Lerapolturev (Formerly Known as PVSRIPO) With or Without Immune Checkpoint Blockade in Advanced PD-1 Refractory Melanoma
Phase: PHASE2
Conditions: Melanoma
Sponsor: Istari Oncology, Inc.

 
 
Confidential 
 
 
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CLINICAL STUDY PROTOCOL 
 
 
 
Lerapolturev (formerly known as PVSRIPO) with and without Immune Checkpoint 
Blockade in Advanced PD-1 Refractory Melanoma 
 
 
 
 
 
 
CONFIDENTIAL 
 
This document contains confidential, proprietary information 
 
Confidentiality Statement 
This study will be performed in compliance with Good Clinical Practices (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 proprietary and may not be further disclosed 
without the express written consent of Istari Oncology, Inc. 
 
Protocol Number 
LUMINOS-102 (PVSRIPO ICI M201) 
Clinical Phase 
Phase 2 
US IND Number 
IND 26877 
Protocol Date: 
Amendment 4 
14JAN2022 
Sponsor: 
Istari Oncology, Inc. 
430 Davis Drive, Suite 560 
Morrisville, NC 27560 

Istari Oncology, Inc.                                                                                                  
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Sponsor Signatory:  
 
 
 
 
 
 
W. Garrett Nichols, MD, MS 
Chief Medical Officer 
Istari Oncology, Inc.  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Istari Oncology, Inc.                                                                                                  
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Investigator Protocol Agreement 
 
I have read this Istari Clinical Study Protocol and agree to conduct the study as outlined 
herein, in accordance with Good Clinical Practice (GCP) requirements and the 
International Conference on 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 protocol. 
 
 
Investigator Name (Print):  
Date Signed: 
 
Investigator Signature: 
 
 
 
 

Istari Oncology, Inc.                                                                                                  
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 4 
LIST OF IN TEXT TABLES AND FIGURES .................................................................... 7 
SYNOPSIS ...................................................................................................................... 8 
CLINICAL TRIAL SCHEMATIC ..................................................................................... 19 
1 
INTRODUCTION ................................................................................................ 30 
1.1 
Background ........................................................................................................ 30 
1.2 
Rationale ............................................................................................................ 31 
1.2.1 Nonclinical Studies ............................................................................................. 34 
1.2.2 Clinical Studies ................................................................................................... 36 
1.3 
Benefit/Risk Assessment .................................................................................... 42 
1.3.1 Known Potential Risks ........................................................................................ 42 
1.3.2 Known Potential Benefits .................................................................................... 45 
1.3.3 Benefit-Risk Summary ........................................................................................ 47 
2 
OBJECTIVES And ENDPOINTS ........................................................................ 48 
2.1 
Objectives and Endpoints ................................................................................... 48 
2.2 
Hypothesis .......................................................................................................... 49 
3 
TRIAL DESIGN ................................................................................................... 50 
3.1 
Overall Design .................................................................................................... 50 
3.1.1 Crossover ........................................................................................................... 51 
3.1.2 Considerations for Modification of Dose and/or Dosing Schedule for Participants 
receiving the Q3/4W Schedule of Injections. ...................................................... 52 
3.1.3 Determination of the Recommended Lerapolturev Dose .................................... 52 
3.1.4 Definition of Dose-Limiting Toxicity ..................................................................... 54 
3.2 
Evaluation of Lerapolturev Shedding .................................................................. 55 
3.3 
Justification for Lerapolturev Dose and Schedule ............................................... 55 
3.4 
End of Study Definition ....................................................................................... 56 
4 
STUDY POPULATION ....................................................................................... 56 
4.1 
Inclusion Criteria ................................................................................................. 56 
4.2 
Exclusion Criteria ................................................................................................ 58 
4.3 
Screen Failures .................................................................................................. 61 
5 
STUDY DRUG (LErapolturev, Nivolumab or pembrolizumab) ............................ 61 
5.1 
Lerapolturev: Packaging, labeling and how supplied .......................................... 61 
5.2 
Preparation/Handling/Storage/Accountability ..................................................... 61 
5.3 
Lerapolturev Dose, Schedule, and Administration .............................................. 62 
5.4 
Prior/Concomitant Therapy ................................................................................. 64 
5.5 
Dose Modification/Toxicity Management Guidelines .......................................... 65 
5.5.1 Lerapolturev........................................................................................................ 65 
5.5.2 Anti-PD-1 Therapy .............................................................................................. 66 
6 
DISCONTINUATION OF STUDY TREATMENT, TREATMENT BEYOND 
PROGRESSION, PARTICIPANT COMPLETION AND WITHDRAWAL, AND 
STUDY TERMINATION ...................................................................................... 70 

Istari Oncology, Inc.                                                                                                  
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6.1 
Discontinuation of Study Treatment .................................................................... 70 
6.2 
Treatment Beyond Progression .......................................................................... 71 
6.3 
Participant Withdrawal from the Trial .................................................................. 71 
6.4 
Study Termination .............................................................................................. 72 
7 
STUDY ASSESSMENTS AND PROCEDURES ................................................. 73 
7.1 
Efficacy Evaluations ........................................................................................... 73 
7.2 
Safety Assessments ........................................................................................... 74 
7.2.1 Physical Examination and Vital Signs ................................................................. 74 
7.2.2 Clinical Safety Laboratory Assessments ............................................................ 74 
7.3 
Adverse Events, Immune-Related Adverse Events, Adverse Events of Interest 
and Serious Adverse Events .............................................................................. 76 
7.3.1 Time Period and Frequency for Collecting Information on Adverse Events, 
Immune-Related Adverse Events, Serious Adverse Events and Adverse Events 
of Special Interest ............................................................................................... 76 
7.3.2 Method of Detecting Adverse Events, Immune-Related Adverse Events, Adverse 
Events of Special Interest and Serious Adverse Events ..................................... 78 
7.3.3 Follow-up of Adverse Events, Immune-Related Adverse Events, Adverse Events 
of Special Interest and Serious Adverse Events ................................................. 78 
7.3.4 Regulatory Reporting Requirements for Serious Adverse Events ...................... 78 
7.3.5 Notification of Pregnancy .................................................................................... 78 
7.4 
Tissue and Blood-Based Biomarker and Cytokine Analyses .............................. 79 
8 
STATISTICAL CONSIDERATIONS .................................................................... 80 
8.1 
Stratification Factors ........................................................................................... 80 
8.2 
Statistical Hypotheses ........................................................................................ 80 
8.3 
Sample Size Determination ................................................................................ 80 
8.4 
Populations for Analyses .................................................................................... 81 
8.5 
Statistical Analyses ............................................................................................. 81 
8.5.1 Efficacy Analyses ............................................................................................... 81 
8.5.2 Translational Analyses ....................................................................................... 82 
8.5.3 Safety Analyses .................................................................................................. 82 
8.5.4 Exploratory Analyses .......................................................................................... 82 
8.6 
Interim Analysis (IA) ........................................................................................... 83 
9 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 84 
9.1 
Regulatory, Ethical, and Trial Oversight Considerations .................................... 84 
9.1.1 Regulatory and Ethical Considerations ............................................................... 84 
9.1.2 Financial Disclosure ........................................................................................... 84 
9.1.3 Informed Consent Process ................................................................................. 84 
9.1.4 Data Protection ................................................................................................... 85 
9.1.5 Data and Safety Monitoring Committee .............................................................. 85 
9.1.6 Data Quality Assurance ...................................................................................... 86 
9.1.7 Protocol Deviations ............................................................................................. 87 
9.1.8 Source Documents ............................................................................................. 87 
9.1.9 Study and Site Closure ....................................................................................... 88 
9.1.10 Confidentiality and Publication Policy ................................................................. 88 

