
consult. 
 
If symptoms improve and immune-
related etiology is ruled out, re-start 
avelumab therapy. If symptoms do not 
improve/worsen, viral myocarditis is 
excluded, and immune-related etiology is 
suspected or confirmed following 
cardiology consult, manage as immune-
related myocarditis. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
33 
Immune-Related Myocarditis 
Permanently discontinue 
avelumab. 
Guideline based supportive 
treatment as appropriate as 
per cardiology consult.** 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids over at 
least 1 month. 
If no improvement or worsening, 
consider additional immunosuppressants 
(e.g., azathioprine, cyclosporine A). 
**Local guidelines, or e.g. European Society of Cardiology or American Heart Association guidelines 
European Society of Cardiology guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-
Guidelines American Heart Association guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-Up Management 
Grade 1 or Grade 2 
Endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, Type I diabetes 
mellitus) 
Continue avelumab therapy. 
Endocrinology consult if 
needed. 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate. 
Rule out secondary 
endocrinopathies (i.e., 
hypopituitarism/hypophysitis). 
Continue hormone replacement/ 
suppression and monitoring of endocrine 
function as appropriate. 
Grade 3 or Grade 4 
Endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, Type I diabetes 
mellitus) 
Withhold avelumab therapy. 
Consider hospitalization. 
Endocrinology consult. 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate. 
Rule out secondary 
endocrinopathies (i.e., 
hypopituitarism/hypophysitis). 
Resume avelumab once symptoms 
and/or laboratory tests improve to Grade 
≤ 1 (with or without hormone 
replacement/suppression). 
Continue hormone replacement/ 
suppression and monitoring of endocrine 
function as appropriate. 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (i.e., subnormal 
serum thyroxine with 
inappropriately low thyroid-
stimulating hormone and/or 
low serum cortisol with 
inappropriately low 
adrenocorticotropic hormone): 
Resume avelumab once symptoms and 
hormone tests improve to Grade ≤ 1 
(with or without hormone replacement). 
In addition, for hypophysitis with 
abnormal MRI, resume avelumab only 
once shrinkage of the pituitary gland on 
MRI/CT scan is documented. 
Continue hormone replacement/ 
suppression therapy as appropriate. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
34 
- 
Refer to endocrinologist 
for dynamic testing as 
indicated and 
measurement of other 
hormones (FSH, LH, 
GH/IGF-1, PRL, 
testosterone in men, 
estrogens in women). 
- 
Hormone replacement/ 
suppressive therapy as 
appropriate. 
- 
Perform pituitary MRI 
and visual field 
examination as 
indicated. 
If hypophysitis confirmed: 
- 
Continue avelumab if 
mild symptoms with 
normal MRI. Repeat the 
MRI in 1 month. 
- 
Withhold avelumab if 
moderate, severe or life-
threatening symptoms of 
hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 
mg/kg/day prednisone 
or equivalent) followed 
by corticosteroids taper 
during at least 1 month. 
- 
Add prophylactic 
antibiotics for 
opportunistic infections. 
Other irAEs (not described above) 
Grade of Other irAEs 
Initial Management 
Follow-Up Management 
Grade 2 or Grade 3 clinical 
signs or symptoms 
suggestive of a potential irAE 
Withhold avelumab therapy 
pending clinical investigation. 
If irAE is ruled out, manage as 
appropriate according to the diagnosis 
and consider re-starting avelumab 
therapy. 
If irAE is confirmed, treat as Grade 2 or 3 
irAE. 
Grade 2 irAE or first 
occurrence of Grade 3 irAE 
Withhold avelumab therapy. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections. 
Specialty consult as 
appropriate. 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month and 
resume avelumab therapy following 
steroids taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue 
avelumab therapy. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
35 
Add prophylactic antibiotics for 
opportunistic infections. 
Specialty consult as 
appropriate. 
Grade 4 
Permanently discontinue 
avelumab therapy. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
and/or other 
immunosuppressant as 
needed. 
Add prophylactic antibiotics for 
opportunistic infections. 
Specialty consult. 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month. 
Requirement for 10 mg per 
day or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency. 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer. 
Permanently discontinue 
avelumab therapy. 
Specialty consult. 
 
