LUMINOS-103: A Basket Trial Evaluating the Safety and Efficacy of Lerapolturev (PVSRIPO) and Lerapolturev in Combination With Anti-PD-1/L1 Checkpoint Inhibitors in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Solid Tumor, Bladder Cancer, Non-muscle-invasive Bladder Cancer
Sponsor: Istari Oncology, Inc.

 
 
 
 
NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) SUBSTUDY 
 
Note: this substudy is part of LUMINOS-103: A Basket Trial Evaluating the Safety and Efficacy 
of PVSRIPO and PVSRIPO in Combination with Anti-PD-1/L1 Checkpoint Inhibitors in Patients 
with Advanced Solid Tumors and is not an independent protocol. Also note that the NMIBC 
substudy is not designed to treat patients with the combination of PVSRIPO and anti-PD-1/L1, 
ie, Phase 2 for the NMIBC substudy is not planned to be enrolled. 
 
 
 
SUBSTUDY DATE: 
18 May 2022 
SUBSTUDY VERSION: 
Version 2.0 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This study will be performed in compliance with Good Clinical Practice (GCP) and applicable regulatory 
requirements, including the archiving of essential documents. Information contained in this protocol is 
confidential in nature, and may not be used, divulged, published, or otherwise disclosed to others except to the 
extent necessary to obtain approval of the institutional review board or independent ethics committee, or as 
required by law. Persons to whom this information is disclosed should be informed that this information is 
confidential and may not be further disclosed without the express written consent of Istari Oncology, Inc (Istari). 
 
 
 

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SPONSOR SIGNATORY 
________________________________________
______________________________
Shannon Morris, MD, PhD 
Date 
Vice President, Clinical Development
Istari Oncology, Inc.
 

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INVESTIGATOR’S AGREEMENT 
 
LUMINOS-103: NON-MUSCLE INVASIVE BLADDER CANCER SUBSTUDY 
A Basket Trial Evaluating the Safety and Efficacy of PVSRIPO in Patients with 
Non-Muscle Invasive Bladder Cancer 
 
I have read the above-referenced Istari Non-Muscle Invasive Bladder Cancer Substudy under the 
LUMINOS-103 master protocol and agree to conduct the study as outlined herein, in accordance 
with Good Clinical Practice (GCP) requirements and the International Council for 
Harmonization (ICH) guidelines, the Declaration of Helsinki and complying with the obligations 
and requirements of Clinical Investigators and all other requirements listed in 21 Code of Federal 
Regulations (CFR) Part 312 and with all applicable local regulations. I agree to maintain the 
confidentiality of all information received or developed in connection with this substudy and 
master protocol. 
 
 
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
 
 
 
 
Principal Investigator Name 
 
Institution 
 
 

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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES  
  
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ....................................4 
LIST OF ABBREVIATIONS ..........................................................................................................7 
SYNOPSIS .......................................................................................................................................9 
Inclusion Criteria ...........................................................................................................................11 
Exclusion Criteria ..........................................................................................................................11 
SCHEDULE OF ASSESSMENTS ................................................................................................14 
1. 
INTRODUCTION ...........................................................................................................17 
1.1. 
Background ......................................................................................................................17 
1.1.1. 
Bladder Cancer ................................................................................................................17 
1.1.2. 
Oncolytic Viruses/Immunomodulatory Agents Delivered by Cystoscopy .....................18 
1.1.3. 
Detergents/Surfactants Administered via Intravesical Instillation ..................................19 
1.2. 
Study Rationale and Risk Benefit Assessment for PVSRIPO as Monotherapy 
Treatment in NMIBC ......................................................................................................20 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................23 
2.1. 
Rationale for Primary and Secondary Endpoints ............................................................24 
2.1.1. 
Safety ...............................................................................................................................24 
2.1.2. 
Biomarkers ......................................................................................................................25 
3. 
INVESTIGATIONAL PLAN .........................................................................................26 
3.1. 
Rationale for Approach ...................................................................................................27 
4. 
STUDY POPULATION ..................................................................................................29 
4.1. 
Inclusion Criteria .............................................................................................................29 
4.2. 
Exclusion Criteria ............................................................................................................29 
5. 
STUDY TREATMENT ...................................................................................................31 
5.1. 
Study Drugs Administered ..............................................................................................31 
5.1.1. 
Dose, Dosing Regimen, Route, Preparation and Handling .............................................31 
5.1.1.1. PVSRIPO .........................................................................................................................31 
5.2. 
Dose Modifications and Toxicity Management Guidelines ............................................32 
5.3. 
Concomitant Medications ................................................................................................33 
6. 
STUDY ASSESSMENTS ...............................................................................................34 
6.1. 
Informed Consent ............................................................................................................34 

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6.2. 
Safety Assessments .........................................................................................................34 
6.2.1. 
Demographics ..................................................................................................................34 
6.2.2. 
Medical History and Solid Tumor Disease History ........................................................34 
6.2.3. 
Vital Signs .......................................................................................................................35 
6.2.4. 
Physical Examination ......................................................................................................35 
6.2.5. 
Clinical Safety Laboratory Assessments .........................................................................35 
6.2.6. 
Electrocardiogram ...........................................................................................................36 
6.2.7. 
Evaluation of PVSRIPO Shedding ..................................................................................37 
6.2.8. 
Cystoscopic Photography ................................................................................................37 
6.3. 
Biomarker Assessments ...................................................................................................37 
6.4. 
Data Safety Monitoring Committee ................................................................................38 
7. 
STATISTICAL CONSIDERATIONS ............................................................................39 
7.1. 
Sample Size Determination .............................................................................................39 
7.2. 
Analysis Population .........................................................................................................39 
7.3. 
Timing of Planned Analyses ...........................................................................................39 
7.4. 
Statistical Analysis Methods ...........................................................................................39 
7.4.1. 
General Considerations ...................................................................................................39 
7.4.2. 
Demographic and Baseline Characteristics .....................................................................39 
7.4.3. 
Prior and Subsequent Anticancer Therapies ....................................................................39 
7.4.4. 
Efficacy Analyses ............................................................................................................40 
7.4.5. 
Safety Analyses ...............................................................................................................40 
8. 
REFERENCES ................................................................................................................41 
 
 
 

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LIST OF TABLES 
Table 1: 
Schedule of Assessments: Cohort E and F .................................................................15 
Table 2: 
AUA Risk Stratification for NMIBC ..........................................................................17 
Table 3: 
Objectives and Endpoints * .........................................................................................23 
Table 4: 
Study Drugs ................................................................................................................31 
Table 5: 
Protocol-Specified Safety Laboratory Assessments ...................................................36 
 
LIST OF FIGURES 
Figure 1: 
Dose Confirmation Scheme ........................................................................................27 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse events of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APC 
antigen presenting cell 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Class 
AUA 
American Urological Association 
BCG 
Bacillus Calmette-Guérin 
CDC 
Center for Disease Control 
CFR 
Code of Federal Regulations  
CIS 
carcinoma in situ 
CNS 
central nervous system 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
cytotoxic T lymphocyte 
CVA21 
coxsackievirus A21 
DC 
dendritic cell 
DLT 
dose-limiting toxicity 
DSMC 
Data Safety Monitoring Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
CRF 
case report form 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
GBM 
glioblastoma multiforme 
GFR 
glomerular filtration rate 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
hCG 
human chorionic gonadotropin 
HR 
heart rate 
HSA 
human serum albumin 

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IB 
Investigator’s Brochure 
ICAM-1 
intercellular adhesion molecule 1 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IFN 
interferon 
INR 
international normalized ratio 
IRES 
internal ribosome entry site 
GCP 
Good Clinical Practice 
MIBC 
muscle invasive bladder cancer 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NMIBC 
non-muscle invasive bladder cancer 
ORR 
overall response rate 
PBS 
phosphate buffered saline 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
pfu 
plaque-forming unit 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFS 
relapse free survival 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TCID50 
50% tissue culture infective dose 
TME 
tumor microenvironment 
TUR 
transurethral resection 
TURBT 
transurethral resection of bladder tumor 
UTI 
urinary tract infection 
WHO 
World Health Organization 

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SYNOPSIS 
Name of Sponsor/Company: Istari Oncology, Inc. 
Name of Investigational Product: PVSRIPO 
Name of Active Ingredient: PVSRIPO 
Protocol Number: LUMINOS-103 
Phase: 1 
Region: United States 
Title of Study: A Basket Trial Evaluating the Safety and Efficacy of PVSRIPO and PVSRIPO in 
Combination with Anti-PD-1/L1 Checkpoint Inhibitors in Patients with Advanced 
Solid Tumors  
Study center(s): Up to 5 centers 
Objectives and Endpoints: 
Objectives and endpoints described in the table below are in addition to those described in the master 
protocol (see Master Protocol Section 2 [Objectives and Endpoints]) and include those specific for 
Cohort E and F. Note that two cohorts of patients will be enrolled: Cohort E will include patients 
with recurrent non-muscle invasive bladder cancer (NMIBC) intended for transurethral resection of 
bladder tumor (TURBT) or cystectomy who will receive PVSRIPO via intravesical instillation and 
Cohort F will include patients with recurrent NMIBC intended for TURBT or cystectomy who will 
receive PVSRIPO via intravesical instillation after a sequence of 5% DDM and saline washes. 
Also note that the NMIBC substudy will NOT be treating patients with the combination of 
PVSRIPO and anti-programmed cell death protein-1/programmed death ligand-1 (PD-1/L1), 
i.e., Phase 2 will not be enrolled in the NMIBC substudy.
Objectives 
Endpoints 
Primary Objectives and Endpoints Phase 1 
Cohort E: 
To evaluate the safety and tolerability of 
PVSRIPO monotherapy administered by 
intravesical instillation to patients with recurrent 
NMIBC intended for TURBT or cystectomy. 
Proportion of patients who undergo TURBT or 
cystectomy as scheduled. This endpoint 
replaces the master protocol endpoint 
described as “proportion of patients who 
received 1, 2 and 3 injections of PVSRIPO”. 
Cohort F: 
To evaluate the safety and tolerability of 
PVSRIPO monotherapy administered by 
intravesical instillation after a sequence of 5% 
DDM and saline washes to patients with 
recurrent NMIBC intended for TURBT or 
cystectomy. 
Proportion of patients who undergo TURBT or 
cystectomy as scheduled. This endpoint 
replaces the master protocol endpoint 
described as “proportion of patients who 
received 1, 2 and 3 injections of PVSRIPO”. 
Secondary Objectives and Endpoints Phase 1 
Cohorts E and F: 
To assess the ability of PVSRIPO administered 
as monotherapy via intravesical instillation 
(Cohort E) or intravesical instillation after a 
sequence of 5% DDM and saline washes  
(Cohort F) to infect bladder cancer cells in 
patients with recurrent NMIBC intended for 
TURBT or cystectomy  
Proportion of patients with evidence of 
PVSRIPO infection in resected tissues. This 
endpoint replaces the master protocol 
antitumor efficacy endpoints which include 
ORR, CBR, DOR, PFS and OS.  