Istari Oncology, Inc.                                                                                                  
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9.2 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................... 90 
10 
ABBREVIATIONS ............................................................................................... 98 
11 
REFERENCES ................................................................................................. 100 
12 
Appendix I ........................................................................................................ 105 
13 
Appendix II........................................................................................................ 107 

Istari Oncology, Inc.                                                                                                  
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LIST OF IN TEXT TABLES AND FIGURES  
 
Tables 
Table 1. 
Schedule of Assessments for Lerapolturev Monotherapy or Lerapolturev 
+ Pembrolizumab ......................................................................................... 20 
Table 2. 
Schedule of Assessments for Lerapolturev + Nivolumab ............................. 25 
Table 3. 
LUMINOS-102 Overall Summary of Adverse Events ................................... 39 
Table 4. 
LUMINOS-102 Lerapolturev-Related Adverse Events by Preferred Term 
in Descending Frequency ............................................................................. 41 
Table 5. 
Oncolytic Virus Doses and Schedules .......................................................... 44 
Table 6. 
Lerapolturev Injection Schedule After Crossover ......................................... 52 
Table 7. 
Recommended Lerapolturev Injection Volumes ........................................... 63 
Table 8. 
Time Windows and Frequency for Reporting Based on AE Type ................. 77 
 
 
Figures 
Figure 1. Lerapolturev is directly lethal to breast and melanoma cell lines, yet 
lerapolturev infection of DCs is sublethal and induces sustained 
proinflammatory cytokine production. ........................................................... 33 
Figure 2. Lerapolturev restricts tumor growth and produces antigen-specific anti-
tumor immunity25 .......................................................................................... 35 
 
 
 

Istari Oncology, Inc.                                                                                                  
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SYNOPSIS 
Protocol Title 
Lerapolturev (formerly known as PVSRIPO) with and without 
Immune Checkpoint Blockade in Advanced PD-1 Refractory 
Melanoma 
Protocol 
Number 
LUMINOS-102 (PVSRIPO ICI M201) 
Rationale and 
Background 
Currently approved systemic immunotherapies fail to provide clinical 
benefit for a significant portion of patients with unresectable 
melanoma. Less than 40% of patients respond to anti-programmed 
cell death receptor-1 (PD-1) therapy (ie, have primary PD-1 
resistance)1,2, and of those who do respond, up to 25% may 
develop an acquired resistance over time3. While combining 
anti-PD-1 with anti-cytotoxic T-lymphocyte-associated protein 4 
(CTLA-4) therapy can increase response rates, this combination is 
associated with significant toxicity4. Options for follow-on therapy 
remain limited, and outcomes are poor for those with advanced 
disease5. Lerapolturev (formerly PVSRIPO) is a recombinant 
rhinovirus/polio virus (PV) chimera which has demonstrated clinical 
anti-tumor activity in primary brain tumors and in a Phase 1 study of 
unresectable, anti-PD-1 refractory (as per investigator 
determination) melanoma6 which warrants further investigation. 
Preliminary data from the current study in unresectable, anti-PD-
1/L1 refractory melanoma (as defined by the Society for 
Immunotherapy in Cancer’s [SITC] Immunotherapy Resistance 
Taskforce Guidance7) show that lerapolturev given every (Q) 3 to 4 
weeks, alone or in combination with anti-PD-1, at a dose of up to 
6 x 108 tissue culture infectious dose 50% (TCID50) is very well 
tolerated (regimen referred to as Q3/4W hereafter); all adverse 
events (AEs) related to lerapolturev and/or anti-PD-1 remain Grade 
1 or 2, with no dose-limiting toxicities (DLTs), treatment-related 
serious AEs (SAEs) or sign/symptoms of cytokine release 
syndrome reported as of the 10DEC2021 data cutoff (Table 3 and 
Table 4).  However, the anti-tumor activity noted in Phase 1 has not 
yet been duplicated. In addition, a literature review shows that other 
innate immune agonists with clinical activity in anti-PD-1/L1 
refractory melanoma, including other oncolytic viruses, use an 
“induction/maintenance” dose schedule, with more frequent (eg, 
weekly) injections for 1 to 2 months, followed by less frequent (eg, 
Q3 or 4 week) maintenance thereafter to induce an upfront 
anti-tumor immune reaction that can be maintained across time. 
Therefore, LUMINOS-102 will test the safety and efficacy of weekly 
x7 lerapolturev followed by Q3 to 4-week administration at a dose of 
up to 1.6 x 109 TCID50, as monotherapy and in combination with 

Istari Oncology, Inc.                                                                                                  
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anti-PD-1 therapy, in a more homogeneous unresectable melanoma 
population that has failed 1 prior line of anti-PD-1/L1-based therapy.  
Key 
Objectives 
Objectives 
Endpoints/Evaluation Criteria 
Primary  
To evaluate the anti-tumor 
activity of lerapolturev with 
and without anti-PD-1, in 
participants who have 
failed anti-PD-1/L1-based 
therapy   
• Overall Response Rate (ORR): 
the proportion of participants 
achieving complete (CR) or 
partial response (PR), per 
RECIST 1.1 
To evaluate the 
safety/tolerability of  
lerapolturev with and 
without anti-PD-1, in 
participants who have 
failed anti-PD-1/L1-based 
therapy     
• The frequency and severity of 
treatment-emergent adverse 
events (AE) via Common 
Terminology Criteria for Adverse 
Events (CTCAE, v5.0) 
• Changes in laboratory 
(hematology, chemistry) and 
vital sign parameters 
• Lerapolturev AESIs 
• Anti-PD-1 immune-related AEs 
(irAEs) 
• Study treatment discontinuation 
due to AEs 
To evaluate the effect of 
lerapolturev on the tumor 
microenvironment of 
injected and non-injected 
lesions when administered 
with and without anti-PD-1 
therapy 
• Changes from baseline in the 
number of CD8+ tumor 
infiltrating lymphocytes (TILs) 
• Changes from baseline in PD-L1 
expression  
Secondary 
To evaluate survival and 
disease control outcomes 
of lerapolturev with and 
without anti-PD-1, in 
participants who have 
failed anti-PD-1/L1-based 
therapy  
• Overall survival (OS): time from 
treatment group assignment until 
death from any cause 
• Duration of Response (DOR): 
time from confirmed objective 
response (CR or PR per 
RECIST 1.1) until unequivocal 
disease progression or death, 
whichever occurs first 
• Disease control rate (DCR): the 
proportion of participants 
achieving confirmed CR, 
confirmed PR, or stable disease 

Istari Oncology, Inc.                                                                                                  
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(SD) per RECIST 1.1, as best 
response  
• Disease control rate-6months 
(DCR-6mo): the proportion of 
participants achieving confirmed 
CR (any duration), confirmed PR 
(any duration) or SD (≥ 6 
months) per RECIST 1.1 as best 
response  
• Durable Response Rate (DRR): 
the proportion of participants 
with confirmed CR or PR (per 
RECIST 1.1) lasting at least 6 
months 
• Progression-free survival (PFS): 
time (number of months) from 
treatment group assignment until 
date of documented radiologic 
disease progression per 
RECIST 1.1 or death due to any 
cause, whichever comes first 
Study Design 
This multi-center, open-label, randomized, Phase 2 study will 
investigate the efficacy and safety of lerapolturev alone (Arm 1) or 
in combination with an anti-PD-1 inhibitor (Arm 2). Following a 6-
participant safety run-in period, up to approximately 50 participants 
with unresectable cutaneous melanoma who previously failed an 
anti-PD-1/L1-based therapy will be randomized 1:1 to receive either 
lerapolturev or lerapolturev plus an anti-PD-1. Based on updated 
eligibility criteria, participants will be stratified based on type of anti-
PD-1/L1 resistance (primary versus secondary as per Kluger et al7.) 
and baseline lactate dehydrogenase (LDH) levels (normal versus 
>ULN).  
 