 
ADL = activities of daily living; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BNP = B-type 
natriuretic peptide; CK = creatine kinase; CT = computed tomography; FSH = follicle-stimulating hormone; GH = growth 
hormone; IGF-1 = insulin-like growth factor 1; irAE = immune-related adverse event; IV = intravenous; LH = luteinizing 
hormone; MRI = magnetic resonance imaging; NCI-CTCAE = National Cancer Institute Common Terminology Criteria 
for Adverse Events; PRL = prolactin; ULN = upper limit of normal. 
*CTCAE definitions may have been modified for this purpose. Definitions may not be identical to the CTCAE 
V.5. 
6.2 
Concurrent Therapies 
6.2.1 
Required and/or Permitted 
Permitted medications include, but are not limited to: 
• 
Supportive and palliative care as required throughout the study. 
• 
Growth factors, according to local institutional policy. 
• 
Anti-emetics or anti-diarrheal agents as required. 
• 
Skeletal protective therapy with bisphosphonates. 
• 
Supportive measures consistent with optimal patient care may be given 
throughout the study. 
6.2.2 
Not Permitted 
● 
Other anti-cancer therapy or investigational therapy. 
● 
Chronic methotrexate, cyclophosphamide, tacrolimus or sirolimus. 
● 
Other monoclonal antibodies. 
● 
Vaccines <14 days prior to beginning study treatment and during Cycle 1. 
Inactivated vaccines (against COVID-19 or seasonal influenza, for example) 
are permitted after Cycle 1 is complete. Live vaccines are not permitted while 
on study treatment. 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
36 
6.2.3 
Concomitant Medications 
Concomitant medications used to treat SAEs are to be recorded in the eCRF. In 
addition, concomitant medications used to treat any AE that, in the Investigator’s 
opinion, is immune-related are to be recorded in the eCRF. Steroids also need to 
be recorded.  
If participants receive an inactivated vaccine after they have completed the first 
cycle of study treatment (see 6.2.2), it must be entered in the eCRF. 
No other concomitant medications need to be captured. 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
37 
7. 
Study Duration and Discontinuation of Therapy 
7.1 
Study Duration – General Considerations 
Study Treatment will continue until disease progression (per RECIST Version 1.1), 
unacceptable toxicity, withdrawal of consent, or EOS. Any patients who remain on study 
treatment when EOS is reached will be eligible to continue that treatment through an expanded 
access protocol. 
Crossover between cohorts is not permitted. 
7.2 
End of Study 
End of Study will occur when all patients have reached at least 2 years of study participation 
(measured from the first day of study treatment; including treatment and follow-up), withdrawn 
consent, been lost to follow up, or died.  
7.3 
Duration of Follow-Up 
Safety Follow-Up: 
Patients will be followed for adverse events for 30 days after their last dose of study 
medication or the initiation of non-protocol therapy after last dose of study medication, 
whichever comes first. However, if a patient experiences a serious adverse event >30 days 
after their last dose of study medication that is felt to be, in the opinion of the Investigator, 
possibly, probably or definitely related to study therapy, the serious adverse event should 
be reported. 
Response Follow-Up: 
Tumor response per to RECIST V1.1 will be assessed by CT scan every 8 weeks until week 
16, and every 12 weeks thereafter until discontinuation of study treatment, regardless of 
dose interruptions or dose delays. Patients who discontinue study treatment for reasons 
other than progression will continue to be followed for tumor response per standard of care 
until progression, initiation of a new therapy, or withdrawal of consent, whichever occurs 
first. 
Survival Follow-Up: 
Patients who discontinue study treatment will continue to be followed by phone for survival 
status every 4-6 months. Patients will be followed until they have withdrawn consent, been lost 
to follow-up, died, or EOS; whichever occurs first. 
Patients who are registered but do not receive any protocol therapy will not be included in 
any analyses and data past baseline will not be collected. 
7.4 
Criteria for Removal from Study Treatment 
Reasons that a patient may discontinue treatment in this clinical study are listed below. The 
reason for discontinuation will be recorded in each patient’s eCRF: 
1. Recurrence of disease or documented progression of disease. 
2. Intercurrent illness that prevents further administration of treatment per Investigator 
discretion. 
3. Unacceptable adverse events. 
4. Treatment interruption of ≥ 8 consecutive weeks. 
5. Pregnancy. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
38 
6.  Second malignancy (except for non-melanoma skin cancer or cervical carcinoma in-
situ) that requires treatment, which would interfere with this study. 
7. Patient withdraws consent at any time for any reason. 
8. General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in the judgment of the Investigator. 
9. Severe non-compliance with protocol as judged by the Investigator. 
10. Lost to follow-up. 
11. Death. 
12. Closure of study by PrECOG. 
Any patient who receives at least one dose of study drug will be included in the safety 
analysis. If a patient is removed from treatment for reason(s) other than progression follow 
with regular tumor assessments per standard of care until progression per RECIST v 1.1, 
start of new treatment, or withdrawal of consent, whichever occurs first. 
Note: Any patients who remain on study treatment when EOS is reached will be eligible to 
continue that treatment through an expanded access protocol. 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
39 
8. 
Adverse Event Reporting 
8.1 
AE Definition 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment. An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with 
the administration of an investigational product, whether or not related to that investigational 
product. 
8.2 
Assessment of Seriousness 
A Serious Adverse Event (SAE) is defined as any AE occurring at any dose that results in 
any of the following outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect 
• 
other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the patient or require intervention to 
prevent one of the outcomes listed. 
Seriousness in relation to adverse events is not the same as severity. For example, an 
adverse event assessed to be severe (Grade 3) per the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) Version 5.0 may not be serious. All adverse events noted as 
“serious” in the eCRF are reported as Serious Adverse Events in accordance with Section 
8.9. 
8.3 
Assessment of Severity 
The Investigator is responsible for assessing severity of each reported AE. The CTCAE 
Version 5.0 should be used to assess and grade AE severity. 
Any event not described in the CTCAE V5.0 may be assigned as follows: 
• 
Grade 1: Mild: An event that is easily tolerated by the patient, causing minimal 
discomfort and not interfering with everyday activities. 
• 
Grade 2: Moderate: An event that causes sufficient discomfort and interferes with 
normal everyday activities. 
• 
Grade 3: Severe: An event that prevents normal everyday activities.  
• 
Grade 4: Life-threatening consequences or urgent intervention indicated (must be 
reported as an SAE). 
• 
Grade 5: Death related to adverse event (must be reported as an SAE). 
8.4 
Assessment of Causality 
The possibility of a causal relationship between each AE and the study treatment should be 
assessed by the Investigator. The causal relationship can be classified as either: 
• 
Related: There is a reasonable causal relationship between study drug administration 
and the AE. 
or 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
40 
• 
Not Related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
If there is a reasonable possibility of a causal relationship between the event and the study 
treatment, i.e. if there are facts (evidence) or arguments to suggest a causal relationship, 
the AE is considered related to the study treatment and an adverse drug reaction (ADR). 
Practical Guidance for Causality Assessments: 
An adverse event will not be considered related to study treatment if it: 
• 
may be judged to be due to extraneous causes such as disease or environment or toxic 
factors. 
• 
may be judged to be due to the patient’s clinical state or therapy other than study 
treatment being administered. 
• 
is not biologically plausible that the event is related to study medication. 
• 
does not reappear or worsen when study treatment is re-administered. 
• 
does not follow a temporal sequence from administration of study treatment. 
An adverse event may be considered related to study treatment if it: 
• 
follows a temporal sequence from administration of study treatment. 
• 
is a known response to the investigational product based on clinical or preclinical data. 
• 
could not be explained by the known characteristics of the patient’s clinical state, 
environmental or toxic factors, or other therapy administered to the patient. 
• 
disappears or decreases upon cessation or reduction of dose of study treatment. 
• 
reappears or worsens when study treatment is re-administered. 
8.5 
Unexpected Adverse Event 
An unexpected AE is not identified in nature, severity, or frequency in the current Reference 
Safety Information (RSI) or is of greater severity or frequency than expected based on the 
information in the respective RSI for the investigational product(s). 
For the purpose of this study, the current Investigator Brochures (IBs) for pelareorep and 
avelumab will be used for assessment of expectedness. 
8.6 
Time Period for Collecting AEs and SAEs 
After informed consent, but prior to initiation of study treatment (paclitaxel, pelareorep, 
and/or avelumab), only AEs/SAEs caused by a protocol-mandated intervention(s) will be 
collected (e.g., SAEs related to invasive procedures such as biopsies). All identified AEs 
and SAEs must be recorded and described on the appropriate page of the electronic Case 
Report Form (eCRF) and reported according to Section 8.9. AEs and SAEs must be 
collected after first treatment dose until 30 days from last dose of study drug or the initiation 
of non-protocol therapy after last dose of study drug, whichever comes first. 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical/Surgical History or Signs and Symptoms, 
as applicable of the eCRF. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to 
be reasonably related to the study intervention or study participation, the Investigator must 
promptly notify Oncolytics. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
41 
The Investigator must report all SAEs to Oncolytics within 24 hours of becoming aware, as 
indicated in Section 8.9. 
SAEs that occur more than 30 days after the last dose of study treatment but while the 
patient is still considered on-study with intent to resume treatment (i.e. if study treatment is 
held for longer than 4 weeks but for fewer than 8 weeks) must be reported. 
8.7 
Documentation of AEs and SAEs 
The Investigator is responsible for detecting, documenting, events that meet the definition 
of an AE or SAE and remains responsible for following up the events that are serious, 
considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study treatment. 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
8.8 
Follow-up of AEs and SAEs 
The Investigator is required to proactively follow each participant at subsequent 
visits/contacts. 
All SAEs will be followed until resolution, stabilization, the event is otherwise explained, or 
the participant is lost to follow-up. Any ongoing events that are considered to be “Related” 
to study treatment will be followed up until they are resolved or deemed to be chronic. 
8.9 
Reporting Serious Adverse Events 
Serious adverse events (SAE) are defined in Section 8.2. The Investigator should inform 
Oncolytics of any SAE within 24 hours of being aware of the event, using the SAE Report  
Form provided for the study via email to <SAE_REO_028@oncolytics.ca> as per the 
instructions found in study materials provided to the site. If email is not feasible, the form 
should be faxed to +403-283-0858. 
The initial report must be as complete as possible, including details of the current illness 
and (serious) adverse event, and an assessment of the causal relationship between the 
event and the investigational product(s). Information not available at the time of the initial 
report (e.g., an end date for the adverse event or laboratory values received after the report) 
must be provided as a follow-up SAE report. The Investigator is responsible for following all 
SAEs until resolution, until the patient returns to baseline status, or until the condition has 
stabilized with the expectation that it will remain chronic, even if this extends beyond study 
participation. 
Investigators should also report event(s) to their IRB as required. 
Collection of complete information concerning SAEs is extremely important. Full 
descriptions of each event will be followed. Thus, follow-up information which becomes 
available as the SAE evolves, as well as supporting documentation (e.g., hospital discharge 
summaries and autopsy reports), should be collected subsequently, if not available at the 
time of the initial report, and immediately sent using the same procedure as the initial SAE 
report. 
NOTE: After study closure, study-drug related SAEs should be reported voluntarily by the 
treating physician to Oncolytics. 
Serious adverse event reporting to regulatory authorities will be conducted by Oncolytics 
(or designee) in accordance with 21CFR312.32, local requirements and international 
regulations, as appropriate. 
PrECOG will provide all participating Investigators with suspected unexpected serious 
adverse reaction (SUSAR) reports received from Oncolytics. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
42 
8.10 
Special Situation Reports 
8.10.1 COVID-19 Reporting 
All positive COVID-19 test results must be reported with the type of test performed 
recorded. 
Coding for COVID-19 adverse events will be as follows. 
• 
Infections and infestations - Other, specify 
• 
Specify = COVID-19 
The categories and definitions of severity used for COVID-19 AEs are defined in 
Section 8.3. 
COVID-19 adverse events that qualify as Serious Adverse Events per Sections 8.2 
and 8.3 must be reported as such, per Section 8.9.The following information will be 
captured: 
• 
Narrative: Identify all pertinent facts related to the COVID-19 infection including, 
but not limited to the following: Presumptive vs confirmed diagnosis. If 
presumptive, please update narrative if/when diagnosis is confirmed, including 
timelines. 
o 
Treatment information 
o 
Recovery information, including timelines 
o 
Outcome information/status 
All deviations or withdrawals due to COVID-19 will documented as such in the 
eCRF. 
8.10.2 Pregnancy and Lactation Exposure 
Pregnancies, suspected pregnancies, and lactation exposures occurring after the 
first exposure to the study treatment, whether or not associated with AEs, will be 
reported by the Investigator to Oncolytics (SAE_REO_028@oncolytics.ca) within 
24 hours of awareness, using the Pregnancy Report Form provided for the study. 
Study treatment is to be discontinued immediately. The Investigator will follow the 
patient until completion or termination of the pregnancy and must notify Oncolytics 
immediately about the outcome of the pregnancy (either normal or abnormal 
outcome).  
If the mother sustained an adverse event (e.g. spontaneous abortion), the Serious 
Adverse Event Report should be submitted (Section 8.9) in addition to the 
Pregnancy Report Form. 
If the foetus or child sustained any adverse events (e.g. congenital defects), the 
Parent-Child/Foetus Report Form should be submitted in addition to the Pregnancy 
Report Form. All neonatal deaths that occur within 28 days of birth, any infant death 
after 28 days that the Investigator suspects is related to the in-utero exposure to 
the study treatment and any congenital anomaly/birth defect in a child born to a 
female patient exposed to study treatment should be classified as a serious adverse 
event and reported to Oncolytics immediately (i.e., no more than 24 hours after 
learning of the event). 
8.10.3 Overdose or Medication Errors 
For this study, the administered doses of pelareorep, avelumab, and paclitaxel 
higher than the doses, defined in Section 5.0, whether accidental or intentional, will 
be considered as an overdose and protocol violation. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
43 
There is no recommended specific treatment for an overdose of pelareorep. 
Overdose of the avelumab and paclitaxel or medication errors will be managed at 
Investigator’s discretion, reported to Oncolytics immediately and documented on 
the relevant AE eCRFs and reported as an SAE, if indicated. The patient is to be 
monitored until they have resolved or returned to a baseline level. 
Signs, symptoms, or the clinical sequelae of a suspected overdoses or medication 
errors should be recorded as AEs in the eCRF. Serious signs, symptoms, or clinical 
sequelae of suspected overdoses or medication errors will be reported to Oncolytics 
according to Section 8.9. 
8.11 
Reporting of Other Second Primary Cancers 
New cancers are those that are not the primary reason for administration of study treatment 
and have been identified after inclusion of the patient into the clinical study. All cases of new 
primary cancers identified during the study, regardless of relationship to protocol treatment, 
must be reported to Oncolytics as serious adverse events. The recurrence or development 
of metastatic disease of cancer under the study is considered disease progression and not 
necessarily a serious adverse event. 
NOTE: Once data regarding remission status are no longer required by the protocol, no 
follow-up data should be submitted. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
44 
9. 
Measurement of Effect 
This is a Phase 2 study to guide the development and design of potential subsequent registration 
studies. Treatment effect will be examined in two ways: 
Primary Endpoint: 
• 
Efficacy in terms of overall response rate (ORR) at week 16 according to RECIST V1.1 (see 
Appendix II), assessed by the study investigator at each site. 
 