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Cohorts E and F:  
To assess viral shedding in urine of PVSRIPO 
administered as monotherapy via intravesical 
instillation (Cohort E) or intravesical instillation 
after a sequence of 5% DDM and saline washes 
(Cohort F) to patients with recurrent NMIBC 
intended for TURBT or cystectomy 
PVSRIPO titers in urine 
NMIBC=non-muscle-invasive bladder cancer; TURBT=transurethral resection of bladder tumor 
*Additional endpoints (e.g. adverse events [AEs], adverse events of special interest [AESI], etc.) can be found in master
protocol.
Study Design: 
The overall study design, including the dose limiting toxicity (DLT) definitions can be found in the 
master protocol (Master Protocol Section 3.1 [Overall Study Design]). This section focuses on those 
aspects of the study design specific to patients with recurrent NMIBC.  
Since the purpose of this substudy is to evaluate different methods of administration of PVSRIPO into 
tumors located within the bladder mucosa, the NMIBC substudy will NOT be treating patients with 
the combination of PVSRIPO and anti-PD-1/L1, i.e., Phase 2 will not be enrolled. 
Two cohorts of patients will be enrolled in this portion of the study. Both Cohort E and F will 
evaluate the administration of PVSRIPO monotherapy in patients with recurrent NMIBC intended for 
TURBT or cystectomy; patients enrolled in Cohort E will receive PVSRIPO via intravesical 
instillation while patients enrolled in Cohort F will receive PVSRIPO via intravesical instillation 
after a sequence of 5% DDM and saline washes.  
Cohort E: Because the dose for PVSRIPO administered by intravesical instillation has not been 
determined, Cohort E has been designed to evaluate 2 different dose levels of PVSRIPO using a 3+3 
dose escalation approach (Figure 1). Three patients will initially be treated with a total dose of 2 x109 
50% tissue culture infectious dose (TCID50) (Low Dose Cohort E) administered by intravesical 
instillation and the frequency of DLTs assessed. The decision to escalate/de-escalate the PVSRIPO 
dose will be based on the presence of DLTs observed during the 14 days following administration of 
PVSRIPO, in consultation with the independent Data Safety Monitoring Committee (DSMC).  
Provided that none of the initial 3 patients experience a DLT, the dose will be considered not to have 
exceeded the maximally tolerated dose (MTD) and the next cohort of patients (n=3) will receive a 
total dose of 1x1010 TCID50 (High Dose Cohort E) via intravesical instillation. However, if 1 out of 
3 patients enrolled in the Low Dose Cohort E experience a DLT, the cohort will be expanded by 
enrolling 3 additional patients. If no additional patient experiences a DLT, then the dose will be 
considered not to have exceeded the MTD and the next cohort of patients (n=3) will receive a total 
dose of 1x1010 TCID50 (High Dose Cohort E) via intravesical instillation. In contrast, if a 2nd patient 
in the Low Dose Cohort E experiences a DLT during the initial enrollment of 3 patients--or 
expanded enrollment to 6 patients--then the maximum dose will have been exceeded, and the dose 
will be de-escalated to a total dose of 2x108 TCID50 (Lowest Dose Cohort E). The evaluation of 
either the High Dose or Lowest Dose Cohort E will follow the same process as outlined above.  
Cohort F: Once enrollment in Cohort E has been completed, Cohort F will open to evaluate 
intravesical instillation of PVSRIPO after a sequence of 5% DDM and saline washes in patients (n=3) 
with recurrent NMIBC using the highest dose evaluated in Cohort E that does not exceed the 
maximum tolerated dose. The purpose of Cohort F is to assess if PVSRIPO infection of cells within 
the bladder mucosa is facilitated by pretreatment with a detergent able to disrupt the GAG layer of the 
epithelium.  
Number of patients (planned): Approximately 3-12 patients will be enrolled in Cohort E and 
3 patients will be enrolled in Cohort F. 

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Sample Size Justification: 
The sample size for Cohorts E will be determined by the assessment of safety observed during the 
DLT period. It is expected that between 3 and 6 patients will be enrolled within each dosing cohort 
for a total sample size ranging from 6 to 12. 
Diagnosis and main criteria for inclusion:  
Eligibility criteria described in this section are in addition to those described in the master protocol 
(Section 4 [Study Population] of the Master Protocol) and are specific for Cohort E and F: patients 
with recurrent NMIBC intended for TURBT or cystectomy.. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
Both Cohorts: 
1.
Prior history of stage Ta, T1, or Tis urothelial carcinoma of the bladder.
a.
Tumors with up to 50% squamous or glandular differentiation are eligible.
b.
History of variant bladder histologies are excluded (e.g. sarcomatoid, plasmacytoid,
small cell or neuroendocrine, pure squamous cell carcinoma, pure adenocarcinoma,
micropapillary, nested, lymphepithelioma-like, clear cell)
2.
Documented tumor recurrence at cystoscopy where the tumor is amenable to TURBT or
cystectomy.
3.
Measured or calculated (per institutional standard) creatinine clearance ≥ 45 ml/min
(glomerular filtration rate [GFR] can also be used in place of creatinine clearance).
4.
If the patient has an available formalin-fixed paraffin-embedded (FFPE) tumor specimen with
an associated pathology report documenting NMIBC, the specimen must be confirmed to be
available to send to the Sponsor. Patients without an available FFPE specimen are still
eligible to enroll.
5.
Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is NOT
required. This is an exception to the inclusion criterion outlined in the master protocol.
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
Both Cohorts: 
1.
Patients with exposure to intravesical agents (e.g. Bacillus Calmette-Guérin [BCG],
mitomycin C, epirubicin, oncolytic viruses, anti-PD-1/L1 inhibitors, investigational therapies,
etc.) within 3 months prior to the administration of PVSRIPO.
2.
Patients whose anticoagulation or antiplatelet medications cannot be managed by local
institutional guidelines to accommodate the safe intravesical instillation of PVSRIPO
followed by TURBT, as determined by the treating physician.
3.
Received prior radiation to the pelvis.
4.
Received prior systemic therapy for bladder cancer, including PD-1/L1 inhibitors.
5.
History of vesicoureteric reflux or an indwelling urinary stent.
6.
History of stage T2 or higher bladder cancer
7.
Medical conditions (as determined by the investigator) that would interfere with the ability of
the patient to retain urine for 2 hours. Examples include urinary incontinence, overactive
bladder, or low bladder compliance.

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Investigational product, dosage, and mode of administration:  
For Cohort E: PVSRIPO is a solution for intravesical instillation, formulated with 50 mM sodium 
phosphate in 0.9% sodium chloride, pH 7.4 with 0.2% human serum albumin (HSA) in phosphate 
buffered saline (PBS).  
 
An initial dose of 2 x109 TCID50  will be administered to patients enrolled in Low Dose Cohort E. 
Depending upon the outcome of the DLT evaluation process as outlined in Section 3 of this 
substudy, the dose will be either escalated to a total dose of 1x1010 TCID50 (High Dose Cohort E) or 
de-escalated to a total dose of 2x108 TCID50 (Lowest Dose Cohort E). 
 
Each dose of PVSRIPO will be administered in a final volume of 60 ml by intravesical instillation; 
see the Pharmacy Manual for detailed instructions on how to prepare PVSRIPO for intravesical 
instillation. A urinary catheter will be inserted into the urethra under aseptic conditions according to 
local hospital protocol and the bladder drained completely. Using a catheter adapter with the syringe, 
the PVSRIPO suspension will then be instilled into the bladder via the catheter over a period 
of several minutes per local practice. After instillation the catheter will be removed, and the patient 
instructed to retain the instilled suspension in the bladder for a period of 2 hours. During this period, 
care should be taken to ensure that the instilled suspension has sufficient contact with the whole 
mucosal surface of the bladder. The patient should be encouraged to mobilize or, if lying down, to 
rotate between prone, supine, left lateral, and right lateral positions every 15 minutes.  
After 2 hours the patient should void the instilled suspension directly into a toilet. After bladder 
evacuation, the next first voided urine sample should be collected for PVSRIPO Shedding. 
The patient should be advised to limit their fluid intake for 4 hours prior to instillation and until 
bladder evacuation is permitted (i.e. 2 hours after instillation).  
For Cohort F: Each patient will receive the following sequence of bladder washes prior to instillation 
of PVSRIPO: 100 ml saline followed by 75 ml 5% DDM followed by 100 ml saline.  A urinary 
catheter will be inserted into the urethra under aseptic conditions according to local hospital protocol 
and the bladder drained completely. Using a catheter adapter with the syringe, each successive wash 
will be instilled over a period of several minutes per local practice. Each saline wash will be retained 
in the bladder for approximately 5 minutes and the 5% DDM wash will be retained within the bladder 
for 15 (±5) minutes.  At the end of each retention period, the bladder will be drained completely, and 
the next wash applied.  Upon completion of the three washes, PVSRIPO will be instilled as described 
for Cohort E and in the Pharmacy manual.  The process for pretreatment washes has been adapted 
from the process described for CG0070.   
The dose administered to each patient enrolled in Cohort F will be the highest dose evaluated in 
Cohort E that does not exceed the maximum tolerated dose. 
 