As of 10DEC2021, the safety run-in has been completed and a total 
of 17 participants have been enrolled (safety run-in, n=6; Arm 1, 
n=5; Arm 2, n=6). Upon review of the safety profile for lerapolturev 
administered as monotherapy or in combination with anti-PD-1 
therapy (Section 1.2.2), and in agreement with the data safety 
monitoring committee (DSMC), the total lerapolturev dose to be 
administered will be a maximum of 1.6 x 109 TCID50/visit, with up to 
6 lesions injected/visit. This dose schedule of administration 
(referred to hereafter as QW) will include weekly injections x 7 
followed by either Q3W dosing (lerapolturev monotherapy or in 
combination with pembrolizumab) or Q4W dosing (combination with 
nivolumab).  
 

Istari Oncology, Inc.                                                                                                  
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Participants enrolled in the safety run-in, or those randomized to 
Arm 1 (lerapolturev only), are allowed to crossover to Arm 2 
following disease progression (per RECIST 1.1), once a PR lasts ≥ 
6 months, or after 26 weeks on study without RECIST-defined 
progression (ie, SD or unconfirmed PR or CR), as described in 
Section 3. In Arm 2, anti-PD-1 will be administered per the 
manufacturer’s prescribing information concurrently with 
lerapolturev beginning Day 1. After 12 participants have been 
treated under Study Protocol Amendment 4 and on study 
approximately 21 days (ie, once n=6 participants per treatment arm 
receiving lerapolturev QW have completed the DLT evaluation 
period), an additional safety review will be performed by the DSMC 
to confirm the safety of lerapolturev with or without anti-PD-1 and/or 
to make recommendations related to lerapolturev dose and/or 
schedule adjustments as described in Section 3.1.3.   
 
Participants currently receiving the Q3/4W schedule of injections 
will be given the option to change to the QW schedule 
(Section 3.1.2). 
 
Participants will be evaluated for key primary and secondary anti-
tumor response endpoints based on RECIST 1.1. Additional primary 
endpoints include characterization of the immunologic response 
(eg, changes in CD8+ TIL levels and PD-L1 expression) to 
lerapolturev with and without anti-PD-1 and safety. Because 
lerapolturev is an immunotherapeutic, participant management with 
respect to treatment decisions (eg, confirmation of PD for study 
discontinuation) will occur based on iRECIST criteria. However, 
participants in the safety run-in or Arm 1 are allowed to crossover to 
Arm 2 upon RECIST-defined PD. ORR, DOR, and DRR based on 
iRECIST are exploratory endpoints.   
Planned 
Number of 
Participants 
Up to approximately 56 participants 
Study Entry 
Criteria 
Inclusion Criteria:  
1. ≥ 18 years of age 
2. Prior 
CDC-recommended 
vaccination 
series 
against 
poliovirus (PV), and has received a boost immunization with 
trivalent IPOL® (Sanofi-Pasteur SA) at least 1 week, but less 
than 6 weeks, prior to Day 1  
a. NOTE: Patients who are unsure of their vaccination 
status must provide evidence of anti-PV immunity prior 
to enrollment, as applicable 

Istari Oncology, Inc.                                                                                                  
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3. Has biopsy proven unresectable cutaneous melanoma and is 
willing to undergo tumor biopsy prior to the first dose of study 
drug(s) and at prespecified intervals during the study. Note the 
following details: 
a. Patients with ocular, acral or mucosal melanoma are 
not eligible 
b. Patients with M1c or M1d disease are NOT eligible 
c. Submission of an archival biopsy sample is allowed in 
lieu of the baseline tumor biopsy, provided the tissue is 
≤4 months old and the participant received no 
intervening systemic/intratumoral anti-cancer therapy 
since the biopsy was acquired. 
d. Must have at least 1 lesion that is amenable to biopsy. 
The lesion must be safely accessible as determined by 
the investigator and should not be located at sites that 
require significant risk procedures to biopsy. Examples 
of sites considered to be of significant risk include but 
are not limited to the following: the brain, lung, 
mediastinum, pancreas, or endoscopic procedures 
extending beyond the esophagus, stomach, or bowel 
wall. 
4. Has ≥ 2 melanoma lesions that are accurately measurable by 
caliper or a radiological method according to RECIST 1.1 
criteria 
a. One lesion must be injectable--defined as a visible or 
palpable 
cutaneous, 
subcutaneous, 
or 
nodal 
melanoma lesion ≥ 10mm in longest diameter or 
multiple 
injectable melanoma 
lesions which 
in 
aggregate have a longest diameter of ≥ 10mm and 
where the minimal lesion size is ≥ 5mm.   
b. Note that visceral lesions (eg, liver, lung, 
retroperitoneal, subpleural lesions) are not considered 
injectable for the purposes of this trial. 
5. Has had confirmed progression of disease (PD) while 
receiving at least 6 weeks (> 1 dose) of an FDA-approved anti-
PD-1/L1 therapy (as monotherapy or in combination) for the 
treatment of melanoma.  Note the following details:   
a. Initial PD as defined by RECIST v1.1 
b. Confirmation of PD per iRECIST must occur by repeat 
assessment ≥ 4 weeks from initial evidence of PD, in 
the absence of rapid clinical progression.  