Exploratory Endpoints: 
• 
ORR per RECIST v 1.1 and OS at EOS. 
• 
PFS per RECIST v 1.1. 
• 
The biomarker analyses on this study will examine the immunological changes within the TME 
and peripheral blood in patients treated with paclitaxel alone, in combination with pelareorep, 
and in combination with pelareorep and avelumab. 
o 
As such, the pretreatment and on-treatment biopsies/blood collections are critical with 
mandatory blood draws and optional tumor biopsies. Key assays will: 
 
Examine the expression of immune-related biomarkers, such as PD-1 and PD-L1. 
 
Identify biological changes, as defined by changes in gene expression within the TME 
and PMBC, between pre-treatment and on-therapy specimens. 
 
Compare changes in the T cell repertoire between pre-treatment and on-therapy tumor 
biopsies; examining common T cell clones between tumor tissue and peripheral blood 
samples. 
 
Compare changes in the T cell repertoire between pre-treatment and on-therapy 
peripheral blood samples. 
 
Examine tumor mutational burden and prevalent DNA mutations in all patients from 
cfDNA. 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
45 
10. 
Study Parameters 
1. All pre-study scans should be done ≤ 4 weeks prior to registration. 
2. All other pre-study assessments should be done ≤ 2 weeks prior to registration. 
3. Study treatment must be initiated ≤ 10 days after registration. 
4. Assessments can be done as clinically indicated, in addition to the time points listed here. 
Procedures 
Screening 
Cycle 1* 
(1 cycle=28 Days) 
Cycle 2 -Cycle 4* 
(1 cycle=28 Days) 
Cycle 5 and Subsequent Cycles* 
Off 
Treatment17 
Follow-
Up19 
Days 
1 
2 
3 
8 
9 
15 
16 
17 
1 
2 
3 
8 
9 
15 
16 
17 
1 
2 
3 
8 
9 
15 
16 
17 
 
 
Windows (+/- days): 
-14 to -1 
 
 
 
2 
 
2 
 
 
2 
 
 
2 
 
2 
 
 
2 
 
 
2 
 
2 
 
 
 
 
Written Informed 
Consent0 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Characteristics1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Baseline 
Signs & Symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam including 
Weight 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
X16 
 
 
 
 
 
 
 
X 
 
Vital Signs 
(Temperature, Pulse, 
Blood Pressure)2 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X16 
X16 
 
X16 
X16 
X16 
X16 
 
X 
 
ECOG Performance 
Status 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X16 
 
 
 
 
 
 
 
X 
 
Urinalysis3,6 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X16 
 
 
 
 
 
 
 
X 
 
CBC/Differential/Platelets
4,6 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X16 
 
 
 
 
 
 
 
X 
 
Chemistry5,6 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
X16 
 
 
 
 
 
 
 
X 
 
Endocrine (Cohort 3)7 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X16 
 
 
 
 
 
 
 
 
 
PTT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lactate Dehydrogenase 
(LDH) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
46 
Procedures 
Screening 
Cycle 1* 
(1 cycle=28 Days) 
Cycle 2 -Cycle 4* 
(1 cycle=28 Days) 
Cycle 5 and Subsequent Cycles* 
Off 
Treatment17 
Follow-
Up19 
Days 
1 
2 
3 
8 
9 
15 
16 
17 
1 
2 
3 
8 
9 
15 
16 
17 
1 
2 
3 
8 
9 
15 
16 
17 
 
 
Optional Tumor Biopsy9 
X 
 
 
 
 
 
 
 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Blood 
Specimens10 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
CA15-3 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Pelareorep 
Administration11 
(Cohorts 2 + 3) 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
Avelumab 
Administration12 
(Cohort 3) 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
Paclitaxel 
Administration13 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Concomitant Medication 
Review14 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Adverse Events 
Assessment 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X18 
 
Chest & Abdominal CT 
Scan, Bone Scan, and 
Other as clinically 
indicated15 
X 
Every 8 weeks until week 16, then every 12 weeks 
 
 
Disease and Survival 
Status 
 
 
 
X 
* 
Scheduled Visits: +/- 2 day window for therapy/tests/visits during therapy (see Section 6). Delay due to holidays, weekends, bad weather or other unforeseen 
circumstances will be permitted (See 6.1). 
0 
A signed ICF must be obtained before any study-specific assessments are initiated. In the event that > 14 days elapse between the initial date of consent and 
C1D1, follow institutional policy regarding re-consent requirements. 
1 
Record date of diagnosis, primary tumor type, histology, and stage. 
2 
Patients will have Temperature, Pulse and Blood Pressure taken at Screening; Day 1, 8 and 15 of each visit; and at Off-Treatment visit. In addition, patients will 
have their blood pressure measured prior to each pelareorep infusion and 30 minutes (+/- 5 minutes) after completion of each pelareorep infusion in Cohort 2 
and Cohort 3. After participants complete Cycle 4, only findings associated with an SAE or with an AE ≥ Grade 3 are to be captured in the CRF, with the 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
47 
exception of Blood Pressure measurements before and after pelareorep administration. 
3 
For protein screen using spot testing; if >Grade 2 repeat with mid-stream urine; if still >Grade 2 then urine collection for 24 hours to confirm <2g/24hours (Grade 
0, 1 or 2). Reduced urinalysis data will be collected after participants complete Cycle 4; see footnote 16. 
4 
CBC with differential and platelet count which includes WBC, ANC, Platelets, Hemoglobin, and Hematocrit required prior to each dose of paclitaxel. Reduced 
hematology data will be collected after participants complete Cycle 4; see footnote 16. 
5 
Albumin, BUN/creatinine, uric acid, sodium, potassium, chloride, glucose, calcium, alkaline phosphatase, AST, ALT, total bilirubin, and total protein. Reduced 
chemistry data will be collected after participants complete Cycle 4; see footnote 16. 
6 
Cycle 1, Day 1 labs do not need to be repeated if screening lab assessments were completed within 7 days prior. Laboratory samples can be drawn within 72 
hours prior to study treatment administration. 
7 
Patients in Cohort 3 require additional monitoring for endocrine disorders and include assays for: adrenocorticotropic hormone (ACTH), serum cortisol, serum 
thyroxin, and thyroid-stimulating hormone (TSH). Perform every 2 cycles of treatment (Cycle 1, Day 1; Cycle 3, Day 1; Cycle 5, Day 1; etc.). Results are not 
required prior to treatment. If Avelumab is discontinued for any reason, additional lab monitoring is not required. Reduced endocrine data will be collected after 
participants complete Cycle 4; see footnote 16. 
8 
Required for sexually active females of child-bearing potential. Women who are not of child-bearing potential need documentation in their source. 
9 
Optional: Patients from each cohort (excluding safety run-in patients) may provide formalin-fixed paraffin-embedded (FFPE) tissue from a needle core biopsy 
collected prior to randomization (archival tissue allowed) and on-treatment from Cycle 1, collected between Days 17 and 28. See Section 13.1 for details. 
NOTE: A maximum of 5 patients in each cohort will have biopsies collected. 
10 Prior to treatment administration, collect one (1) 2 mL K2EDTA tube and two (2) 10 mL K2EDTA tubes. See Section 13.2 for details. 
11 Patients will receive pelareorep by IV infusion on Days 1, 2, 8, 9, 15 and 16. In Cohorts 2 and 3, pelareorep is to be administered 30 minutes after completion 
of paclitaxel infusion on Days 1, 8 and 15. Patients may receive premedications prior to infusion. See Section 5 for dosing instructions and Section 6 for dose 
delays/modifications. 
12 Patients will receive avelumab on Days 3 and 17. Patients may receive premedications prior to infusion. See Section 5 for dosing instructions and Section 6 for 
dose delays/modifications 
13 Patients will receive paclitaxel on Days 1, 8, and 15. Patients may receive premedications prior to infusion. See Section 5 for dosing instructions and Section 6 
for dose delays/modifications. 
14 Includes review of all Concomitant medications taken within 30 days prior to randomization. Concomitant medications associated with an SAE or with any AE 
that the Investigator assesses to be immune-related must be entered in the eCRF. Steroids must also be entered. Vaccines are not permitted <14 days prior to 
C1D1 nor in first cycle of study treatment; inactivated vaccines administered after completion of Cycle 1 must be documented. No other concomitant medications 
need to be recorded. 
15 Chest and Abdominal CT scan in order to obtain clinical tumor measurements. PET scans may not be used to assess response or progression; if PET CT was 
performed, the CT component may be used if CT was obtained per RECIST V1.1 guidelines for gap thickness. Bone Scan must be completed at Screening and 
repeated only if positive, per institutional standard of care. Tumor assessment to be performed every 8 weeks (± 7 days) for 16 weeks, then every 12 weeks 
from C1D1, regardless of dose interruptions or dose delays. Post-screening assessments should be performed using the same technique used at screening. 
Screening CT must be conducted ≤ 4 weeks prior to registration. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
48 
16 After participants complete Cycle 4, only findings associated with an SAE or with an AE ≥ Grade 3 must be recorded in the CRF. Laboratory values ≥ CTCAE 
Grade 3 must also be captured. Blood pressure measurements taken before and after pelareorep administration must still be captured. 
17 The Off Treatment visit takes place when the decision to remove a patient from study treatment has been made. If patient is removed from treatment for reason(s) 
other than progression, follow with regular tumor assessments per standard of care until progression, initiation of a new therapy, or withdrawal of consent, 
whichever occurs first. 
18 Patients will be followed for adverse events for 30 days after their last dose of study medication or the initiation of non-protocol therapy after last dose of study 
medication, whichever comes first. If the Off Treatment visit occurs ≤ 30 days after the patient’s last dose of study treatment, the patient must be contacted by 
telephone at 30 days (up to 37 days) after the last dose of study treatment (or prior to initiation of subsequent therapy, whichever comes first) to assess AEs. 
However, a serious adverse event occurring at any time after discontinuation of study therapy that is felt to be at least possibly related to study therapy should 
be recorded. 
19 When patients discontinue study treatment, they will be followed for survival status every 4-6 months until they have withdrawn consent, been lost to follow-up, 
died, or EOS is reached, whichever occurs first. If a patient discontinues study treatment for reasons other than progression, follow with regular tumor 
assessments per standard of care until progression, initiation of a new therapy, or withdrawal of consent, whichever occurs first.  