Reference therapy, dosage, and mode of administration: Not applicable. 
Criteria for evaluation: 
Efficacy: 
Since NMIBC is not routinely detected on imaging, it is not possible to assess responses to anti-
cancer therapy using traditional oncology imaging endpoints like overall response rate (ORR). 
Therefore, histologic evaluation of surgical specimens after treatment is the most sensitive way to 
assess tumor response to PVSRIPO administration with a focus on quantifying the proportion of 
patients who have demonstrable infection of tumor tissue.  
Safety: Safety will assess the frequency of DLTs observed during the 14 days following 
administration of PVSRIPO, evaluated by monitoring AEs, clinical laboratory test results 

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(hematology, clinical chemistry, and coagulation), vital sign measurements (blood pressure, heart rate 
[HR], and oral body temperature), and physical examination findings.  
Statistical methods: 
A statistical analysis plan (SAP) will be developed and finalized prior to the first planned database 
lock and will include more details related to the statistical analysis of this study’s data.  
Analysis Populations 
The full analysis set (FAS) population includes all eligible patients who receive at least 1 dose of 
study drug. Analyses for the FAS population will be conducted based on the actual treatment 
received. Unless otherwise specified, the FAS population is the primary population for all efficacy 
and safety analyses.  
Safety Analyses 
Refer to the Master Protocol. 

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SCHEDULE OF ASSESSMENTS 
The procedures and assessments to be performed for both Cohort E and F during the study are 
outlined in Table 1. The timing and number of blood or urine samples collected for biomarker 
testing may be altered based on emerging data without requiring an amendment if the blood 
volume per day or overall does not increase and the patient is not required to have additional 
clinic visits or prolongation of a clinic visit, i.e., the risk-benefit profile for the patient does not 
worsen.  
Study visits are outlined in the Schedule of Assessments. Unscheduled assessments and visits to 
manage patient safety may occur at the Investigator’s discretion. Study procedures performed at 
unscheduled visits should be recorded in the appropriate case report form (CRF). 

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Table 1: 
Schedule of Assessments: Cohort E and F 
Protocol Activity 
Screening 
Period 
DLT Period 
Day 30 
(± 2 Days) j 
Cycle 1 
End of 
Treatment 
≤ 28 Days 
Day 1 
Day 2-5 
Day 14 
(+3 Days) 
Informed Consenta 
X 
Polio Vaccine Booster 
X 
Demographics 
X 
Eligibility Evaluation 
X 
Medical History, Surgical 
History, and Bladder Cancer 
History 
X 
Complete Physical Examination 
X 
X 
Abbreviated Physical 
Examination 
X 
X 
Height (at Screening 
only)/Weight 
X 
X 
X 
X 
Vital Signsb 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
Triplicate 12 Lead ECGc 
X 
Laboratoryd 
Hematology 
X 
X 
X 
Clinical Chemistry 
X 
X 
X 
Coagulation 
X 
X 
Urinalysis 
X 
X 
X 
Serum or Urine Pregnancy Test 
(WOCBP) 
X 
X 
Study Treatment 
PVSRIPO intravesical instillation 
without washes (Cohort E) or 
with washes (Cohort F) 
X 
TURBT or Cystectomy 
X 
Tumor Assessments 
Images Obtained via Cystoscopee 
X 
X 
Other Samples 
Tumor Tissue Samplesf 
X (archival if 
available or 
optional pre-
dose biopsy) 
X (surgical 
specimen) 
PVSRIPO Shedding: Urineg 
X (pre- and 
post-dose) 
X 
X 
X 
PVSRIPO Shedding: Stoolh 
X 
X 
X 

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Protocol Activity 
Screening 
Period 
DLT Period 
Day 30 
(± 2 Days) j 
Cycle 1 
End of 
Treatment 
≤ 28 Days 
Day 1 
Day 2-5 
Day 14 
(+3 Days) 
Blood Samples for Biomarker 
and Cytokine Analysis  
X (serum prior 
to Polio 
Vaccine 
booster) 
X (predose) 
 X 
X 
X 
Other Clinical Assessments 
Adverse Eventsi 
AEs up to 30 days post dose 
Concomitant Medication and 
Non-Drug Supportive 
Interventions 
Con meds up to 30 days post dose 
AE=adverse event; Con meds=concomitant medications; DLT=dose-limiting toxicity; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; TURBT=transurethral resection of bladder tumor; WOCB=women 
of childbearing potential. 
a Patient registration should be completed after all eligibility criteria are confirmed and as close to Cycle 1 Day 1 as 
possible. 
b Vital signs: includes temperature (oral, tympanic, or axillary), blood pressure, and pulse rate to be recorded in the 
sitting position after 5 minutes of rest.  
c Cardiologist review is not required for Screening ECG. 
d If the screening assessments are conducted within 3 calendar days prior to Cycle 1 Day 1, they do not need to be 
repeated. 
e Images to be obtained prior to instillation on the day of PVSRIPO intravesical instillation, and prior to surgical 
resection on the day of TURBT or cystectomy.  
f See Section 6.3  for details regarding tissue biopsies.  
g All urine samples should be collected as described in the lab manual. On Cycle 1 Day 1, the pre-dose urine sample 
should be collected within 1 calendar day prior to PVSRIPO instillation. On Cycle 1 Day 1, the patient should void 
in the toilet after the 2-hour instillation and the next first voided urine sample should be collected for PVSRIPO 
Shedding. Urine samples should also be collected on Days 2, 4, 6, 8 and 14 of Cycle 1. If the day of the 
TURBT/cystectomy happens to coincide with a urine collection day, the urine sample should be collected prior to 
the surgery. 
h All stool samples should be collected as described in the lab manual.  
i Refer to Master Protocol Section 6.1 for details on adverse event reporting. 

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1.
INTRODUCTION
1.1. 
Background
Background information on PVSPIRO, including available nonclinical and clinical data and 
known potential risks, can be found in Section 1 (Introduction) of the Master Protocol. 
1.1.1. 
Bladder Cancer 
Cancer of the bladder, also known as urological cancer and urinary bladder cancer, is the 10th 
most common cancer worldwide and 13th most deadly, with a globally rising incidence rate 
(Saginala 2020). Within the United States, it is estimated that approximately 81,000 patients will 
be diagnosed with, and 18,000 patients will die from bladder cancer in 2020, with around 75% of 
the cases occurring in men and an average diagnosis age of 73 years (Richters 2020). Up to 
95% of bladder cancer cases arise from urothelial cells that line the bladder and urinary tract 
(termed urothelial carcinoma or transitional cell carcinoma), with the strongest risk factors being 
tobacco smoking (~65% of cases) or occupational or environmental hazards (20% of cases). The 
remaining cases are attributed to squamous cell bladder cancer (due to the protozoan infection 
schistosomiasis) or rare subtypes such as adenocarcinoma, sarcoma, and metastases to the 
bladder (Saginala 2020). The average 5-year survival rate for bladder cancer in the United States 
is 77.1%, ranging from 95.8% for low risk localized disease to 4.6% for metastatic disease 
(SEER 2020). Fortunately, the majority of patients (~80%) are diagnosed with localized disease 
(non-muscle invasive bladder cancer ([NMIBC], stages Ta, T1) which carries a better prognosis 
than more advanced stages where the cancer has invaded the muscle layer of the bladder (muscle 
invasive bladder cancer [MIBC]) and/or metastasized to the regional lymph nodes or beyond 
(American Cancer Society 2020).  
Non-muscle invasive bladder cancer comprises noninvasive papillary carcinomas (Ta; 48%), 
submucosal invasive tumors (T1; 27%), carcinoma in situ (CIS; 2%) or some combination of 
these types (Boustead 2014; Chang 2016); and may be categorized as low-, intermediate-, or 
high risk (Table 2). 
Table 2: 
AUA Risk Stratification for NMIBC 
Low Risk 
Intermediate Risk 
High Risk 
Low grade solitary Ta ≤ 3cm 
Low grade Ta that recurs within 
1 year 
High grade T1 
Papillary urothelial neoplasm of 
low malignant potential 
Solitary low grade Ta > 3cm 
Any recurrent high grade Ta 
Multifocal low grade Ta 
High trade Ta > 3cm or 
multifocal 
High grade Ta ≤ 3cm 
Any carcinoma in situ 
Low grade T1 
Any BCG failure in high grade 
patient 
Any variant histology 
Any lymphovascular invasion 