Istari Oncology, Inc.                                                                                                  
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c. Those who discontinue anti-PD-1/L1 therapy after at 
least 6 weeks (> 1 dose) and have confirmed PD per 
iRECIST within 12 weeks of their last anti-PD-1/L1 
dose are also eligible, provided the anti-PD-1/L1 was 
not stopped due to toxicity requiring permanent 
discontinuation 
a. Those treated with anti-PD-1/L1 in the adjuvant setting 
and who have biopsy-confirmed progression either 
while receiving anti-PD-1/L1-based therapy or ≤ 12 
weeks after their last dose of anti-PD-1/L1 therapy are 
allowed 
NOTE: Adjuvant is defined as therapy received after surgical 
resection of disease such that the patient has no evidence of disease 
when the anti-PD-1/L1 therapy is initiated. Patients with known BRAF 
mutation must have also failed or refused to receive BRAF-targeted 
therapy (alone or in combination with MEK inhibitor) to be eligible. 
6. Eastern Cooperative Oncology Group (ECOG) status of 0-1 
7. Serum lactate dehydrogenase (LDH) levels ≤3 x upper limit of 
normal (ULN) 
8. Adequate bone marrow, liver and renal function as assessed 
by the following: 
a. Hemoglobin ≥9.0 g/dl, patients may be transfused  
b. Lymphocyte count ≥0.5 x 109/L (500 µL) 
c. Absolute neutrophil count (ANC) ≥1.5 x 109/L (1500 µL) 
d. Platelet count ≥100 x 109/L (100,000 µL) without 
transfusion 
e. AST, ALT, and alkaline phosphatase (ALP) ≤2.5 x 
upper limit of normal (ULN), with the following 
exceptions: 
i. Patients with documented liver metastases:  
AST and ALT ≤5 x ULN 
ii. Patients with documented liver or bone 
metastases:  ALP ≤5 x ULN 
f. Serum bilirubin ≤1.5 x ULN with the following exception: 
i. Patients with known Gilbert disease:  serum 
bilirubin level ≤3 x ULN 
g. Measured or calculated (per institutional standards) 
creatinine clearance ≥30 ml/min (GFR can also be used 
in place of creatinine clearance) 
h. For patients not receiving therapeutic anticoagulation:  
INR, PT, PTT (or aPTT) ≤1.5 x ULN 
9. Life expectancy of >12 weeks 

Istari Oncology, Inc.                                                                                                  
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10. Signed informed consent form (ICF) indicating that 
participant understands the purpose of, and procedures 
required for the study, and is willing/able to participate in the 
study  
 
Exclusion Criteria:  
1. Has biopsy-proven ocular, acral or mucosal melanoma 
2. Has M1c or M1d disease 
3. No more than one prior systemic anti-cancer regimen 
(monotherapy or combination) for management of melanoma. 
Additional details noted below: 
a. Adjuvant anti-cancer therapy administered ≥ 6 months 
prior to the first injection of lerapolturev does NOT 
count as a line of treatment.  
b. Patients with BRAF mutant melanoma may enroll if 
they have received ≤ 2 prior lines of systemic anti-
cancer therapy only if one of those lines of therapy was 
a BRAF-targeted regimen (alone or in combination with 
MEK inhibitor). 
c.  A line of therapy is defined as a regimen in which at 
least 2 doses of systemic anti-cancer therapy 
(monotherapy or combination) was administered, and 
the regimen was discontinued because of progressive 
disease 
4. Uncontrolled tumor-related pain.  Participants requiring pain 
medication must be on a stable regimen at study entry 
a. Symptomatic 
lesions 
amenable 
to 
palliative 
radiotherapy (eg, bone metastases or metastases 
causing nerve impingement) should be treated prior to 
enrollment.  Patients should be recovered from the 
effects of radiation.  There is no required minimum 
recovery period 
b. Asymptomatic metastatic lesions that would likely 
cause functional deficits or intractable pain with further 
growth (eg, epidural metastasis that are not currently 
associated with spinal cord compression) should be 
considered for loco-regional therapy if appropriate prior 
to enrollment 
5. Grade ≥2 pleural effusion, pericardial effusion, or ascites  
6. Active or history of autoimmune disease or immune deficiency 
within previous 2 years, with the following exceptions: 

Istari Oncology, Inc.                                                                                                  
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a. History of autoimmune-related endocrinopathy (e.g. 
adrenal insufficiency, hypothyroidism, Type 1 diabetes 
mellitus, etc.) that is managed by hormone replacement 
therapy (e.g. hydrocortisone, thyroid hormone, insulin, 
etc.) 
b. Eczema, psoriasis, or lichen simplex chronicus with 
dermatologic manifestations only (eg, patients with 
psoriatic arthritis are excluded), provided all of the 
following conditions are met: 
i. Rash must cover <10% of body surface area 
ii. Disease is well-controlled at baseline and 
requires only low-potency topical corticosteroids 
iii. No occurrence of acute exacerbations of the 
underlying condition requiring psoralen plus 
ultraviolet A radiation, methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, or 
high potency or oral corticosteroids within 
12 months of Day 1 
7. History of idiopathic pulmonary fibrosis, organizing pneumonia 
(eg, bronchiolitis obliterans), drug-induced or idiopathic 
pneumonitis, or evidence of active pneumonitis on screening 
chest computed tomography (CT) scan 
a. History of radiation pneumonitis in the radiation field 
(fibrosis) is allowed 
8. History of a positive HIV RNA test (HIV 1 or 2 RNA by PCR) 
9. Known active hepatitis B virus (HBV) infection (chronic or 
acute) 
a. NOTE: Participants with a negative HBsAg test and a 
positive total hepatitis B core antibody (HBcAb) test are 
allowed  
10. Known active hepatitis C virus (HCV) infection 
a. NOTE: History of a positive HCV antibody test, but 
negative HCV RNA test, is allowed 
11. Active tuberculosis 
12. Significant cardiovascular disease, such as New York Heart 
Association Class II or greater cardiac disease, myocardial 
infarction, or cerebrovascular accident within 3 months of 
Day 1, unstable arrhythmia, or unstable angina  
13. Has received prior systemic anti-cancer therapy including 
investigational agents within 4 weeks or 5 elimination half-

Istari Oncology, Inc.                                                                                                  
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lives—whichever is shorter—prior to treatment, or has not 
recovered from all AEs due to previous therapies to ≤Grade 1 
or baseline. Participants with ≤Grade 2 neuropathy are eligible 
a. Note: Anti-PD-1/L1 within 4 weeks of Day 1 is allowed 
b. If participant received major surgery, they must have 
recovered adequately from the toxicity and/or 
complications from the intervention prior to starting 
study treatment 
14. History of other malignancy within 2 years prior to Day 1, with 
the exception of those with a negligible risk of metastasis or 
death (eg, resected cutaneous basal cell carcinoma, or other 
cancers with 5-year OS of >90%) 
15. Severe infection within 4 weeks prior to Day 1, including, but 
not limited to, hospitalization for complications of infection, 
bacteremia, or severe pneumonia 
a. Prophylactic antibiotics (eg, to prevent a urinary tract 
infection or chronic obstructive pulmonary disease 
exacerbation) are allowed 
16. Prior allogeneic stem cell or solid organ transplantation 
17. Treatment with a live, attenuated vaccine within 4 weeks prior 
to Day 1 
18. Treatment with systemic immunosuppressive medication 
within 4 weeks prior to Day 1, with the following exceptions: 
a. Participants who received acute, low-dose systemic 
immunosuppressant medication or a one-time pulse 
dose of systemic immunosuppressant medication (eg, 
48 hours of corticosteroids for a contrast allergy) are 
eligible  
b. Patients 
receiving 
mineralocorticoids 
(eg, 
fludrocortisone), or systemic prednisone equivalent 
corticosteroid doses of <10mg per day are eligible for 
the study 
19. Known hypersensitivity to pembrolizumab, nivolumab, or any 
of the respective excipients  
20. Requires therapeutic anticoagulation and cannot discontinue 
anticoagulation safely during the day prior, day of, and day 
after each lerapolturev injection 
a. NOTE: Participants receiving anticoagulation with 
warfarin at the time of study entry are allowed if they 
can be transitioned to an alternative anticoagulant (eg, 
low molecular weight heparin or direct oral 
anticoagulants) prior to the first dose of lerapolturev. 