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
49 
11. 
Drug Formulation and Procurement 
11.1 
Pelareorep 
11.1.1 Other Names 
Reovirus type 3 Dearing 
11.1.2 Classification  
Immuno-oncolytic virus 
11.1.3 Storage and Stability 
Pelareorep may be stored at -20°C or ≤ -60°C for up to 72 months from date of drug 
product fill. Product should be maintained at whichever storage temperature is initially 
chosen when the product is received and should not be transferred between storage 
temperature conditions. 
Upon receipt of shipment, the investigator or designee must confirm appropriate 
temperature conditions have been maintained during transit of pelareorep by 
inspecting the enclosed temperature device, as well as inspecting the contents for 
accuracy versus the packing list. Any discrepancies must be resolved before use of 
the study drug. 
11.1.4 Dose Specifics 
Pelareorep will be provided in glass vials. It is a clear to translucent colorless to light 
blue liquid containing 4.5x1010 TCID50 of reovirus Serotype 3 – Dearing Strain per mL. 
11.1.5 Preparation 
The dilution or mixing will be done at the study sites. Vial labels will indicate the 
product, lot number, and concentration and will include all required regulatory label 
elements. Full instructions are provided in the study Pharmacy Manual. 
The mixing and preparation procedures must be done in a biological safety cabinet 
(BSC) with appropriate precautions including mask, gown and gloves. All material that 
comes into contact with the viral preparation will be placed in sodium hypochlorite (800 
ppm chlorine) or 70% ethanol and disposed of as biohazardous waste. 
11.1.6 Route of Administration 
Intravenous 
11.1.7 Drug Interactions 
See Pelareorep Investigator’s Brochure. 
11.1.8 Agent Availability 
Pelareorep will be supplied by Oncolytics Biotech Inc. and distributed to sites by 
Oncolytics designated depot. 
The initial supply of pelareorep will be sent directly to the site upon site activation. As 
needed, pelareorep may be requested by the Principal Investigator (or their authorized 
designees) at each participating institution. The Investigator, or a responsible party 
designated by the Investigator, must maintain a careful record of the receipt, 
disposition, and return/destruction (site’s drug destruction policy must be reviewed and 
approved by PrECOG before any study drug can be destroyed at a site) of pelareorep. 
11.1.9 Agent Ordering 
Sites will be responsible for ordering drug for re-supply from Oncolytics. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
50 
11.1.10 Agent Accountability 
Pelareorep will be stored in a secure location. Only authorized pharmacy and study 
staff will have access to this agent. Drug accountability will be verified by PrECOG. 
11.1.11 Side Effects 
See Pelareorep Investigator’s Brochure  
11.1.12 Nursing/Patient Implications 
See Pelareorep Investigator’s Brochure  
11.2 
Avelumab 
11.2.1 Other Names 
Bavencio® 
11.2.2 Classification 
Anti-PDL1 monoclonal antibody 
11.2.3 Storage and Stability 
BAVENCIO® (avelumab) Injection is a sterile, preservative-free, and clear, colorless 
to slightly yellow solution for intravenous infusion supplied as a single-dose vial of 200 
mg/10 mL (20 mg/mL), individually packed into a carton. 
Store refrigerated at 36°F to 46°F (2°C to 8°C) in original package to protect from light. 
Do not freeze or shake the vial. 
The vial stopper is not made with natural rubber latex. 
11.2.4 Dose Specifics 
200 mg/10 mL (20 mg/mL) solution in single-dose vial. 
11.2.5 Preparation 
● 
Visually inspect vial for particulate matter and discoloration. Avelumab is a clear, 
colorless to slightly yellow solution. Discard vial if the solution is cloudy, discolored, 
or contains particulate matter. 
● 
Withdraw the required volume of avelumab from the vial(s) and inject it into a 250 
mL infusion bag containing either 0.9% Sodium Chloride Injection or 0.45% 
Sodium Chloride Injection. 
● 
Gently invert the bag to mix the diluted solution and avoid foaming or excessive 
shearing. 
● 
Inspect the solution to ensure it is clear, colorless, and free of visible particles. 
● 
Discard any partially used or empty vials. 
Storage of Diluted Avelumab Solution 
Protect from light. 
Store Diluted Avelumab Solution 
At room temperature up to 25°C for no more than 8 hours from the time of dilution 
or 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
51 
Under refrigeration at 2°C to 8°C for no more than 24 hours from the time of dilution. 
If refrigerated, allow the diluted solution to come to room temperature prior to 
administration. 
Do not freeze or shake diluted solution. 
11.2.6 Route of Administration 
Administer the diluted solution over 60 minutes through an intravenous line containing 
a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micron). 
Do not co-administer other drugs through the same intravenous line. 
11.2.7 Drug Interactions 
See Avelumab Investigator’s Brochure. 
11.2.8 Agent Availability 
Avelumab will be supplied by Oncolytics Biotech Inc. and provided to sites by 
Oncolytics designated depot. 
The initial supply of avelumab will be sent directly to the site upon site activation. As 
needed, avelumab may be requested by the Principal Investigator (or their authorized 
designees) at each participating institution. The Investigator, or a responsible party 
designated by the Investigator, must maintain a careful record of the receipt, 
disposition, and return/destruction (site’s drug destruction policy must be reviewed and 
approved by PrECOG before any study drug can be destroyed at a site) of avelumab. 
11.2.9 Agent Ordering 
Sites will be responsible for ordering drug for re-supply from Oncolytics. 
11.2.10 Agent Accountability 
Avelumab will be stored in a secure location. Only authorized pharmacy and study 
staff will have access to this agent. Drug accountability will be verified by PrECOG. 
11.2.11 Side Effects 
See Avelumab Investigator’s Brochure. 
11.2.12 Nursing/Patient Implications 
See Avelumab Investigator’s Brochure. 
Please refer to the commercial package insert for full prescribing information. 
11.3 
Paclitaxel 
Paclitaxel will be obtained by the individual study sites as standard of care treatments from 
commercial stock and is not an investigational product on this trial. Paclitaxel is generic and 
may be obtained from multiple manufacturers. Please refer to the commercial package insert 
for full prescribing information. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
52 
12. 
Statistical Considerations 
This is an open-label randomized Phase 2, 3-cohort study for patients with HR+/HER2-, endocrine-
refractory metastatic breast cancer. A total of 48 patients will be enrolled and will be treated until 
progression, unacceptable toxicity, withdrawal of consent, or EOS. 
A three patient safety run-in will be conducted in Cohort 3 (pelareorep+avelumab+paclitaxel) prior to 
beginning randomization into all three cohorts. 
Following the safety run-in, eligible patients will be randomized 1: 1: 1. Each cohort will enroll 15 
patients. Patients will be stratified for visceral versus non-visceral metastatic disease and randomized 
to receive: 
Cohort 1: Control group with dosing of weekly paclitaxel (PTX) according to standard of care (SOC) 
Cohort 2: Investigate treatment with pelareorep added to SOC (PTX) 
Cohort 3: Investigate treatment with pelareorep in combination with avelumab added to SOC (PTX). 
12.1 
Cohort 3 Safety Run-In 
A three patient safety run-in will be conducted in Cohort 3 (pelareorep+avelumab+paclitaxel) 
prior to beginning randomization into all three cohorts. A safety evaluation will be conducted 
after all 3 patients have completed one cycle of treatment (i.e., received all the doses for all 
the drugs per protocol) or discontinued the therapy before completion of Cycle 1 due to toxicity 
(i.e., permanently discontinued or dose held). Patients who discontinue the therapy before 
completion of Cycle 1 due to reason other than toxicity will be replaced. Refer to Table 5-1 for 
criteria for DLT. 
During the safety review a Steering Committee will review all the safety data captured during 
the first cycle of treatment and make recommendations to continue, alter, or permanently 
suspend the study based on this analysis. The Steering Committee may recommend 
amendments to explore alternate dosing schedules or lower doses based on the overall toxicity 
experience, even if the criteria for DLT are not met. 
12.2 
Analysis Populations 
Full Analysis Set 
The Full Analysis set (Intention-to-Treat or ITT set) comprises all patients who are enrolled into 
the Safety Run-in or randomized to treatment. 
Randomized Analysis Set  
The Randomized Analysis set comprises all patients who were randomized to a study 
treatment arm. 
Safety Analysis Set 
The Safety Analysis set comprises all patients who received any amount of study treatment. 
Full Response Evaluable Set 
The Full Response Evaluable set comprises all patients with measurable disease on the 
baseline tumor assessment who received any amount of study treatment and have at least 1 
post-baseline radiographic tumor assessment. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
53 
Randomized Response Evaluable Set 
The Randomized Response Evaluable set comprises all patients with measurable disease on 
the baseline tumor assessment who were randomized to a study treatment arm, received any 
amount of study treatment, and have at least 1 post-baseline radiographic tumor assessment. 
12.3 
General Considerations 
Continuous variables will be summarized using mean, standard deviation, median, minimum 
value, and maximum value. Categorical variables will be summarized using frequency counts 
and percentages. Time to event variables will be summarized using the Kaplan-Meier method. 
Where appropriate, confidence intervals around point estimates will be presented, and 
estimates of the median and other quantiles, as well as individual time points (for time to event 
data) will be produced. 
All confidence intervals will be 2-sided at the 80% level. 
12.4 
Efficacy Analyses 
ORR at week 16 and EOS will be analyzed using the Full Analysis set, the Randomized 
Analysis set, the Full Response Evaluable set, and the Randomized Response Evaluable set. 
OS and PFS will be analyzed using the Randomized Analysis set and the Full Analysis set. 
The study is not powered to make comparisons between treatment arms. Statistical tests, if 
performed, will be considered exploratory. Comparative results will be summarized 
descriptively, and consistency in trends in clinical and biological effects will be evaluated 
across clinical and biomarker endpoints, to provide an overall assessment of the relative 
benefits of each treatment. 
Tumor response rates in each arm will be reported with category counts, percentage, and 
confidence intervals using the Clopper-Pearson method for individual treatment groups. 
Comparison of tumor response rates between groups will be based on a difference in 
proportions and confidence intervals using a normal approximation with continuity correction. 
Further analyses using logistic regression, exploring potentially influential covariates, may be 
performed. 
12.5 
Biomarker Analyses 
Patients in the Safety Analysis Set who have relevant blood or tissue sampling will be included 
in the biomarker analyses. 
Biomarker endpoints will be summarized by treatment group at baseline and at each applicable 
post-baseline time point, and compared between treatment groups at post-baseline time 
points. Changes from baseline will also be summarized by group and compared between 
groups. 
Comparisons between groups will use difference of means for continuous variables (e.g., T 