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Low Risk 
Intermediate Risk 
High Risk 
Any high grade prostatic 
urothelial involvement 
AUA=American Urological Association; BCG= Bacillus Calmette-Guérin; NMIBC=non-muscle invasive bladder 
cancer 
The recommended standard of care for patients with NMIBC involves transurethral resection of 
bladder tumor (TURBT) followed by intravesical chemotherapy or Bacillus Calmette-Guérin 
(BCG) depending on the patient’s risk group (Flaig 2020; Chang 2016; Babjuk 2019). Low-risk 
tumors are conventionally managed with single dose intravesical chemotherapy while high-risk 
tumors are managed with adjuvant intravesical BCG. Intermediate-risk tumors may be managed 
with either intravesical chemotherapy or BCG. 
Transurethral resection (TUR) of all visible lesions is a standard treatment for NMIBC (Babjuk 
2017) but is accompanied with a high tumor recurrence rate ranging from 50% to 70% as well as 
a high tumor progression rate between 10% and 20% over a period of 2 to 5 years (Chen 2010). 
Thus, guidelines recommend intravesical chemotherapy or immunotherapy in the management of 
NMIBC to reduce these risks of recurrence and progression (Babjuk 2017). Immunotherapy with 
BCG decreases the frequency of and delays the time to cancer recurrence and progression in 
patients with NMIBC (Babjuk 2017; Braasch 2008). However, 33% of NMIBC patients 
experience serious local and systemic side effects of BCG infection, and 33% do not respond 
(Bassi 2002; Fuge 2015). Treatment options for BCG-refractory patients are limited and patients 
are often recommended to undergo cystectomy. Combining the concerns/limitations with BCG 
immunotherapy and a potential worldwide shortage of BCG (Fankhauser 2020), there is an 
urgent need to develop novel therapies for this disease. 
Overall, these data indicate that there is still significant unmet medical need for patients with all 
stages of bladder cancer, including NMIBC, where the goal of improving therapy ranges from 
decreasing the frequency of/need for repeat surgical intervention and preserving the 
bladder/avoiding cystectomy, to prolonging survival without adding additional toxicity.  
1.1.2. 
Oncolytic Viruses/Immunomodulatory Agents Delivered by Cystoscopy 
The gold standard precedent for delivery of immunomodulatory agents to the bladder via 
cystoscopy is BCG, which is traditionally delivered via intravesical instillation. However, review 
of the published literature indicates that oncolytic viruses have also been administered via 
cystoscopy, either by direct intratumoral injection or intravesical instillation where the virus is 
distributed to the entire bladder mucosa as well as the tumor. Key results are summarized below: 
1. Twelve patients with MIBC were treated with a single dose of a replication-defective
recombinant adenoviral vector encoding the complete human wild type p53 cDNA
(SCH 58500) where the vector was administered by intratumoral injection via cystoscopy
(n=3) or intravesical instillation (n=9) one day prior to radical cystectomy for MIBC. The
3 patients treated by intratumoral injection received dose level 1 (7.5x1011 viral particles),
while the patients treated by intravesical instillation received dose levels 1, 2, or 3
(7.5x1011 to 7.5x1013 viral particles). The only toxicity experienced by the patients treated
by intratumoral injection was World Health Organization (WHO) Grade 1 fatigue (n=1).
Compared with those treated by intratumoral injection, patients treated by intravesical

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instillation experienced more toxicity including WHO Grade 2 and 3 urethral and vesical 
burning which required a decrease in the contact time for 4 of the 9 patients. No systemic 
symptoms were experienced by the patients treated via intravesical instillation. Eleven of 
the 12 patients underwent cystectomy while the 12th patient was found to have disease 
unable to be resected for curable intent at the time of laparotomy (1 day after intravesical 
instillation) (Kuball 2002).  
2. Four patients with MIBC were treated with 3 intravesical instillations of increasing doses
(1x106 to 250x106 plaque-forming units [pfu]) of vaccinia virus over the course of
2 weeks prior to cystectomy. AEs included dysuria requiring no intervention and new or
increasing proteinuria and microscopic hematuria which was tolerated without difficulty.
Pathological analysis of the resection specimen revealed mucosal and submucosal
inflammatory infiltrates in 3 of the 4 patients and significant viral infection. All patients
were able to undergo surgical resection which implies that inflammation did not preclude
cystectomy (Gomella 2001).
3. Fifteen patients with NMIBC were treated with 1 or 2 increasing doses (1x108 to 3x108
50% tissue culture infectious dose [TCID50]) of an intercellular adhesion molecule 1
(ICAM-1)-targeted immunotherapeutic coxsackievirus A21 (CVA21) ± mitomycin C
administered via intravesical instillation between 8 and 11 days prior to TURBT. When
6 patients developed urinary tract infections (UTI) due to instrumentation, the protocol
was amended to require prophylactic antibiotics which resulted in no further UTIs. Only
3 AEs (all Grade 1) were considered related to CVA21; these included “tight feeling on
the left side of the abdomen”, “shivers/feeling cold”, and “nausea”. All patients were able
to undergo TURBT and evaluation of resection specimens confirmed viral staining in 12
of 14 specimens available for study (Annels 2019). One patient had a complete
pathologic response.
4. Thirty-five patients with NMIBC were treated with single (n=13) or multiple (n=9 in
weekly x 6 cohort; n=13 in q28days x 3 cohort) increasing doses (1x1012 to 3x1013 viral
particles) of a granulocyte macrophage-colony stimulating factor (GM-CSF) expressing
oncolytic adenovirus (CG0070) administered by intravesical instillation. The most
common AEs were transient, Grade 1 or 2, local bladder toxicities including dysuria,
hematuria, urinary frequency, urgency, and urine abnormality. No serious adverse events
(SAEs) related to CG0070 were reported. The complete response rate for all patients was
48.6% (Burke 2012).
These results suggest that intravesical instillation and intratumoral delivery (including repeat 
instrumentation every week x 6 or every 28 days x 3) of oncolytic viruses is feasible and safe, 
particularly if patients are treated with prophylactic antibiotics to prevent UTIs associated with 
instrumentation. These studies also suggest that inflammation induced by cystoscopic 
administration of oncolytic viruses will not preclude surgical intervention and that localized 
delivery of oncolytic viruses can result in tumor regression. 
1.1.3. 
Detergents/Surfactants Administered via Intravesical Instillation 
Given its function as a urinary reservoir, the bladder epithelium has evolved a series of 
adaptations to effectively prohibit both urine and infectious organisms from accessing deeper 

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tissues.  Those adaptations include urothelial plaques, tight junctions, and a polyanionic 
glycosaminoglycan (GAG) layer overlaying the epithelium, all of which create a relatively 
impermeable barrier.  While these adaptations benefit the organism, they also have the potential 
to prevent infectious organisms administered with therapeutic intent from realizing their full 
potential clinical utility; in other words, they could prevent PVSRIPO from access to the target 
tissues.  One way to address this issue is to pretreat the bladder mucosa with a mild polar 
surfactant that disrupts the GAG layer thereby allowing access of the virus to the underlying 
epithelium.  
Precedent for this approach comes from the intravesical instillation of CG0070, a genetically 
modified adenovirus, where instillation of the drug is preceded by a sequence of washes with 
normal saline and 5% dodecyl-B-D-maltoside (DDM). In animal studies, DDM has been shown 
to disrupt the GAG layer and improve adenovirus transduction efficacy without adding 
significant toxicity (Ramesh 2004). In clinical studies with CG0070, a comparison of 
transduction with and without the series of washes has not been done, however, an analysis of 
viral genomes in the urine of treated patients suggests that ≈ 60% of patients had evidence of 
viral replication after received CG0070 with washes (Burke 2012).   
1.2. 
Study Rationale and Risk Benefit Assessment for PVSRIPO as 
Monotherapy Treatment in NMIBC 
The overall study rationale and risk/benefit assessment can be found in Section 1.2 (Study 
Rationale and Benefit/Risk Assessment) and Section 1.1.4 (Known Potential Risks) of the 
Master Protocol. This section specifically focuses on the rationale, risks, and associated 
mitigation strategies for patients with NMIBC treated with PVSRIPO. 
Potential Benefits: 
Historically, bladder cancer has been considered an immune responsive tumor as evidenced by 
the observation that the use of intravesical instillation of BCG to treat NMIBC was first reported 
in 1976 (Song 2019). While the mechanism of action of BCG remains unclear, currently 
available data suggest that BCG attaches to the urothelium leading to internalization of BCG into 
cells and the subsequent activation of the innate immune system (Redelman-Sidi 2014). 
The accessibility and superficial location of NMIBC allows direct intravesical administration of 
antitumor agents and is an ideal model for evaluation of new therapies intended to treat patients 
with bladder cancer. Through insertion of a conventional urinary catheter, instillation of the 
antitumor agent, and transient retention of the antitumor agent, frequent minimally invasive 
treatments can be easily achieved (Annels 2018).  
There are a variety of molecules (including oncolytic viruses and immunostimulants like toll-like 
receptor 9 [TLR9] agonists) in development that are proposed to stimulate an antitumor 
response. As described in Section 1.1.2, the CANON study evaluated CVA21 as a novel 
oncolytic agent against NMIBC. Given the similarities between CVA21 and PVSRIPO (both are 
picornaviruses and enteroviruses), this study serves as a clinical example to guide the initial 
evaluation of PVSRIPO in patients with NMIBC and serves as reassurance that an oncolytic 
virus similar to PVSRIPO can be safely administered to patients with NMIBC. Since one of the 
patients in the CANON study also had a pathological complete response after CVA21 treatment, 
the study also suggests that patients may receive clinical benefit.  