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Anyone transitioned from warfarin to an oral 
anticoagulant prior to the first dose of lerapolturev 
should have an INR <1.5x upper limit of normal in 
order to participate. Antiplatelet agents (eg, aspirin, 
clopidogrel, etc.) are not considered anticoagulants for 
the purposes of this study (ie, are allowed) 
21. A pregnant or nursing female, or women of child-bearing 
potential and men who are sexually active and not 
willing/able to use medically acceptable forms of 
contraception starting from signed ICF through 150 days 
after last anti-PD-1 dose 
22. History of human serum albumin allergy 
23. History of neurological complications due to polio virus 
infection 
24. History of agammaglobulinemia 
25. Concurrent participation in a separate interventional clinical 
trial during this study 
26. Any underlying medical condition for which, in the opinion of 
the investigator, participation would not be in the best interest 
of the participant (eg, compromises the participant’s well-
being) or that could prevent, limit, or confound protocol-
specified assessments 
Concomitant 
Treatment 
Pembrolizumab or nivolumab (Arm 2 only) 
Investigational 
Drugs 
Lerapolturev (formerly PVSRIPO): Oncolytic Polio/Rhinovirus 
Recombinant  
Planned Study 
Sites 
Up to approximately 30 sites 
Criteria for 
Assessments 
Efficacy: Changes in skin lesion and/or radiographic tumor 
measurements and survival will be assessed per RECIST 1.1 at 
regular intervals to evaluate efficacy: participants achieving 
objective response (along with associated durations) or disease 
control by Week 26 or upon anti-PD-1 re-challenge (Arm 1 and 
safety run-in participants that crossover to Arm 2, analyzed from 
time of crossover but separately from Arm 2) through study 
completion. Assessment of anti-tumor response by iRECIST will be 
exploratory. 
 
Safety: Laboratory and spontaneously reported AEs, to evaluate 
safety and tolerability to determine incidence and severity of 
treatment-emergent AEs for duration of the study 
 

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Biomarkers: Biological samples will be collected as indicated in the 
schedule of assessments (SOA) to evaluate immune, genetic, or 
cytologic factors impacting lerapolturev mechanism of action 
(MOA), anti-tumor response, and/or to evaluate immune-related 
AEs 
Statistical 
Methods 
The primary endpoint for measuring anti-tumor activity will be ORR, 
based on RECIST 1.1, which will be summarized as the overall 
number (%) of participants with CR or PR in each treatment arm, 
along with 95% confidence interval (CI). Participants will be 
analyzed based on the treatment arm to which they were 
randomized, as well as by lerapolturev dose/schedule (ie, QW and 
Q3/4W).  
 
Other endpoints will be summarized by descriptive statistics, as 
appropriate. Further details for these and other analyses will be 
described in the statistical analysis plan (SAP).  
Determination 
of Sample 
Size 
Sample size was determined based on feasibility and logistical 
considerations. Based on an estimated sample size of 15 
participants in Arm 2 receiving lerapolturev QW in combination with 
anti-PD-1, five objective responses are needed for the 95% 
confidence interval (CI) to be above 10% (33% ORR; 95% CI: 
11.8% to 61.6%), which would indicate the combination has anti-
tumor activity in this anti-PD-1 resistant population. See Section 8.3 
for additional details regarding sample size determination.  
Study 
Duration 
Up to approximately 24 months (104 weeks) 

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CLINICAL TRIAL SCHEMATIC 
 
 
 
.

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Table 1. 
Schedule of Assessments for Lerapolturev Monotherapy or Lerapolturev + Pembrolizumab  
NOTE: Cycle length for lerapolturev monotherapy or lerapolturev + pembrolizumab is 3 weeks. Lerapolturev is 
administered weekly during Cycles 1 & 2 and every 3 weeks thereafter on the days indicated in the table below. Refer to 
the table below for the timing of other study assessments to be completed within each cycle.    
 
Study Procedure3 
Screening 
Period 
Treatment 
EOT 
Visit15 
Survival 
Follow-
up16 
Cycle 1 
Cycle 2 
≥ Cycle 3  
 
 
(≤ 28D prior 
to C1D1) 
 
+3W 
(+7D) 
Q3W (+7D) 
≤28D 
after last 
treatment 
 
Informed Consent1 
X 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
Physical Exam 2,3 
X 
C1D1 
C2D1 
Day 1 of each Cycle 
X 
 
Vital Signs3 
X 
C1D1, 
C1D8, 
C1D15 
C2D1, 
C2D8, 
C2D15 
Day 1 of each Cycle 
X 
 
ECOG Performance Status3 
X 
C1D1 
C2D1 
Day 1 of each Cycle 
X 
 
PV Immunization Booster1 
≥1W, but 
≤6W before 
C1D1 
 
 
 
 
 
Adverse Events 
Continuous from signing ICF until 30 days after last dose of study therapy 
 
Concomitant Medications 
Continuous from signing ICF until 30 days after last dose of study therapy 
 
Subsequent Anticancer 
Therapy 
 
 
 
 
X 
X 
AESI, irAEs and SAEs 
Continuous from signing ICF until 90 days after last dose of study therapy or resolution/stabilization 
 
Hematology 3,4 
X 
C1D1 
C2D1 
C3D1 then Q6W (ie, at every other visit) and as clinically 
indicated 
X 
 
Chemistry3,4 
X 
C1D1 
C2D1 
C3D1 then Q6W (ie, at every other visit) and as clinically 
indicated 
X 
 
INR, PT, PTT (or aPTT) 
X 
As clinically indicated 
 
Thyroid Monitoring 3,5 
X 
Q6W (±7D) and as clinically indicated 
 
Pregnancy Test3,6 
≤2D before 
C1D1 
Q12W (±14D) 
 

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Cutaneous, Subcutaneous and 
Nodal Lesion Measurement and 
Photographs3,7 
X 
C1D1, 
C1D8, 
C1D15 
C2D1, 
C2D8, 
C2D15 
Day 1 of each Cycle 
X 
per SOC 
Tumor Imaging8 
≤6W before 
C1D1 
6 & 12W after C1D1, then Q12W thereafter. Crossover participants must have re-baseline imaging 
within 28D prior to administration of crossover C1D1 (i.e. first dose of anti-PD-1 therapy) 
per SOC 
Tissue Biopsy9  
All samples to be collected prior to 
dosing at the given timepoint 
Prior to PV 
Immunization 
Booster 
C1D8 
C2D1 
At the time of PD ± 1 week (per RECIST) 
Crossover Only: within 1 week prior to crossover C1D1, 1 
week after crossover C1D1 (pre-dose, if applicable), 3 weeks 
(+7d; pre-dose) after crossover C1D1, and at the time of PD ± 
1 week (per RECIST) on the crossover regimen  
 
 
Blood Collection10 
All samples to be collected prior to 
dosing at the given timepoint 
Prior to PV 
Immunization 
Booster 
C1D1, 
C1D8 
C2D1 
C3D1 and at the time of PD ± 1 week (per RECIST) 
Crossover Only: within 1 week prior to crossover C1D1, 1 
week after crossover C1D1 (pre-dose, if applicable), 3 weeks 
(+7d; pre-dose) after crossover C1D1, and at the time of PD ± 
1 week (per RECIST) on the crossover regimen 
 