cell clonality, diversity, TMB), and difference of proportions and/or odds ratios for categorical 
or clinically relevant discretizations of continuous variables (e.g., high/low clonality). 
Univariate and multivariate modeling will be performed to characterize the strength of 
association between biomarker measures (or discretizations thereof) and clinical outcomes. 
12.6 
Sample Size Considerations 
The sample size for this Phase 2 exploratory study is based on practical considerations to 
enable the assessment of safety, tolerability, and preliminary biological and clinical activity. As 
formal tests of statistical significance are not planned, power calculations will not be performed. 
The level of uncertainty around between-group comparisons on the key clinical endpoint of 
ORR can be quantified in terms of the width of the confidence interval for the treatment effect: 
with 15 patients per arm, the 80% confidence interval for the difference in ORR between 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
54 
treatment arms will have half-width of about 28%. This quantity is commensurate with the 
anticipated magnitude of difference expected in the comparison of Cohort 1 vs Cohort 2 (about 
25% difference expected) and Cohort 1 vs Cohort 3 (about 50% difference expected). 
12.7 
Additional Analyses 
Demographic and baseline characteristics will be summarized using data from all patients in 
the Full Analysis (ITT) set and in the Safety Analysis set by treatment group. Treatment 
exposure, including duration on treatment and extent of exposure, will be summarized by 
treatment group. 
Safety analysis will include summaries by treatment group of: AEs, laboratory measures, 
physical examinations, and vital signs using data from patients in the Safety Analysis set. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
55 
13. 
Laboratory and Pathology Correlative Studies 
Biomarkers on this study will examine the immunological changes within the TME and peripheral blood 
in patients treated with paclitaxel alone, in combination with pelareorep, and in combination with 
pelareorep and avelumab. 
As such, the pretreatment and on-treatment biopsies/blood collections are critical with mandatory blood 
draws and optional tumor biopsies. Key assays will: 
● 
Examine the expression of immune-related biomarkers, such as PD-1 and PD-L1. 
● 
Identify biological changes, as defined by changes in gene expression within the TME and PBMCs, 
between pre-treatment on-therapy specimens. 
● 
Compare changes in the T cell repertoire between pre-treatment and on-therapy tumor biopsies; 
examining common T cell clones between tumor tissue and peripheral blood samples. 
● 
Compare changes in the T cell repertoire between pre-treatment and on-therapy peripheral blood 
samples. 
● 
Examine tumor mutational burden and prevalent DNA mutations in all patients from cfDNA. 
13.1 
Correlative Studies: Optional Tumor Samples 
Patients from each cohort (excluding safety run-in) may provide formalin-fixed paraffin-
embedded tissue from a needle core biopsy collected prior to randomization (archival tissue 
allowed) and on-treatment from Cycle 1, collected between days 17 and 28. 
NOTE: A maximum of 5 patients in each cohort will have biopsies collected. 
13.1.1 Pathology Sample Processing and Shipment 
Sites should submit Formalin-Fixed Paraffin-Embedded (FFPE) tumor tissue blocks 
(preferred) or up to 15 unstained FFPE slides (2 sections per slide) plus H&E slide 
from a tumor tissue block. Thickness of the sections should be at 4-5 micron. 
A copy of the pathology report from initial diagnosis and/or subsequent tumor sampling 
should be sent when the sample is shipped. If a pathology report is not available for 
the subsequent tumor sample completed for research purposes only, it is acceptable 
not to provide. Samples should be shipped Monday-Thursday. Samples will be 
shipped ambient via overnight courier. 
All samples collected will be labeled with a unique numeric identifier that will be coded 
for patient privacy protection. 
Kits will be supplied. Instructions and shipping address will be provided. 
13.2 
Correlative Studies: Mandatory Peripheral Blood Samples 
Blood draws for biomarker analyses will be performed prior to treatment administration on 
Cycle 1 Day 1, Cycle 1 Day 8, and on Day 1 of all remaining cycles. 
13.2.1 Peripheral Blood Sample Processing and Shipment 
Instructions, shipping labels, supplies and address will be provided in the kits. 
All samples collected will be labeled with a unique numeric identifier that will be coded 
for patient privacy protection. 
Blood Sample Processing: 
Draw whole blood into (1) 2 mL K2EDTA tube and (2) 10 mL K2EDTA tubes. The draw 
tube should be at room temperature 18°C to 25°C prior to collection. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
56 
After collection, the sample must be immediately inverted 8 to 10 times. 
2 mL K2EDTA Tube 
Immediately store 2 mL K2EDTA tube at -20°C. Tube can also be stored at ≤ -70°C 
(preferably -80°C) long term. 
Cycle 1, Day 1; Cycle 1 Day 8 and Cycle 2 Day 1 samples for each patient will be 
shipped to the Central Biorepository Pathology Facility (CBPF) once all 3 samples are 
available on a patient. Remaining samples will be batch shipped approximately every 
3 months to the CBPF for storage. 
2 x 10 mL K2EDTA Tubes 
**Process sample within 4 hours of collection** 
• 
Gently mix blood sample by inversion 10 times (do not shake). 
• 
Place tube immediately on wet ice for 5 minutes. 
• 
Centrifuge at 1200 relative centrifugal force (RCF) for 15 minutes at 4°C. If a 
refrigerated centrifuge is not available, spin sample at room temperature (1200 
RCF for 15 minutes). Immediately place the tube on wet ice after centrifugation. 
After centrifugation, the plasma layer will be at the top half of the tube. The nucleated 
cells (WBC) will be in a whitish layer, called the “buffy coat”, just under the plasma and 
above the red blood cells. 
Plasma Preparation: 
• 
Using a transfer pipette take the top two-thirds of the plasma and transfer plasma 
into a 15 mL conical centrifuge tube, be careful not to disturb the buffy coat layer 
in the EDTA tube (NOTE: see below for buffy coat processing instructions). 
Centrifuge the 15 mL conical tube at 1200 RCF for 15 minutes at 4°C. If a 
refrigerated centrifuge is not available, spin sample at room temperature (1200 
RCF for 15 minutes). Immediately place the conical tube on wet ice after 
centrifugation. 
• 
Transfer equal amounts of plasma into two (2) properly labeled polypropylene 
tubes for cryopreservation being careful not to disturb the small PBMC/pellet. 
• 
Store the two aliquots of plasma samples in the freezer at ≤ -70°C (preferably -
80°C) until they are shipped to central lab. 
Buffy Coat Preparation: 
• 
From the EDTA tube remove and aliquot the “buffy coat”; be careful not to disturb 
the layer of red blood cells. 
• 
Store the aliquot of cells in one (1) properly labeled polypropylene tube for 
cryopreservation. 
• 
Store the sample in the freezer at ≤ -70°C (preferably -80°C) until it is shipped to 
central lab. 
Plasma and buffy coat samples should be batched together and shipped 
approximately every 3 months. Individual patients should only be included in the 
shipment if all of their samples have been completed. Samples should be shipped 
Monday-Thursday. Samples must be shipped on dry ice via overnight courier. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
57 
14. 
Administrative 
14.1 
Protocol Compliance 
The study shall be conducted as described in this protocol. All revisions to the protocol must 
be discussed with and be prepared by PrECOG and/or representatives. The Investigator 
should not implement any deviation or change to the protocol or consent without prior review 
and documented approval from PrECOG and/or representatives and the Institutional Review 
Board (IRB) of an amendment, except where necessary to eliminate an immediate hazard(s) 
to study patients. 
If a deviation or change to the approved protocol is implemented to eliminate an immediate 
hazard(s) prior to obtaining IRB approval, notification will be submitted to the IRB for review 
and approval as soon as possible afterward. Documentation of approval signed by the 
chairperson or designee of the IRB(s) should be in the study records. If PrECOG and/or 
representatives provides an amendment that substantially alters the study design or increases 
the potential risk to the patient; the consent form must be revised and submitted to the IRB(s) 
for review and approval; the revised form must be used to obtain consent from patients 
currently enrolled in the study if they are affected by the Amendment; and the new form must 
be used to obtain consent from new patients prior to study entry. Information as to whom 
Investigators should send correspondence will be provided in additional study documents. 
14.2 
Institutional Review Board (IRB) 
Before study initiation, the Investigator must have written and dated approval from their 
respective IRB for the protocol, consent form, patient recruitment materials/process and any 
other written information to be provided to patients. The Investigator should also provide the 
IRB with a copy of the Investigator’s Brochure or product labeling, and any updates. 
The Investigator should provide the IRB with reports, updates, and other information (e.g., 
Safety Updates, amendments, and administrative letters) according to regulatory 
requirements, IRB or study site procedures. 
14.3 
Informed Consent Procedures 
Investigators must ensure that patients who volunteer for clinical trials or their legally 
acceptable representative are clearly and fully informed about the purpose, potential risks and 
other information. 
A protocol specific informed consent form (ICF) template will be provided to sites. Preparation 
of the site-specific consent form is the responsibility of the site Investigator and must include 
all applicable regulatory and IRB requirements, and must adhere to Good Clinical Practices 
(GCP) and to the ethical principles that have their origin in the Declaration of Helsinki. All 
changes to the ICF template will be approved by PrECOG and/or their representatives prior to 
implementation. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
consent process will also include written authorization by patients to release medical 
information to allow PrECOG and/or its agents, regulatory authorities, and the IRB of record at 
the study site for access to patient records and medical information relevant to the study, 
including the medical history. This will be documented in the informed consent form or other 
approved form obtained at the time of informed consent per institutional policies. This form 
should also be submitted to PrECOG and/or its agents for review prior to its implementation. 
The Investigator must provide the patient or legally acceptable representative with a copy of 
the consent form and written information about the study in the language in which the patient 
is most proficient. The language must be non-technical and easily understood. The Investigator 
should allow time necessary for patient or patient's legally acceptable representative to inquire 
about the details of the study, then informed consent must be signed and personally dated by 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
58 
the patient or the patient's legally acceptable representative and by the person who conducted 
the informed consent discussion. The patient or legally acceptable representative should 
receive a copy of the signed informed consent and any other written information provided to 
study patients prior to patient's participation in the trial. The investigator is responsible for 