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As outlined in the master protocol, PVSRIPO exhibits selective cytotoxicity of infected CD155-
expressing malignant cells—both MIBC and NMIBC express CD155 (Luo 2021; Takai 2008; 
Chandramohan 2017; Liu 2019; Masson 2001; Bevelacqua 2012; Carlsten 2009; Nishiwada 
2015; Sun 2020; Zhang 2020), upregulates antigen presentation in antigen presenting cells 
(APCs)/dendritic cells (DCs) (Brown 2017), triggers Type 1 interferon (IFN) inflammation in the 
tumor microenvironment (TME) (Brown 2017), and downregulates CD155 expression in 
infected cells (Mosaheb 2020), all of which are hypothesized to generate systemic anti-tumor 
cytotoxic T lymphocyte (CTL) effector responses without causing significant off-target effects 
(Brown 2017). 
In addition, as described in Section 1.1.2 of the Master Protocol, PVSRIPO has demonstrated 
preliminary anti-tumor activity in patients with recurrent glioblastoma multiforme and melanoma 
which indicate it is an active drug.  
Potential Risks: 
The potential risks to patients enrolled in either Cohort E or F include UTIs, 
bleeding/hematuria, localized discomfort, urinary outlet obstruction, dysuria, bacteriuria, 
delaying curative resection, and risk of viral shedding in the urine and stool. Each of these is 
discussed below. 
To limit the risk to patients, the number of PVSRIPO instillations will be limited to 1. In 
addition, all patients will receive prophylactic antibiotics to prevent procedure-related UTIs, and 
both anticoagulant and antiplatelet agents will be managed by the treating physician per local 
institutional guidelines to reduce the risk of procedure-induced bleeding.  
Review of the AE profile for injection of visible/palpable cutaneous/subcutaneous/nodal 
melanoma lesions in 12 patients indicates (1) only Grade 1 or 2 toxicities were observed, (2) that 
they occurred and resolved within the 21 days between injections, (3) that these were primarily 
localized reactions consistent with the mechanism of action of PVSRIPO (ie, pruritis and 
erythema at the site of injection), and (4) that they did not require intervention (Master Protocol 
Table 2). For patients with NMIBC, the most likely potential consequence of localized 
inflammation due to PVSRIPO is localized discomfort and/or urinary obstruction. In addition, 
the most likely complication of cystoscopy is UTIs, dysuria, bacteriuria, and hematuria. To 
monitor for urinary obstruction in the NMIBC substudy, patients will be required to void in the 
clinic after intravesical instillation, and prior to discharge home. They will be followed closely 
by the treating physician for complications and offered appropriate symptomatic care which 
could include antihistamines, phenazopyridine, and/or non-steroidal anti-inflammatory 
medications. 
With respect to the risk of delayed curative resection due to localized inflammation, the 
published literature reviewed in Section 1.1.2 suggest that inflammation induced by 
intravesicular or cystoscopic administration of oncolytic viruses does not preclude curative 
resection. Therefore, it is expected that administration of PVSRIPO via intravesical instillation, 
will also not preclude curative resection. Patients in this substudy will only receive 1 instillation 
of PVSRIPO followed by TURBT or curative resection after 2-5 days; therefore, the delay will 
be minimal.  
As a result of administration of PVSRIPO via cystoscopy, there is the potential for viral shedding 
of PVSRIPO directly into the urine of treated patients. Therefore, urine viral shedding studies 

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will be conducted as outlined in this substudy and in Schedule of Assessments (Table 1). 
However, even if PVSRIPO is detected in the urine, the potential for clinically significant 
toxicity to the patient or associated household contacts is predicted to be nominal given the 
following observations: 
• Limitation of systemic spread by the immunologic recall responses initiated by the 
booster vaccine required prior to enrollment of the patient. 
• Elimination of neurovirulence by the foreign internal ribosome entry site (IRES). 
• Near universal poliovirus vaccination status of the global population. 
• Compromised replication in non-malignant CD155+ cells.  
• Limited cell types that express CD155. 
Additional details on the risk of viral shedding to household contacts are provided in the master 
protocol (Master Protocol Section 1.1.4.1).  
For those patients enrolled in Cohort F, there is a potential risk for increased bladder irritation 
associated with pretreatment of the bladder with 5% DDM.  This risk is predicted to be low to 
negligible based on published literature indicating that intravesical instillation of 0.1% DDM in 
mice and rats did not result in clinically relevant irritation and that this procedure is being used in 
patients receiving CG0070 (Burke 2012, Ramesh, 2004). 
Taken together, the data generated to date suggest PVSRIPO is well-tolerated and that PVSRIPO 
may have direct anti-tumor activity. Therefore, the overall risk/benefit ratio is favorable.  

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2.
OBJECTIVES AND ENDPOINTS
Objectives and endpoints described in Table 3 are in addition to those described in the master 
protocol (see Master Protocol Section 2 [Objectives and Endpoints]) and include those specific 
for Cohort E and F. Note that two cohorts of patients will be enrolled: Cohort E will include 
patients with recurrent NMIBC intended for TURBT or cystectomy who will receive PVSRIPO 
via intravesical instillation and Cohort F will include patients with recurrent NMIBC intended 
for TURBT or cystectomy who will receive PVSRIPO via intravesical instillation after a 
sequence of 5% DDM and saline washes. 
Note that the NMIBC sub study will NOT be treating patients with the combination of 
PVSRIPO and anti-PD-1/L1, i.e., Phase 2 will not be enrolled in the NMIBC substudy. 
Table 3: 
Objectives and Endpoints * 
Objectives 
Endpoints 
Primary Objectives and Endpoints Phase 1 
Cohort E: 
To evaluate the safety and tolerability of PVSRIPO 
monotherapy administered by intravesical 
instillation to patients with recurrent NMIBC 
intended for TURBT or cystectomy. 
Proportion of patients who undergo TURBT or 
cystectomy as scheduled. This endpoint replaces 
the master protocol endpoint described as 
“proportion of patients who received 1, 2 and 3 
injections of PVSRIPO”. 
Cohort F: 
To evaluate the safety and tolerability of PVSRIPO 
monotherapy administered by intravesical 
instillation after a sequence of 5% DDM and saline 
washes to patients with recurrent NMIBC intended 
for TURBT or cystectomy. 
Proportion of patients who undergo TURBT or 
cystectomy as scheduled. This endpoint replaces 
the master protocol endpoint described as 
“proportion of patients who received 1, 2 and 3 
injections of PVSRIPO”. 
Secondary Objectives and Endpoints Phase 1 
Cohorts E and F: 
To assess the ability of PVSRIPO administered as 
monotherapy via intravesical instillation 
(Cohort E) or intravesical instillation after a 
sequence of 5% DDM and saline washes (Cohort 
F) to infect bladder cancer cells in patients with
recurrent NMIBC intended for TURBT or
cystectomy
Proportion of patients with evidence of 
PVSRIPO infection in resected tissues. This 
endpoint replaces the master protocol antitumor 
efficacy endpoints which include ORR, CBR, 
DOR, PFS and OS. 
Cohorts E and F: 
To assess viral shedding in urine of PVSRIPO 
administered as monotherapy via intravesical 
instillation (Cohort E) or intravesical instillation 
after a sequence of 5% DDM and saline washes 
(Cohort F) to patients with recurrent NMIBC 
intended for TURBT or cystectomy 
PVSRIPO titers in urine 

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2.1. 
Rationale for Primary and Secondary Endpoints 
The master protocol contains rationale for primary and secondary endpoints which are not 
specific to NMIBC (Master Protocol Section 2.1 [Rationale for Primary and Secondary 
Endpoints]). 
2.1.1. 
Safety 
Since surgical resection (TURBT or cystectomy) is one component of the standard of care 
treatment for patients with recurrent NMIBC, it is important to evaluate whether PVSRIPO 
administered via intravesical instillation impacts the ability of a patient to undergo surgical 
intervention.  
As described in the master protocol and in the Investigator’s Brochure (IB), PVSRIPO has been 
subjected to extensive nonclinical and clinical viral shedding studies, all of which suggest the 
risk of extra-tumoral PVSRIPO dissemination and shedding is extremely low. However, because 
PVSRIPO shedding in patients with NMIBC receiving PVSRIPO via intravesical instillation has 
not been characterized, it is important to evaluate the potential for shedding of PVSRIPO in the 
urine for these patients. In addition, since PVSRIPO is a replication-competent enterovirus, it is 
important to determine if the virus is shed in the stool after intravesical instillation, an analysis 
which could indicate systemic spread of the virus beyond the site of administration within the 
bladder. 
The timepoints of stool and urine sample collection for viral shedding analysis (Table 1) were 
chosen based on the following considerations: 
5.
Ease of sample collection and patient burden.
6.
Timing of stool sample collection in patients with glioblastoma multiforme (GBM) 
evaluated for viral shedding (Week 1, 2, 4, and 8 after one intracerebral infusion of 
PVSRIPO) (Section 6.2.7; Final Clinical Shedding Study Report for PVSRIPO for 
Recurrent Glioblastoma [GBM] dated August 6, 2017 [IND 14735, Serial 0131]).
7.
Food and Drug Administration (FDA) guidance titled “Design and Analysis of Shedding 
Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products,” which 
suggests “shedding is most likely to occur in the period immediately following product 
administration”, and that a “second peak of shedding may be noted in the days/weeks 
after administration of a replication competent product as a result of its
multiplication/amplification in vivo”.
8.
Timing of urine sample collection in animal studies (Day 14, 28, and 56 after 
intrathalamic inoculation of Macaca fascicularis with PVSRIPO on Day 0)
(Dobrikova 2012).
9.
After intratumoral injection or intravesical instillation, PVSRIPO is predicted to replicate 
within the tumor for approximately 1-2 weeks.
10. Alignment of shedding time points across bodily fluids (including urine) being evaluated 
in the PVSRIPO program.

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2.1.2. 
Biomarkers 
Since PVSRIPO infection cannot be detected on imaging or physical examination, evaluation of 
surgical specimens is the only way to directly assess the ability of PVSRIPO to infect bladder 
cancer cells after administration via intravesical instillation.  