 
Lerapolturev Administration12 
 
C1D1, 
C1D8, 
C1D15 
C2D1, 
C2D8, 
C2D15 
C3D1 and Q3W thereafter 
 
 
ARM 2: Anti-PD-1 
Administration (pembrolizumab) 
11 
 
C1D1 
C2D1 
(if given 
Q3W) 
C3D1 and Q3W or Q6W thereafter per pembrolizumab 
package insert 
 
 
Crossover from Arm 1 to Arm 
2 13 
 
If participant meets protocol-defined criteria 
 
 
Lerapolturev Shedding: Injected 
Lesion14 
 
C1D1 
(post-
injection), 
C1D4, 
C1D8, 
C1D15 
(post-
injection), 
C1D18 
C2D1, 
C2D15 
(post-
injection), 
C2D18 
C3D1 
 
 
Lerapolturev Shedding: Stool 
 
 
C2D8 
(±3D) 
 
 
 
AESI = adverse event of special interest; aPTT = activated partial thromboplastin time; C= cycle; CBC = complete blood count; CMP = comprehensive 
metabolic panel; CT = computed tomography; D = day; ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; ICF = Informed consent 
form; IgG = immunoglobulin G; INR = international normalized ratio; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; PD-1 = Programmed 
cell death protein 1; PT = prothrombin time; PTT = partial thromboplastin time; PV = poliovirus; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating 
hormone; SAE = serious adverse event; W = weeks 
1. Informed Consent must be signed prior to initiation of screening activities.  

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2. Physical Exam: The screening physical examination should be a complete physical exam of major body systems and include the general appearance 
of the participant, height and weight, vital signs (temperature, respiratory rate, blood pressure (systolic and diastolic [mmHg]), and heart rate [bpm]), 
examination of the skin, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system. 
During treatment and at the end of treatment (EOT) visit, weight assessment and limited symptom-directed physical examination are required. An 
evaluation of all skin lesions, including those injected with lerapolturev at the previous treatment visit, should be performed prior to subsequent 
lerapolturev injection.  
3. Procedures and/or Assessments unless otherwise specified should occur on D1 of each Cycle. Any assessment or procedure scheduled on the 
same day as lerapolturev and/or anti-PD-1 administration should always precede receipt of study treatments. Note that laboratory assessments (e.g. 
hematology, chemistry, thyroid monitoring) may be done up to 2 calendar days prior to Day 1 of the cycle.  
4. Hematology and Chemistry: Blood draws for hematology and chemistry occurring on the same day as study treatment should be collected prior to 
lerapolturev injection and/or prior to anti-PD-1 infusion (as applicable). Hematology should include hemoglobin, white blood cell (WBC) count with 
differential and platelet count. Chemistry measured in serum should include the following: LDH, glucose, calcium, sodium, potassium, bicarbonate, 
chloride, BUN, creatinine, total protein, albumin, ALP, AST, ALT, total bilirubin, amylase, and lipase. 
5. Thyroid Monitoring: Should include TSH, free T4, and free T3.  
6. Pregnancy Test: A pregnancy test (urine-based allowed) must be performed for all female participants of childbearing potential during Screening (≤2 
days of lerapolturev injection) and approximately every 12 weeks while on study. If a urine-based test produces an equivocal result, a serum-based 
test should be performed.  
7. Measurement of Cutaneous, Subcutaneous and Nodal Lesions: Measurement by ruler or caliper (along with photographs) should occur prior to 
lerapolturev administration to determine/verify lerapolturev injection volumes for each lesion. For timepoint response assessment of target lesions not 
visible by radiography, ruler/caliper measurement with photographs should be performed prior to lerapolturev injection.  
8. Tumor Imaging: Baseline imaging assessments should include CT of the chest, abdomen, and pelvis, a brain MRI, as well as photography of all 
cutaneous/visible lesions. Participants without evidence of central nervous system (CNS) disease at screening are not required to have brain imaging 
on study, provided clinical evidence of CNS disease does not emerge. All imaging should be performed with and without IV contrast (oral contrast can 
be used per institutional guidelines), provided participant can tolerate contrast agent (brain CT—preferably with IV contrast--is acceptable for those 
who cannot tolerate MRI). Photographic evaluation of visible lesions should precede lerapolturev injection, if occurring in the same visit. All qualifying 
scans prior to and during screening used to determine enrollment eligibility (ie, baseline scans prior to initiating anti-PD-1, as well as initial and 
confirmatory scans demonstrating disease progression per iRECIST prior to enrollment) should be provided to the central imaging vendor, where 
possible. Imaging should be performed using identical techniques and equipment, where possible. 
9. Tissue Biopsy for Biomarker Assessment: Participants are required to provide a qualifying biopsy. Archival tissue collected ≤4 months prior to Day 
1 is allowed in lieu of the qualifying biopsy, provided the participant has not received intervening systemic/intratumoral anti-cancer therapy since the 
biopsy was performed; if not available, the participant should have a qualifying biopsy taken during the Screening Period prior to polio boost 
vaccination. Biopsy of a previously irradiated lesion is not allowed unless there is documented disease progression in that lesion.  
• 
NOTE: At all timepoints, biopsies from all three sites (injected lesion, noninjected lesions and draining lymph nodes) should be collected if the 
biopsy is technically feasible and does not put the participant at significant risk. Examples of sites considered to be of significant risk include, 
but are not limited to, the following: biopsies of the brain, lung, mediastinum, pancreas, or endoscopic procedures extending beyond the 
esophagus, stomach, or bowel wall. For situations where the investigator determines biopsy of a lesion would (1) result in a 
significant decrease in the size of the lesion such that RECIST 1.1 response assessment would be confounded, or (2) increase the risk of 
lerapolturev leakage from the lesion, the mandatory biopsy for that timepoint can be waived. In addition, complete resection of target lesions is 
prohibited unless necessary for participant’s safety as determined by the investigator. 
• 
Tissue from additional biopsies taken as part of standard of care may also be collected for analysis. 