assuring adequate documentation of this process and for storage and maintenance of the 
original signed consent form for each patient/patient. 
The informed consent and any other information provided to patients or the patient's legally 
acceptable representative, should be revised whenever important new information becomes 
available that is relevant to the patient's consent, and should receive IRB approval prior to use. 
The Investigator, or a person designated by the Investigator should inform the patient or the 
patient's legally acceptable representative of all pertinent aspects of the study and of any new 
information relevant to the patient's willingness to continue participation in the study. This 
communication should be documented in the patient record. During a patient's participation in 
the trial, any updates to the consent form and any updates to the written information will be 
provided to the patient. 
14.4 
Safety Communication 
Investigators will be notified of all AEs that are serious, unexpected, and related to the 
investigational product(s). Upon receiving such notices, the Investigator must review and retain 
the notice with the Investigator’s Brochure and submit a copy of this information to the IRB 
according to local regulations. The Investigator and IRB will determine if the informed consent 
requires revision. The Investigator should also comply with the IRB procedures for reporting 
any other safety information. All revisions should be submitted to PrECOG and/or agents for 
review. 
14.5 
Monitoring 
Representatives and agents of PrECOG and, as applicable to the study, the manufacturer of 
investigational product must be allowed to visit all study site locations periodically to assess 
the data, quality and study integrity. The purpose of this visit is to review study records and 
directly compare them with source documents and discuss the conduct of the study with the 
Investigator and verify that the facilities remain acceptable. Monitoring of drug accountability 
will also occur. 
The study may be evaluated by other auditors and government inspectors who must be 
allowed access to electronic Case Report Forms (eCRFs), source documents and other study 
files. The Investigator must notify PrECOG of any scheduled visits by regulatory authorities 
and submit copies of all reports. Information as to who investigators should notify of an audit 
or where to address questions will be provided in additional study materials. 
14.6 
Study Records 
An Investigator is required to maintain adequate regulatory files with corresponding 
communication and approvals, accurate histories, observations and other data on each 
individual treated. Full details of required regulatory documents will be provided in additional 
study materials. Data reported on the eCRFs must be consistent with the source documents 
as part of the patient record. 
The confidentiality of records that could identify patients must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
A unique identifier will be assigned to each patient, and any patient records, samples (e.g. 
blood, urine, or tumor tissue) or datasets that are transferred to the sponsor or vendor will 
contain the identifier only; patient names or any information which would make the patient 
identifiable will not be transferred. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
59 
A study specific signature record will be maintained to document signatures and initials of all 
persons at a study site who are authorized to make entries and/or corrections on eCRFs as 
well as document other study-specific roles. 
14.7 
Electronic Case Report Form (eCRF) Information 
Additional information regarding eCRF instructions, timelines for data entry/ submission and 
query completion can be found in supplemental materials provided to the site. Sites will be 
expected to complete eCRFs as per the schedule provided and submit all relevant data as per 
the specified timelines. All items recorded on eCRFs must be found in source documents. 
The completed eCRF must be promptly reviewed, electronically signed, and dated by the 
Principal Investigator. 
Instructions for management of patients who do not receive any protocol therapy: 
If a patient is registered and does not receive any assigned protocol treatment, baseline data 
will be entered. No data past baseline will be collected. Document the reason for not starting 
protocol treatment on the appropriate electronic off treatment form. 
14.8 
Records Retention 
FDA Regulations (21CFR 312.62) require clinical investigators to retain all trial-related 
documentation, including source documents for the periods described below for studies 
performed under a US Investigational New Drug (IND): 
• two years after the FDA approves the marketing application, or 
• two years after the FDA disapproves the application for the indication being studied, or 
• two years after the FDA is notified by the Sponsor of the discontinuation of trials and that 
an application will not be submitted. 
The Investigator must retain investigational product disposition records, copies of eCRFs (or 
electronic files), and source documents for the maximum period required by applicable 
regulations and guidelines, or Institution procedures, whichever is longer. The Investigator 
must contact PrECOG and/or representatives prior to destroying any records associated with 
the study. 
Information as to who investigators should contact for questions will be provided in additional 
study documents. PrECOG and/or representatives will notify the Investigator when the trial 
records for this study are no longer needed. 
14.9 
Publication Policy 
The Sponsor/PrECOG recognizes the importance of communicating medical study data and 
therefore encourages their publication in reputable scientific journals and at seminars or 
conferences. Written approval from the Sponsor and PrECOG is required before disclosing 
any information related to this clinical trial, and no publications initiated by Investigators may 
be published until all protocol defined primary and exploratory endpoints are published in a 
manuscript. Investigators in this study agree to have their name listed as an Investigator in any 
publication reporting results from this study, whether or not they are an author on the 
publication. 
The details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this study will be described in the Clinical Trial 
Agreement between the Sponsor and PrECOG and the Task Order between PrECOG and the 
institution of the Investigator. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
60 
14.10 
Study and Site Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of Oncolytics. All study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
Oncolytics may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Oncolytics may include but are not limited to: 
● 
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines. 
● 
Safety or ethical issues. 
● 
Inadequate recruitment of patients by the Investigator. 
● 
Discontinuation of further study treatment development. 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
61 
15. 
References 
Adams, S. et al., 2018. Atezolizumab Plus nab-Paclitaxel in the Treatment of Metastatic Triple-Negative Breast 
Cancer With 2-Year Survival Follow-up: A Phase 1b Clinical Trial. JAMA oncology. 
Berman, A.T., Thukral, A.D., Hwang, W.T., Solin, L.J. and Vapiwala, N., 2013. Incidence and patterns of distant 
metastases for patients with early-stage breast cancer after breast conservation treatment. Clin Breast Cancer, 
13(2): 88-94. 
Brockton, N.T. et al., 2015. The Breast Cancer to Bone (B2B) Metastases Research Program: a multi-
disciplinary investigation of bone metastases from breast cancer. BMC Cancer, 15: 512. 
Dirix, L.Y. et al., 2018. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast 
cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat, 167(3): 671-686. 
Gutierrez, A.A. et al., 2017. Pooled data analysis of the safety and tolerability of intravenous Pelareorep in 
combination with chemotherapy in 500 + cancer patients. Annals of Oncology. 28 (suppl_5): v403-v427. 
10.1093/annonc/mdx376. 
Heinemann, L. et al., 2011. Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate 
cancer. BMC Cancer, 11: 221. 
Herrinton, L.J. et al., 2005. Efficacy of prophylactic mastectomy in women with unilateral breast cancer: a 
cancer research network project. J Clin Oncol, 23(19): 4275-86. 
International Agency for Research on Cancer, 2012. Breast cancer: estimated incidence, mortality and 
prevalence worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer. 
Jackson, G.G., Muldoon, R.L., Johnson, G.C. and Dowling, H.F., 1963. Contributions of Volunteers to Studies 
on the Common Cold. Am Rev Respir Dis, 88: SUPPL 120-7. 
Jackson, G.G.M., R. L.; Cooper, G. S.;, 1961. Reovirus type 1 as an etiologic agent of the common cold. Journal 
of Clinical Investigation, 40(6): 1022-1072. 
Jarudi, N.I., Huggett, D.O. and Golden, B., 1973. Reovirus keratoconjunctivitis. Can J Ophthalmol, 8(2): 371-
3. 
Lerner, A.M., Cherry, J.D., Klein, J.O. and Finland, M., 1962. Infections with reoviruses. N Engl J Med, 267: 
947-52. 
Marcato, P., Dean, C.A., Giacomantonio, C.A. and Lee, P.W., 2009. Oncolytic reovirus effectively targets breast 
cancer stem cells. Mol Ther, 17(6): 972-9. 
Minuk, G.Y., Paul, R.W. and Lee, P.W., 1985. The prevalence of antibodies to reovirus type 3 in adults with 
idiopathic cholestatic liver disease. J Med Virol, 16(1): 55-60. 
Minuk, G.Y. et al., 1987. Reovirus type 3 infection in patients with primary biliary cirrhosis and primary 
sclerosing cholangitis. J Hepatol, 5(1): 8-13. 
Mostafa, A.A. et al., 2018. Oncolytic Reovirus and Immune Checkpoint Inhibition as a Novel Immunotherapeutic 
Strategy for Breast Cancer. Cancers (Basel), 10(6). 
National Cancer Institute, N.I.o.H., U.S. Department of Health and Human Services, 2014. SEER Cancer 
Statistics Review 1975-2011. http://seer.cancer.gov/archive/csr/1975_2011/. 
Norman, K.L. et al., 2002. Reovirus oncolysis of human breast cancer. Hum Gene Ther, 13(5): 641-52. 
O'Shaughnessy, J., 2005. Extending survival with chemotherapy in metastatic breast cancer. Oncologist, 10 
Suppl 3: 20-9. 
Rosen, L., Evans, H.E. and Spickard, A., 1963. Reovirus infections in human volunteers. Am J Hyg, 77: 29-37. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
62 
Rosen, L., Hovis, J.F., Mastrota, F.M., Bell, J.A. and Huebner, R.J., 1960. An outbreak of infection with a type 
1 reovirus among children in an institution. American Journal of Epidemiology, 71(2): 266-274. 
Sabin, A.B., 1959. Reoviruses. A new group of respiratory and enteric viruses formerly classified as ECHO 
type 10 is described. Science, 130(3386): 1387-9. 
Sei, S. et al., 2009. Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-
small cell lung cancer cells. Mol Cancer, 8: 47. 
Siegel, R.L., Miller, K.D. and Jemal, A., 2016. Cancer statistics, 2016. CA Cancer J Clin, 66(1): 7-30. 
Smith, I., 2006. Goals of treatment for patients with metastatic breast cancer. Semin Oncol, 33(1 Suppl 2): S2-
5. 
Sundquist, M., Brudin, L. and Tejler, G., 2017. Improved survival in metastatic breast cancer 1985-2016. 
Breast, 31: 46-50. 
Torre, L.A. et al., 2015. Global cancer statistics, 2012. CA Cancer J Clin, 65(2): 87-108. 
Tyler, K.L. and Fields, B.N., 1990. Reoviruses. In: B.N. Fields and D.M. Knipe (Editors), Virology. Raven Press 
Ltd, New York, pp. 1307-1328. 
World Health Organization, 2013. Projections of mortality and causes of death, 2015 and 2030. 
http://www.who.int/healthinfo/global_burden_disease/projections/en/. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
63 
Appendix I 
ECOG Performance Status 
 