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3.
INVESTIGATIONAL PLAN
The overall study design, including the dose limiting toxicity (DLT) definitions can be found in 
the master protocol (Master Protocol Section 3.1 [Overall Study Design]). This section focuses 
on those aspects of the study design specific to patients with recurrent NMIBC.  
Since the purpose of this substudy is to evaluate different methods of administration of 
PVSRIPO into tumors located within the bladder mucosa, the NMIBC substudy will NOT be 
treating patients with the combination of PVSRIPO and anti-PD-1/L1, i.e., Phase 2 will not 
be enrolled. 
Two cohorts of patients will be enrolled in this portion of the study. Both Cohort E and F will 
evaluate the administration of PVSRIPO monotherapy in patients with recurrent NMIBC 
intended for TURBT or cystectomy; patients enrolled in Cohort E will receive PVSRIPO via 
intravesical instillation while patients enrolled in Cohort F will receive PVSRIPO via 
intravesical instillation after a sequence of 5% DDM and saline washes.  
Cohort E: Because the dose for PVSRIPO administered by intravesical instillation has not been 
determined, Cohort E has been designed to evaluate 2 different dose levels of PVSRIPO using a 
3+3 dose escalation approach (Figure 1). Three patients will initially be treated with a total dose 
of 2 x109 TCID50 (Low Dose Cohort E) administered by intravesical instillation and the 
frequency of DLTs assessed. The decision to escalate/de-escalate the PVSRIPO dose will be 
based on the presence of DLTs observed during the 14 days following administration of 
PVSRIPO in consultation with the independent Data Safety Monitoring Committee (DSMC).  
Provided that none of the initial 3 patients experience a DLT, the dose will be considered not to 
have exceeded the maximally tolerated dose (MTD) and the next cohort of patients (n=3) will 
receive a total dose of 1x1010 TCID50 (High Dose Cohort E) via intravesical instillation. 
However, if 1 out of 3 patients enrolled in the Low Dose Cohort E experience a DLT, the cohort 
will be expanded by enrolling 3 additional patients. If no additional patient experiences a DLT, 
then the dose will be considered not to have exceeded the MTD and the next cohort of patients 
(n=3) will receive a total dose of 1x1010 TCID50 (High Dose Cohort E) via intravesical 
instillation. In contrast, if a 2nd patient in the Low Dose Cohort E experiences a DLT during the 
initial enrollment of 3 patients--or expanded enrollment to 6 patients--then the maximum dose 
will have been exceeded, and the dose will be de-escalated to a dose of 2x108 TCID50 (Lowest 
Dose Cohort E). The evaluation of either the High Dose or Lowest Dose Cohort E will follow 
the same process as outlined above and in Figure 1.  

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Figure 1: 
Dose Confirmation Scheme 
 
 
Cohort F: Once enrollment in Cohort E has been completed, Cohort F will open to evaluate 
intravesical instillation of PVSRIPO after a sequence of 5% DDM and saline washes in patients 
(n=3) with recurrent NMIBC using the highest dose evaluated in Cohort E that does not exceed 
the maximum tolerated dose. The purpose of Cohort F is to evaluate if PVSRIPO infection of 
cells within the bladder mucosa is facilitated by pretreatment with a detergent able to disrupt the 
GAG layer of the epithelium.  
In the event tissue from a TURBT or cystectomy in a given patient is not available after 
completion of standard of care pathologic review, that patient may be replaced as long as the 
dose administered to the replacement patient does not exceed the maximum tolerated dose.  
3.1. 
Rationale for Approach 
The total starting dose of 2x109 TCID50 to be used in Low Dose Cohort E was chosen based on 
the following observations: 
1. The range of PVSRIPO doses to be administered by intratumoral injection via cystoscopy 
to patients with MIBC in the bladder cancer substudy is 1x108 to 6x108 TCID50. Since the 
total dose of 2x109 TCID50 will be diluted into a final volume of 60 mL for intravesical 
instillation, the bladder mucosa/tumor will be exposed to a PVSRIPO concentration of 
3.33x107 TCID50/ml which is ½ to 1 log lower than would be expected with direct 
intratumoral injection. 
2. CVA21, a virus similar to PVSRIPO (both are classified Picornaviridae, Enterovirus) has 
been administered as repeat dose (Day 1 and Day 2) monotherapy (or in combination 

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with intravesical mitomycin C) via intravesical instillation (30 ml) to patients with 
recurrent NMIBC at a total dose of 3x108 TCID50 per day. Patients receiving this dose of 
CVA21 experienced minimal toxicity and limited efficacy (Section 1.1.2) suggesting that 
evaluating a higher dose to improve efficacy would be safe and tolerable (Annels 2019).  
3. Nadofaragene firadenovec is a replication-deficient recombinant adenovirus with a 
human interferon alfa-2b payload that has been administered at a total dose of 2.25x1013 
viral particles via intravesical instillation (75 ml) to patients with recurrent NMIBC. 
Patients who received this dose—which is up to 4 logs higher than the 2x109 TCID50 
PVSRIPO dose--experienced few (4%) Grade 3 drug related AEs and no Grade ≥4 AEs 
(Boorjian 2020). 
4. Each stock vial contains 2x109 TCID50 PVSRIPO such that using a starting dose of 2x109 
TCID50 will facilitate easier handling in the pharmacy and decrease the possibility of 
errors in preparation and handling.  
In summary, a dose of 2x109 TCID50 PVSRIPO represents a reasonable starting dose in that it 
falls within the range of the PVSRIPO dose predicted to be delivered by intratumoral injection 
and the dose of similar viral products delivered by intravesical instillation where safety and 
tolerability were acceptable.  
An increase in PVSRIPO dose to 1x1010 TCID50—which is an increase of 1 log—was chosen to 
ensure that the higher dose was sufficiently different from the lower dose to facilitate evaluation 
of any potential dose/response (dose/toxicity) relationship.  
The dose of PVSRIPO administered in Cohort F will be the highest dose evaluated in Cohort E 
which does not exceed the maximum tolerated dose.  Since the bladder washes implemented in 
Cohort F are predicted to improve PVSRIPO infectivity of the bladder mucosa, the highest 
tolerable PVSRIPO dose administered without washes was chosen to maximize potential patient 
benefit. As discussed above, preclinical and clinical data suggest that adding washes to the 
intravesical instillation of viruses does not increase clinically relevant toxicity (Burke 2012).   
The timing of PVSRIPO administration prior to TURBT or cystectomy was chosen to be 2 to 
5 days based on the following criteria: 
1. Delaying TURBT or cystectomy by 2-5 days is not predicted to have a substantial impact 
on the clinical outcomes of the patients. 
2. Preclinical studies with intratumoral injection of PVSRIPO suggest that PVSRIPO 
replication lasts for approximately 1-2 weeks after injection with peak viral load within 
5 days of injection, such that PVSRIPO should still be detectable in the tumor tissue 
(Yang 2021).  
3. Preclinical studies suggest that the innate immune effects of intratumoral injection of 
PVSRIPO peak before 5 days post treatment such that collecting tissue at 2-5 days will 
optimize the probability of seeing an effect. 
PVSRIPO in combination with anti-PD-1/L1 therapy is not being investigated in this substudy 
because NMIBC has an exceedingly good prognosis such that systemic therapies with their 
associated toxicities are generally not used in this patient population because of the poor 
risk/benefit profile.  

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4.
STUDY POPULATION
Eligibility criteria described in this section are in addition to those described in the master 
protocol (Section 4 [Study Population] of the Master Protocol) and are specific for Cohort E 
and F: patients with recurrent NMIBC intended for TURBT or cystectomy. 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
Both Cohorts: 
1. Prior history of stage Ta, T1, or Tis urothelial carcinoma of the bladder.
a.
Tumors with up to 50% squamous or glandular differentiation are eligible.
b. History of variant bladder histologies are excluded (e.g. sarcomatoid,
plasmacytoid, small cell or neuroendocrine, pure squamous cell carcinoma, pure
adenocarcinoma, micropapillary, nested, lymphepithelioma-like, clear cell)
2. Documented tumor recurrence at cystoscopy where the tumor is amenable to TURBT or
cystectomy.
3. Measured or calculated (per institutional standard) creatinine clearance ≥ 45 ml/min
(glomerular filtration rate [GFR] can also be used in place of creatinine clearance).
4. If the patient has an available formalin-fixed paraffin-embedded (FFPE) tumor specimen
with an associated pathology report documenting NMIBC, the specimen must be
confirmed to be available to send to the Sponsor. Patients without an available FFPE
specimen are still eligible to enroll.
5. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is
NOT required. This is an exception to the inclusion criterion outlined in the master
protocol.
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Both Cohorts: 
1. Patients with exposure to intravesical agents (e.g. BCG, mitomycin C, epirubicin,
oncolytic viruses, anti-PD-1/L1 inhibitors, investigational therapies, etc.) within 3 months
prior to the administration of PVSRIPO.
2. Patients whose anticoagulation or antiplatelet medications cannot be managed by local
institutional guidelines to accommodate the safe intravesical instillation of PVSRIPO
followed by TURBT, as determined by the treating physician.
3. Received prior radiation to the pelvis.
4. Received prior systemic therapy for bladder cancer, including PD-1/L1 inhibitors.
5. History of vesicoureteric reflux or an indwelling urinary stent.

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6. History of stage T2 or higher bladder cancer 
7. Medical conditions (as determined by the investigator) that would interfere with the 
ability of the patient to retain urine for 2 hours. Examples include urinary incontinence, 
overactive bladder, or low bladder compliance. 
 