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10. Blood Collection: Participants who experience an AE of Special Interest (AESI) of cytokine release syndrome (CRS) or immune effector cell-
associated neurotoxicity syndrome (ICANS) should have a blood sample drawn as soon as possible upon learning of the AESI, in order to allow for the 
profiling of cytokine changes related to the event. 
11. Arm 2 Anti-PD-1 Administration: Participants randomized to Arm 2 should receive anti-PD-1 concurrently with lerapolturev while on study. 
Administration of the first anti-PD-1 dose should begin on C1D1 (+2 days). Where possible, participants should receive the same anti-PD-1 therapy 
that they previously failed prior to enrollment, dosed according to manufacturer’s prescribing information.  
12. Lerapolturev Administration: Up to 6 lesions may be injected with lerapolturev injection volume proportional to lesion size as determined from 
Table 7. The same or different lesion(s) may be injected at each treatment visit, as described in Section 5.3. The lerapolturev treatment cycle is Q3W 
for participants on Arm 1 and for Arm 2 or crossover participants receiving pembrolizumab, whether pembrolizumab is given Q3 or Q6W.  
• 
After Cycle 3, lerapolturev should be administered Q3W. If pembrolizumab is administered Q6W, lerapolturev should be continued Q3W.  
• 
NOTE: Participants previously treated with the Q3/4W lerapolturev schedule are allowed to receive the QW lerapolturev schedule per the guidance 
in Section 3.1.2.  
• 
Where possible, at least one target lesion should remain uninjected for as long as feasible while on study to facilitate the anti-tumor response 
assessment of non-injected target lesions 
13. Crossover from Arm 1 to Arm 2: Participants enrolled in the safety run-in or randomized to Arm 1 are allowed to crossover to Arm 2 following 
radiologic disease progression (per RECIST criteria), once a PR lasts ≥ 6 months, or after 26 weeks on study without progression or confirmed PR 
(per RECIST criteria). Where possible, participants should receive the same anti-PD-1 therapy on which they had disease progression prior to 
enrollment, which should be administered according to manufacturer’s prescribing information. The below assessments should be completed for 
participants at the time of crossover: 
• 
Tumor Imaging: All participants crossing over to Arm 2 should have a complete tumor assessment (ie, scans and ruler/caliper measurement of 
skin lesions with photography) within 28 days prior to the first cycle of the lerapolturev/anti-PD-1 combination. Scans and photographic 
ruler/caliper assessments performed to document disease progression prior to crossover are acceptable, provided they occur within 28 days prior 
to the initial treatment with the lerapolturev/anti-PD-1 combination. 
• 
Cutaneous and Subcutaneous Measurements and Imaging: For participants crossing over from Arm 1 to Arm 2, ruler/caliper measurement 
with photographs should be performed within 28 days prior to their first treatment with the lerapolturev/anti-PD-1 combination (along with scans).  
• 
Lerapolturev Administration: See Section 3.1.2 for guidance. 
• 
Tissue Biopsy: Prior to crossover, a mandatory tissue biopsy (injected lesions, noninjected lesions and draining lymph nodes) should be 
performed, within 1 week prior to the first cycle of the lerapolturev/anti-PD-1 combination (see Section 7.4); the biopsy taken at the time of PD can 
be used as the biopsy prior to the first crossover treatment cycle. Additional mandatory biopsies (injected lesions, noninjected lesions, and 
draining lymph nodes) should be performed 1 week (±2days) and 3 weeks (+7d) after Day 1 of crossover, and within 7 days of confirmed 
crossover PD. Any biopsy scheduled on same day as lerapolturev injection should be collected prior to treatment. .  
14. Lerapolturev Viral Shedding:  
• 
The individual lesion receiving the largest injection volume of lerapolturev at C1D1, C1D15, and C2D15 should be designated for swabbing during 
that treatment cycle on the days indicated above (ie, the same lesion should be swabbed at each timepoint within a given cycle). Separate swabs 
should be used to test each area in triplicate (ie, samples are not to be combined or pooled), as described. Following sample collection, the 
swabbed lesion should be wiped with alcohol, and redressed with an occlusive dressing as required.  
• 
The lesion injected with lerapolturev at C1D1, C1D15, and C2D15 should be swabbed at least 15 minutes, but less than 4 hours, after the injection 
site has been cleaned and bandaged post-lerapolturev injection, as described in Section 3.2. All other lesion swabbing timepoints have a ±1D 
window for collection, but those scheduled on the same day of a given treatment cycle must be collected prior to lerapolturev administration.  

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• 
The injection site, as well as the inside and outside of the occlusive dressing should be swabbed independently (ie, samples are not to be 
combined or pooled into a single collection tube) in triplicate (ie, 3 swabs collected per area of interest), with the corresponding swab for each 
tested area labeled and placed into its own container of viral transport medium, according to the laboratory manual. The swabbed lesion should be 
cleaned and redressed with a new occlusive dressing once lesion swabbing has been completed, as described in Section 5.3.  
• 
Stool samples may be collected at the participant’s home up to 3 days prior to or after the C2D8 clinic visit, per the lab manual.   
15. End of Treatment Visit should be performed within 28 days after the last dose of study drug(s). The visit should include a focused and symptom-
directed physical assessment, cutaneous, subcutaneous, and nodal tumor measurements (including photographs), as well as radiographic tumor 
imaging.  
16. Survival Follow-up: Scans and cutaneous, subcutaneous and nodal lesion measurements performed per SOC should still be collected for 
participants in post-EOT survival follow-up who discontinued study treatments for reasons other than disease progression. The collection of lesion 
measurement (cutaneous, subcutaneous, and nodal, and scans) performed per SOC should continue until confirmed progression or the start of the 
next anti-cancer therapy. Sites should continue to collect post-study therapies and survival status for follow-up duration 
 
 
 
 

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Table 2. 
Schedule of Assessments for Lerapolturev + Nivolumab  
NOTE: Cycle length for lerapolturev + nivolumab is 4 weeks. Lerapolturev is administered weekly during Cycles 1 & 2 and 
every 4 weeks thereafter on the days indicated in the table below. Refer to the table below for the timing of other study 
assessments to be completed within each cycle.    
 
Study Procedure3 
Screening 
Period 
Treatment 
EOT 
Visit15 
Survival 
Follow-
up16 
Cycle 1 
Cycle 2 
≥ Cycle 3  
 
 
(≤ 28D prior 
to C1D1) 
 
+4W  
(+7D) 
Q4W (+7D) 
≤28D 
after last 
treatment 
 
Informed Consent1 
X 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
Physical Exam 2,3 
X 
C1D1 
C2D1 
Day 1 of each Cycle 
X 
 
Vital Signs3 
X 
C1D1, 
C1D8, 
C1D15 
C1D22 
C2D1, 
C2D8, 
C2D15 
Day 1 of each Cycle 
X 
 
ECOG Performance Status3 
X 
C1D1 
C2D1 
Day 1 of each Cycle 
X 
 
PV Immunization Booster1 
≥1W, but 
≤6W before 
C1D1 
 
 
 
 
 
Adverse Events 
Continuous from signing ICF until 30 days after last dose of study therapy 
 
Concomitant Medications 
Continuous from signing ICF until 30 days after last dose of study therapy 
 
Subsequent Anticancer 
Therapy 
 
 
 
 
X 
X 
AESI, irAEs and SAEs 
Continuous from signing ICF until 90 days after last dose of study therapy or resolution/stabilization 
 
Hematology 3,4 
X 
C1D1 
C2D1 
C3D1 then Q8W (ie, at every other visit) and as clinically 
indicated 
X 
 
Chemistry3,4 
X 
C1D1 
C2D1 
C3D1 then Q8W (ie, at every other visit) and as clinically 
indicated 
X 
 
INR, PT, PTT (or aPTT) 
X 
As clinically indicated 
 
Thyroid Monitoring 3,5 
X 
 
X 
Day 1 of each Cycle 
X 
 
Pregnancy Test6 
≤2D before 
C1D1 
Q12W (±14D) 
 

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Cutaneous, Subcutaneous, and 
Nodal Lesion Measurement and 
Photographs3,7 
X 
C1D1, 
C1D8, 
C1D15 
C1D22 
C2D1, 
C2D8, 
C2D15 
Day 1 of each Cycle 
X 
per 
SOC 
Tumor Imaging8 
≤6W before 
C1D1 
6 & 12W after C1D1, then Q12W thereafter. Crossover participants must have re-baseline imaging 
within 28D prior to administration of crossover C1D1 (i.e. first dose of anti-PD-1 therapy) 
per 
SOC 
Tissue Biopsy9  
All samples to be collected prior to 
dosing at the given timepoint 
Prior to PV 
Immunization 
Booster 
C1D8, 
C1D22 
 