PS 0 
Fully active, able to carry on all pre-disease performance 
without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature e.g. 
light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry 
out any work activities. Up and about more than 50% of 
waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
Source: Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
64 
Appendix II: RECIST Version 1.1 
Malignant Disease Evaluation 
Response and progression will be evaluated in this study using the international criteria proposed by the 
revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline Version 1.1. Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in RECIST. 
To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which 
subsequent measurements will be compared. Measurable disease is defined by the presence of at least one 
measurable lesion. 
All measurements should be recorded in metric notation by use of a ruler or calipers. The same method of 
assessment and the same technique should be used to characterize each identified lesion at baseline and 
during follow-up. All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than four weeks before registration. 
The term evaluable in reference to measurability will not be used because it does not provide additional 
meaning or accuracy. 
At baseline, tumor lesions will be characterized as either measurable or non-measurable. 
o 
Measurable 
Measurable tumor lesions are those that can be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
• 
≥ 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness 
and a minimum of 10 mm) 
• 
≥ 10 mm caliper measurement by clinical exam (when superficial) 
• 
≥ 20 mm by chest x-ray (if clearly defined and surrounded by aerated lung) 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
o 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in short axis 
(perpendicular to longest diameter) when assessed by CT scan. 
o 
Non-Measurable 
All other lesions (or sites of disease), including small lesions not meeting the criteria in “Measurable” and 
“Malignant Lymph Nodes” above, are considered non-measurable lesions. This includes lymph nodes 
measured at ≥ 10 to <15 mm in the short axis. NOTE: Lymph nodes measured at <10 mm in the short axis 
are considered normal. 
Lesions considered to be non-measurable include the following: leptomeningeal disease, ascites, 
pleural/pericardial effusions, inflammatory breast disease, lymphangitic involvement of the skin or lung, 
and abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
NOTE: 
‘Cystic lesions’ that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, if non-cystic lesions are present in the 
same patient, these are preferred for selection as target lesions. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
65 
Lytic bone lesions, with an identifiable soft tissue component, evaluated by CT or MRI, can be considered 
as measurable lesions if the soft tissue component otherwise meets the definition of measurability in 
“Measurable” above. Blastic bone lesions are non-measurable. 
Tumor lesions that are situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in the 
lesion. 
Definitions of Response 
o 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all 
involved organs, should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (those with the longest diameters), be representative 
of all involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured reproducibly should 
be selected. 
The sum of the target lesions (longest diameter for non-nodal lesions, short axis for nodal lesions) will be 
calculated and reported as the baseline sum. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum of the diameters/axes will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
• 
Complete Response (CR) 
The disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to <10 mm (the sum may not be “0” if there are target nodes). To be 
assigned a status of complete response, changes in tumor measurements must be confirmed by 
repeat assessments performed ≥ 4 weeks after the criteria for response are first met. 
• 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters/axes of target lesions, taking as reference the 
baseline sum diameters/axes. To be assigned a status of partial response, changes in tumor 
measurements must be confirmed by repeat assessments performed ≥ 4 weeks after the criteria for 
response is met. 
• 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters/axes 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 
over the nadir. (NOTE: the appearance of one or more new lesions is also considered progression). 
• 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters/axes while on study. (NOTE: a change of 20% or more that 
does not increase the sum of the diameters by 5 mm or more is coded as stable disease). 
To be assigned a status of stable disease, measurements must have met the stable disease criteria 
at least once after study entry at a minimum interval of ≥ 4 weeks. 
o 
Non-Target Lesions 
All other lesions or sites of disease including any measurable lesions over and above the 5 target lesions 
and lymph nodes measured at ≥ 10 to <15 mm in the short axis should be identified as non-target lesions 
and should also be recorded at baseline. Measurements of these lesions are not required, but the presence 
or absence of unequivocal progression of each should be noted throughout follow-up. 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
66 
• 
Complete Response (CR) 
The disappearance of all non-target lesions and normalization of tumor marker levels, if applicable. All 
lymph nodes must be non-pathological in size (<10 mm short axis). To be assigned a status of 
complete response, changes in tumor measurements must be confirmed by repeat assessments 
performed ≥ 4 weeks after the criteria for response are first met. 
NOTE: If tumor markers are initially above the upper normal limit, they must normalize for a patient to 
be considered in complete clinical response. 
• 
Non-CR/Non-PD 
The persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker levels 
above the normal limits. To be assigned a status of Non-CR/Non-PD, measurements must have met 
the Non-CR/Non-PD criteria at least once after study entry at a minimum interval of ≥ 4 weeks. 
• 
Progressive Disease (PD) 
The appearance of one or more new lesion(s) and/or unequivocal progression of existing non-target 
lesions. Unequivocal progression should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion increase. 
When the patient also has measurable disease, there must be an overall level of substantial worsening 
in non-target disease such that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal progression status. 
The designation of overall progression solely on the basis of change in non-target disease in the face 
of SD or PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the increase in overall disease burden should be 
comparable in magnitude to the increase that would be required to declare PD for measurable disease: 
i.e., an increase in tumor burden from “trace” to “large”, an increase in nodal disease from “localized” 
to “widespread”, or an increase sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances. 
o 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive Disease (PD). 
o 
Symptomatic Deterioration 
Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. Every 
effort should be made to document the objective progression even after discontinuation of treatment. 
Evaluation of Patient’s Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until confirmed disease 
progression or non-protocol therapy (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient's best response assignment will depend on the achievement 
of both measurement and confirmation criteria (Table V-1). 
To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed 
by repeat assessments performed ≥ 4 weeks after the criteria for response are first met. 
To be assigned a status of stable disease, measurements must have met the stable disease criteria at least 
once after study entry at a minimum interval of ≥ 4 weeks. 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
67 
Table II-1: Overall Response for All Possible Combinations of Tumor Response 
Target 
Lesions 
Non-Target 
Lesions 
New Lesion 
Overall 
Response 
Remarks 
CR 
CR 
No 
CR 
Confirmation at ≥ 4 weeks 
CR 
Non-CR/Non-
PD* 
No 
PR 
Confirmation at ≥ 4 weeks 
CR 
Not Evaluated 
No 
PR 
Confirmation at ≥ 4 weeks 
PR 
Non-PD*/Not 
Evaluated 
No 
PR 
Confirmation at ≥ 4 weeks 
SD 
Non-PD*/Not 
Evaluated 
No 
SD 
Documented at least once ≥ 4 
weeks from study entry 
Not All 
Evaluated 
Non-PD 
No 
Not Evaluable 
 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD* 
Any 
Any 
Yes 
PD 
* PD in non-target lesions should not normally trump target lesion status. It must be representative 
of overall disease status change, not a single lesion increase. Please refer to Non-Target Lesions-
Progressive Disease for further explanation. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
NOTE: If patients respond to treatment and are able to have their disease resected; the patient’s 
response will be assessed prior to the surgery. However, the patient will be considered inevaluable for 
survival analysis. 
Methods of Measurement 
Imaging based evaluation is preferred to evaluation by clinical examination. The same imaging modality should 
be used throughout the study to measure disease (preferred but not mandated). Below is a list of methods that 
may be used depending on location and type of cancer. 
o 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and 
palpable lymph nodes) and ≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules). In the 
case of skin lesions, documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended. 
o 
CXR 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT is preferable. 
o 
CT and MRI 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for 
body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI which greatly impact image quality, 
lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, 
if an MRI is performed, the technical specifications of the scanning sequences used should be optimized 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
68 
for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up 
should be the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used 
and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
o 
PET-CT 
At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of 
optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that 
the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, 
that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely 
or serially performed. 
o 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. 
Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, 
because they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound 
in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
o 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques 
may be useful to confirm complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following CR or surgical resection is an endpoint. 
o 
Tumor Markers 
Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal 
limit, they must normalize for a patient to be considered in complete clinical response. 
o 
Cytology, Histology 
These techniques can be used to differentiate between PR and CR in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment 
when the measurable tumor has met criteria for response or SD is mandatory to differentiate between response 
or SD (an effusion may be a side effect of the treatment) and PD. 
 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
69 
Appendix III: NYHA Classification 
 