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5.
STUDY TREATMENT
Information regarding discontinuation of study treatment, discontinuation/withdrawal from the 
study, treatment beyond progression, patients who are lost to follow-up, and site and study 
termination can be found in Master Protocol Section 5 (Study Treatment). 
5.1. 
Study Drugs Administered 
Study drugs are defined as any investigational agent(s) or marketed product(s) intended to be 
administered to a study patient according to the study protocol. Study drugs used in this protocol 
are described in Table 4.  
Table 4: 
Study Drugs 
Name 
PVSRIPO 
Type 
Investigational Product 
Dose 
Formulation 
50 mM sodium phosphate in 0.9% sodium chloride, pH 7.4 with 0.2% human serum 
albumin (HSA) in phosphate buffered saline (PBS). 
Unit Dose 
Strength(s) 
Refer to the Pharmacy Manual 
Dosage 
Level(s) 
Described in Section 3 
Route of 
Administration 
Intravesical 
Use 
Experimental 
Packaging and 
Labeling 
Study drug will be provided in sterile, single use containers. Each single use 
container will be labeled as required per country requirement. 
5.1.1. 
Dose, Dosing Regimen, Route, Preparation and Handling 
5.1.1.1. 
PVSRIPO 
Cohort E: Each dose of PVSRIPO will be administered in a final volume of 60 ml by 
intravesical instillation; see the Pharmacy Manual for detailed instruction on how to prepare 
PVSRIPO for intravesical instillation. A urinary catheter will be inserted into the urethra under 
aseptic conditions according to local hospital protocol and the bladder drained completely. Using 
a catheter adapter with the syringe, the PVSRIPO suspension will then be instilled into the 
bladder via the catheter over a period of several minutes per local practice. After instillation the 
catheter will be removed, and the patient instructed to retain the instilled suspension in the 
bladder for a period of 2 hours. During this period, care should be taken to ensure that the 
instilled suspension has sufficient contact with the whole mucosal surface of the bladder. The 
patient should be encouraged to mobilize or, if lying down, to rotate between prone, supine, left 
lateral, and right lateral positions every 15 minutes.  
After 2 hours the patient should void the instilled suspension directly into a toilet. After bladder 
evacuation, the next first voided urine sample should be collected for PVSRIPO Shedding. 

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The patient should be advised to limit their fluid intake for 4 hours prior to instillation and until 
bladder evacuation is permitted (i.e. 2 hours after instillation).  
Cohort F: Each patient will receive the following sequence of bladder washes prior to 
instillation of PVSRIPO: 100 ml saline followed by 75 ml 5% DDM followed by 100 ml saline.  
A urinary catheter will be inserted into the urethra under aseptic conditions according to local 
hospital protocol and the bladder drained completely. Using a catheter adapter with the syringe, 
each successive wash will be instilled over a period of several minutes per local practice. Each 
saline wash will be retained in the bladder for approximately 5 minutes and the 5% DDM wash 
will be retained within the bladder for 15 (±5) minutes.  At the end of each retention period, the 
bladder will be drained completely, and the next wash applied.  Upon completion of the three 
washes, PVSRIPO will be instilled as described for Cohort E and in the Pharmacy manual. The 
process for pretreatment washes has been adapted from the process described for CG0070 
(Burke 2012).  
Both Cohorts: 
The dose and dose escalation approach for PVSRIPO is described in Section 3. The timing of 
administration is outlined in Table 1; in general, PVSRIPO will be administered 2-5 days prior to 
TURBT or cystectomy.  
PVSRIPO preparation, handling, and administration should be performed in accordance with the 
Pharmacy Manual.  
Only staff trained in cystoscopy and intravesical instillation who have read the Pharmacy Manual 
are allowed to administer PVSRIPO. 
Patients should not have a UTI at the time of treatment, as determined by the Investigator. 
Prophylactic antibiotics should be administered 1-3 days pre-treatment, on the treatment day, and 
1-3 days post-treatment to reduce the likelihood of a procedure-related UTI. 
Anticoagulant and antiplatelet medications will be managed by the treating physician, per local 
institutional guidelines, to optimize the safety of intravesical instillation of PVSRIPO.  
Investigators should confirm that patients are suitable for the administration procedure prior to 
each planned administration of PVSRIPO. 
5.1.1.2. 
Intervention After Discontinuation of Study Treatment 
Patients in either cohort may receive standard of care treatment after TURBT or cystectomy as 
determined by the Investigator per institutional guidelines; this includes immediate post-
operative chemotherapy. 
5.2. 
Dose Modifications and Toxicity Management Guidelines 
Detailed dose modification and toxicity management guidelines can be found in the 
corresponding section of the master protocol (Master Protocol Section 5.2 [Dose Modification 
and Toxicity Management Guidelines]). 

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5.3. 
Concomitant Medications 
Concomitant medications described in this section are in addition to those described in the 
master protocol and are specific for patients enrolled in Cohort E and F.  
Patients should not have a UTI at the time of treatment, as determined by the Investigator. 
Prophylactic antibiotics should be administered 1 to 3 days pre-treatment, on the treatment day, 
and 1 to 3 days post-treatment to reduce the likelihood of a procedure-related UTI. 
Patients may be offered appropriate symptomatic care which could include antihistamines for 
pruritis, phenazopyridine for dysuria, and/or non-steroidal anti-inflammatory medications for 
pain. Topical or local anesthetics may be used per local institutional guidelines for management 
of pain associated with injection. 
Warfarin is prohibited. Anticoagulant and antiplatelet medications will be managed by the 
treating physician, per local institutional guidelines, to optimize the safety of intravesical 
instillation of PVSRIPO. 
 

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6.
STUDY ASSESSMENTS
Study assessments described in this section are in addition to those described in the master 
protocol (Master Protocol Section 6 [Study Assessments]) and are specific for patients enrolled 
in Cohort E and F. Adherence to the study design requirements, including those specified in the 
Schedule of Assessments (Table 1), is essential and required for study conduct. Immediate safety 
concerns should be discussed with the study Medical Monitor upon occurrence or awareness to 
determine if the patient should continue or discontinue study treatments. 
The Investigator or Designee will record minimal data in the eCRF of all patients screened and to 
confirm eligibility or record reasons for screening failure, as applicable.  
Procedures conducted as part of the patient’s routine clinical management (eg, hematology, 
clinical chemistry, cystoscopy) and obtained before signing of the informed consent form (ICF) 
may be utilized for screening or baseline purposes provided the procedures met the protocol-
specified criteria and are performed within the time frame defined in the Schedule of 
Assessments. 
Screening assessments may be repeated if the initial evaluation makes the patient ineligible for 
enrollment. 
6.1. 
Informed Consent 
Patients and the authorized person obtaining the informed consent will be required to sign a 
statement of informed consent prior to the conduct of any study-related procedures. The 
Investigator or Designee will explain the nature of the study to the patient and answer all 
questions regarding the study.  
Eligibility should be determined after the patient signs the informed consent and prior to the start 
of study treatment. Eligible patients will be instructed on all protocol requirements, including 
any restrictions on concomitant medication usage. 
6.2. 
Safety Assessments 
Details regarding AEs, SAEs, and AESIs are provided in Section 6.1 (Adverse and Serious 
Adverse Events) and Section 6.2 (Adverse Events of Special Interest) of the Master Protocol. 
6.2.1. 
Demographics 
Age, gender, race, and ethnicity will be collected during the Screening period. 
6.2.2. 
Medical History and Solid Tumor Disease History 
Medical and surgical history, including past and current conditions and procedures, will be 
collected. Concomitant medications taken within 28 days prior to Cycle 1 Day 1 will be 
recorded. 
Bladder cancer history, including date of diagnosis and prior surgery (including TURBT), will be 
recorded. 

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6.2.3. 
Vital Signs 
The following will be collected per the Schedule of Assessments (Table 1): 
•
Body temperature, pulse rate, and blood pressure (diastolic and systolic).
•
Blood pressure and pulse measurements should be assessed in the sitting position.
•
Blood pressure and pulse measurements should be preceded by at least 5 minutes of
rest for the patient in a quiet setting without distractions (eg, television, cell phones).
•
Height (Screening visit only) and body weight.
6.2.4. 
Physical Examination
Full physical examination evaluations at screening should include general appearance, skin, 
neck, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and 
neurological examinations. Subsequent physical exams should include body systems as 
appropriate (eg, brief physical exam). 
Information about the physical examination must be present in the source documentation at the 
study site. Clinically relevant findings observed prior to the start of study drug, should be 
recorded as medical history. Clinically relevant findings observed after the start of study drug 
until 30 days after the last dose of study drug that meet the definition of an AE must be recorded 
on the AE eCRF. 
6.2.5. 
Clinical Safety Laboratory Assessments 
Hematology, clinical chemistry, coagulation (international normalized ratio [INR], prothrombin 
time [PT], partial thromboplastin time [PTT], activated partial thromboplastin time [aPTT]), and 
urinalysis will be performed at the site’s local certified laboratory per the schedule outlined in 
the Schedule of Assessments (Table 1). Additional tests may be performed at any time during the 
study as determined necessary by the Investigator or required by local regulations. A list of 
clinical laboratory tests to be performed is provided in Table 5. Clinical chemistry, hematology, 
coagulation, and urinalysis results should be reviewed before dosing. Laboratory toxicities will 
be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE), v5.0. 
An abnormal laboratory value is not an AE unless it is considered to be clinically significant. 
Laboratory parameters for which clinically significant values are noted will be re-measured on 
the appropriate clinical follow-up arranged by the Investigator. Any laboratory value that 
remains abnormal at the end of the study and that is considered clinically significant should be 
followed according to accepted medical standards for up to 30 days or until the values return to 
normal or baseline or are no longer considered clinically significant by the Investigator. If such 
values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified, and the Medical Monitor notified.  
If laboratory values from non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory as part of the monitoring of an SAE, then the results should be 
entered into the eCRF as part of safety reporting.  

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Table 5: 
Protocol-Specified Safety Laboratory Assessments 
Laboratory 
Assessment 
Parameters 
Hematology 
Platelet Count 
Hemoglobin 
Complete Blood Count (CBC) with Differential (% and/or absolute values) 
for neutrophils, monocytes, and lymphocytes 
Clinical 
Chemistry 
Blood Urea Nitrogen 
(BUN) or Urea 
Serum Creatinine 
Lactate 
Dehydrogenase 
Albumin 
Aspartate 
Aminotransferase 
(AST) 
Alanine 
Aminotransferase 
(ALT) 
Alkaline 
Phosphatase 
(ALP) 
Total 
Bilirubin 
Potassium 
Sodium 
Calcium 
Chloride 
Inorganic Phosphorous 
or Phosphate 
Total Protein 
Glucose  
(non-fasting) 
Bicarbonate 
Coagulation 
International 
Normalized 
Ratio  
(INR) 
Prothrombin 
Time (PT) 
Partial Thromboplastin Time (PTT) OR 
Activated Partial Thromboplastin Time 
(aPTT) 
Urinalysis 
Semiquantitative dipstick: specific gravity, pH, evaluation of glucose, 
protein, bilirubin, ketones, leukocytes, and hemoglobin 
Microscopic examination (including red blood cell, white blood cell, and 
casts) will be performed, if clinically warranted 
Other Tests 
Serum or urine human chorionic gonadotropin (hCG) pregnancy test (for 
persons of childbearing potential only) 
6.2.6. 
Electrocardiogram 
Standard 12-lead electrocardiograms (ECGs) will be performed in triplicate at Screening 
(Table 1). Additional ECGs may be performed as clinically indicated at any time during the 
study. All 12-lead ECGs will be obtained after the patient has been resting for at least 10 minutes 
and shall be recorded at 25 mm/sec. All ECGs for an individual patient shall be recorded with the 
patient in the same physical position. The 3 ECG recordings shall be taken within an 
approximate 5-minute period. A cardiologist is not required to review the Screening ECG. 

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6.2.7. 
Evaluation of PVSRIPO Shedding 
As described in the master protocol and in the IB, PVSRIPO has been subjected to extensive 
non-clinical and clinical viral shedding studies, all of which suggest the risk of extra-tumoral 
PVSRIPO dissemination and shedding is extremely low.  
Non-human primate studies in Cynomolgus macaques were unable to detect PVSRIPO in saliva, 
stool, or urine up to 56 days post intracerebral inoculation, with a PVSRIPO dose of 5 x 109 
TCID50 (Dobrikova 2012). Likewise, PVSRIPO shedding was undetected in the stool (the main 
excretory pathway for polio) of patients treated with PVSRIPO for recurrent GBM following 
administration of intracerebral doses of up to 1 x 1010 TCID50 or in melanoma patients receiving 
3 PVSRIPO injections (1 x 108 TCID50 each).  
All patients are required to have received a Center for Disease Control (CDC)-recommended 
immunizing vaccination against polio virus, as well as a polio vaccine booster prior to study 
entry, which has resulted in extremely high levels of neutralizing anti-poliovirus antibodies in 
GBM and melanoma patients who have participated in a previous or ongoing PVSRIPO clinical 
study. Therefore, the Sponsor believes the risk of extra-tumoral PVSRIPO dissemination and 
shedding is extremely low. 
However, because PVSRIPO shedding in patients with NMIBC receiving PVSRIRPO by 
intravesical instillation has not been characterized, samples will be collected to test for the 
presence of PVSRIPO in urine and stool for all patients as described in the Schedule of 
Assessments (Table 1). All samples will be collected and evaluated for the presence of 
PVSRIPO as described in the laboratory manual.  
All samples related to the analysis of viral shedding may be collected during clinic visits, where 
feasible. Otherwise, samples may be collected at home and brought to the next clinic visit, as 
appropriate. Refer to the laboratory manual for additional details related to sample collection and 
storage. 
6.2.8. 
Cystoscopic Photography 
Pre- and post-PVSRIPO administration photos of the treated bladder/tumor will be collected (as 
available) and sent to the Sponsor or Designee for storage. If needed, guidelines for collection 
and storage of the photographic images will be provided in a separate document.  
6.3. 
Biomarker Assessments 
If available (Section 4.1), archival tissue from the most recent tissue biopsy/resection should be 
collected for each patient within 2 months after enrollment. Additional details are outlined in the 
laboratory manual. 
Pre-dose tissue biopsies are optional and should be collected prior to PVSRIPO administration 
as outlined in Table 1. Additional details are outlined in the laboratory manual. If at the time of 
the optional biopsy, it is judged that the biopsy is not clinically feasible (ie, poses an 
unacceptable medical risk to the patient) as judged by the investigator, then the biopsy should 
not be performed. 
TURBT or cystectomy specimens should be processed per standard of care for local pathological 
evaluation with an expectation that a portion of the specimen will be made available to the 

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Sponsor; details are provided in the Laboratory Manual. Pathologic review of resected surgical 
specimens will be performed per institutional standards, and the final pathologic staging will be 
recorded in the eCRF. Any remaining tissue (after pathologic review) will be evaluated for the 
presence of PVSRIPO and changes in the immune milieu within the tumor microenvironment. If 
any tissue biopsies or surgical specimens are collected as standard of care (even if not specified 
in Table 1), any remaining tissue (after standard of care analysis) will be made available to the 
Sponsor provided the patient agrees by signing consent.  
Blood samples should be collected at the time points described in Table 1 and processed as 
described in the Laboratory Manual. 
6.4. 
Data Safety Monitoring Committee 
The external independent DSMC is described in the Master Protocol. The text below is specific 
for patients enrolled in Cohort E and F. The schedule of meetings is as follows: 
•
When dose escalation/de-escalation decisions are required (Section 3) prior to
initiating enrollment in the next cohort. For example, prior to opening the
1x1010 TCID50 intravesical instillation dose in Cohort E or prior to opening Cohort
F.
•
Additional reviews may occur based on DSMC requests.
•
The DSMC will review any Suspected Unexpected Serious Adverse Reaction
(SUSAR) that occurs during the study and may recommend enrollment be paused
until the event is reviewed.
Note that the timing of DSMC meetings as outlined in Section 6.3 of the Master Protocol are 
superseded by the text above. This change is implemented because the structure of the Phase 1 
portion of this substudy is slightly different than that described in the Master Protocol, i.e. the 
timings outlined in the Section 6.3 of the Master Protocol are not applicable. 
Note that the text below from Section 6.3 of the Master Protocol will still apply to this substudy. 
During the study, accrual of patients will be suspended for the following safety events pending 
evaluation and recommendations by the DSMC: 
•
Any Grade 5 AE considered to be at least possibly related to study drug(s).
•
If two or more of up to 6 DLT-evaluable subjects in Cohort E experience DLTs.
•
A death within 30 days of study treatment (other than death related to progressive
disease).
•
Any unexpected Grade 4 AE considered at least possibly related to study drug(s).

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7.
STATISTICAL CONSIDERATIONS
Full details on the statistical analyses to be performed will be provided in a separate statistical 
analysis plan (SAP).  
7.1. 
Sample Size Determination 
As outlined in Section 3, the sample size for Cohorts E will be determined by the assessment of 
safety observed during the DLT period. It is expected that between 3 and 6 patients will be 
enrolled within each dosing cohort for a total sample size ranging from 6 to 12.  
7.2. 
Analysis Population 
The full analysis set (FAS) population includes all eligible patients who receive at least 1 dose of 
study drug. Analyses for the FAS population will be conducted based on the actual treatment 
received. Unless otherwise specified, the FAS population is the primary population for all 
efficacy and safety analyses.  
7.3. 
Timing of Planned Analyses 
Planned safety analyses by the DSMC are outlined in Section 6.4. 
7.4. 
Statistical Analysis Methods 
A SAP will be developed and finalized prior to the first planned database lock and will include 
more details related to the statistical analysis of this study’s data. This section is a summary of 
the key aspects of the planned statistical analyses. 
7.4.1. 
General Considerations 
All statistical analyses will be performed using appropriate statistical software. The exact 
software and versions will be described in the SAP. 
Data will be summarized descriptively by treatment group. The descriptive summary for the 
categorical variables will include counts and percentages. The descriptive summary for the 
continuous variables will include means, medians, standard deviations, 25% and 75% 
percentiles, and minimum and maximum values.  
7.4.2. 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the FAS population 
descriptively by treatment and overall.  
7.4.3. 
Prior and Subsequent Anticancer Therapies 
Prior and subsequent anticancer therapy verbatim terms will be coded to Anatomical Therapeutic 
Class (ATC) and preferred term using the most recent WHO-DD. For the FAS population, 
summary statistics will be provided for prior or subsequent systemic anticancer therapies by 
treatment group and overall. For the subsequent systemic anticancer therapies, the lines of 
therapy, response to each treatment regimen, and disease progression status will also be 
summarized by treatment group and overall. 

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7.4.4. 
Efficacy Analyses 
The proportion of patients with demonstrable PVSRIPO infection of excised tumor tissue by 
dose group and cohort will be described.  
7.4.5. 
Safety Analyses 
Refer to Section 7.4.5 of the Master Protocol. 
Additional safety analyses specific for NMIBC will include the number and percentage of 
patients who undergo TURBT or cystectomy. 

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