Class 
Symptoms 
Class I 
Patients with cardiac disease but without resulting limitation of 
physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea (shortness of breath), or 
anginal pain. 
Class II 
Patients with cardiac disease resulting in slight limitation of 
physical activity. Comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of 
physical activity. Comfortable at rest. Less than ordinary 
physical activity causes fatigue, palpitation, dyspnea or anginal 
pain. 
Class IV 
Patients with cardiac disease resulting in inability to carry out 
any physical activity without discomfort. Symptoms of cardiac 
insufficiency or the anginal syndrome may be present even at 
rest. If any physical activity is undertaken, discomfort is 
increased. 
Oxford Textbook of Internal Medicine. Vol. 2, pp 2228. Oxford University Press. 1997 

PrECOG Protocol Number: PrE0113 
IND Number: 12318 
Confidential 
Version 3.0 | Version Date: 21 July 2022 
 
70 
Appendix IV: Investigator’s Statement 
1. 
I have carefully read this protocol entitled “A study to assess overall response rate by inducing 
an inflammatory phenotype in Metastatic BReast cAnCEr with the Oncolytic Reovirus 
PeLareorEp in CombinaTion with anti-PD-L1 Avelumab and Paclitaxel – BRACELET-1 Study”, 
Version 3.0 dated 07/21/2022 (Protocol Number PrE0113) and agree that it contains all the 
necessary information required to conduct the study. I agree to conduct the study as outlined 
in the protocol. 
2. 
I agree to conduct this study according to the moral, ethical and scientific principles 
governing clinical research as set out in the Declaration of Helsinki, the principles of 
Good Clinical Practice (GCP) as described in 21 Code of Federal Regulations (CFR) 
and any applicable local requirements. 
3. 
I understand that this trial and any subsequent changes to the trial will not be initiated 
without approval of the appropriate Institutional Review Board, and that all 
administrative requirements of the governing body of the institution will be complied 
with fully. 
4. 
Informed written consent will be obtained from all participating patients in accordance 
with institutional and Food and Drug Administration (FDA) requirements as specified in 
Title 21, CFR, Part 50. 
5. 
I understand that my signature on the electronic Case Report Form (eCRF) indicates 
that I have carefully reviewed each page and accept full responsibility for the contents 
thereof. 
6. 
I understand that the information presented in this study protocol is confidential, and I 
hereby assure that no information based on the conduct of the study will be released 
without prior consent from PrECOG, LLC unless this requirement is superseded by the 
FDA. 
Principal Investigator (PI): 
PI Name: 
 
 
 
 
 
 
 
 
 
 
Site Name: 
 
 
 
 
 
 
 
 
 
 
Signature of PI: 
 
 
 
 
 
 
 
 
 
Date of Signature: 
 
 
\ 
 
\ 
 
 
 
 
 
 
 
MM 
 
DD 
 
YYYY