 At the time of PD ± 1 week (per RECIST) 
Crossover Only: within 1 week prior to crossover C1D1, 1 
week after crossover C1D1 (pre-dose, if applicable), 3 weeks 
(+7d; pre-dose) after crossover C1D1, and at the time of PD 
± 1 week (per RECIST) on the crossover regimen 
 
 
Blood Collection10 
All samples to be collected prior to 
dosing at the given timepoint 
Prior to PV 
Immunization 
Booster 
C1D1, 
C1D8, 
C1D22 
C2D15 
At the time of PD ± 1 week (per RECIST) 
Crossover Only: within 1 week prior to crossover C1D1, 1 
week after crossover C1D1 (pre-dose, if applicable), 3 weeks 
(+7d; pre-dose) after crossover C1D1, and at the time of PD 
± 1 week (per RECIST) on the crossover regimen 
 
 
Lerapolturev Administration12 
 
C1D1, 
C1D8, 
C1D15 
C1D22 
C2D1, 
C2D8, 
C2D15 
C3D1 and Q4W thereafter 
 
 
ARM 2: Anti-PD-1 
Administration (nivolumab) 11 
 
C1D1 
(C1D15 if 
nivolumab 
Q2W) 
C2D1 
(C2D15 if 
nivolumab 
Q2W) 
C3D1 and Q2W or Q4W thereafter per nivolumab package 
insert 
 
 
Crossover from Arm 1 to Arm 
2 13 
 
If participant meets protocol-defined criteria 
 
 
Lerapolturev Shedding: Injected 
Lesion14 
 
C1D1 
(post-
injection), 
C1D4, 
C1D8, 
C1D15 
(post-
injection), 
C1D18 
C1D22 
C2D8 
(post-
injection), 
C2D11, 
C2D15 
 
 
 
Lerapolturev Shedding: Stool 
 
 
C2D1 
(±3D) 
 
 
 
AESI = adverse event of special interest; aPTT = activated partial thromboplastin time; C= cycle; CBC = complete blood count; CMP = comprehensive 
metabolic panel; CT = computed tomography; D= day; ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; ICF = Informed consent 

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form; IgG = immunoglobulin G; INR = international normalized ratio; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; PD-1 = 
Programmed cell death protein 1; PT = prothrombin time; PTT = partial thromboplastin time; PV = poliovirus; T3 = triiodothyronine; T4 = thyroxine; TSH = 
thyroid stimulating hormone; SAE = serious adverse event; W = weeks 
1. Informed Consent must be signed prior to initiation of screening activities.  
2. Physical Exam: The screening physical examination should be a complete physical exam of major body systems and include, the general 
appearance of the participant, height and weight, vital signs (temperature, respiratory rate, blood pressure (systolic and diastolic [mmHg]), and heart 
rate [bpm]), examination of the skin, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous 
system. During treatment and at the end of treatment (EOT) visit, weight assessment and limited symptom-directed physical examination are required. 
An evaluation of all skin lesions, including those injected with lerapolturev at the previous treatment visit, should be performed prior to subsequent 
lerapolturev injection.  
3. Procedures and/or Assessments unless otherwise specified should occur on D1 of each Cycle. Any assessment or procedure scheduled on the 
same day as lerapolturev and/or anti-PD-1 administration should always precede receipt of study treatments. Note that laboratory assessments (e.g. 
hematology, chemistry, thyroid monitoring) may be done up to 2 calendar days prior to Day 1 of the cycle.  
4. Hematology and Chemistry: Blood draws for hematology and chemistry occurring on the same day as study treatment should be collected prior to 
lerapolturev injection and/or prior to anti-PD-1 infusion (as applicable). Hematology should include hemoglobin, white blood cell (WBC) count with 
differential and platelet count. Chemistry measured in serum should include the following: LDH, glucose, calcium, sodium, potassium, bicarbonate, 
chloride, BUN, creatinine, total protein, albumin, ALP, AST, ALT, total bilirubin, amylase, and lipase. 
5. Thyroid Monitoring: Should include TSH, free T4, and free T3.  
6. Pregnancy Test: A pregnancy test (urine-based allowed) must be performed for all female participants of childbearing potential during Screening (≤2 
days of lerapolturev injection) and approximately every 12 weeks while on study. If a urine-based test produces an equivocal result, a serum-based 
test should be performed.  
7. Measurement of Cutaneous, Subcutaneous, and Nodal Lesions: Measurement by ruler or caliper (along with photographs) should occur prior to 
lerapolturev administration to determine/verify lerapolturev injection volumes for each lesion. For timepoint response assessment of target lesions not 
visible by radiography, ruler/caliper measurement with photographs should be performed prior to lerapolturev injection.  
8. Tumor Imaging: Baseline imaging assessments should include CT of the chest, abdomen, and pelvis, a brain MRI, as well as photography of all 
cutaneous/visible lesions. Participants without evidence of central nervous system (CNS) disease at screening are not required to have brain imaging 
on study, provided clinical evidence of CNS disease does not emerge. All imaging should be performed with and without IV contrast (oral contrast can 
be used per institutional guidelines), provided participant can tolerate contrast agent (brain CT—preferably with IV contrast--is acceptable for those 
who cannot tolerate MRI). Photographic evaluation of visible lesions should precede lerapolturev injection, if occurring in the same visit. All qualifying 
scans prior to and during screening used to determine enrollment eligibility (ie, baseline scans prior to initiating anti-PD-1, as well as initial and 
confirmatory scans demonstrating disease progression per iRECIST prior to enrollment) should be provided to the central imaging vendor, where 
possible. Imaging should be performed using identical techniques and equipment, where possible. 
9. Tissue Biopsy for Biomarker Assessment: Participants are required to provide a qualifying biopsy. Archival tissue collected ≤4 months prior to Day 
1 is allowed in lieu of the qualifying biopsy, provided the participant has not received intervening systemic/intratumoral anti-cancer therapy since the 
biopsy was performed; if not available, the participant should have a qualifying biopsy taken during the Screening Period prior to polio boost 
vaccination. Biopsy of a previously irradiated lesion is not allowed unless there is documented disease progression in that lesion.  
• 
NOTE: At all timepoints, biopsies from all three sites (injected lesion, noninjected lesions and draining lymph nodes) should be collected if the 
biopsy is technically feasible and does not put the participant at significant risk. Examples of sites considered to be of significant risk include, but 
are not limited to, the following: biopsies of the brain, lung, mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, 
stomach, or bowel wall. For situations where the investigator determines biopsy of a lesion would (1) result in a significant decrease in the size of 

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the lesion such that RECIST 1.1 response assessment would be confounded, or (2) increase the risk of lerapolturev leakage from the 
lesion, the mandatory biopsy for that timepoint can be waived. In addition, complete resection of target lesions is prohibited unless necessary 
for participant’s safety as determined by the investigator. 
• 
Tissue from additional biopsies taken as part of standard of care may also be collected for analysis. 
10. Blood Collection: Participants who experience an AE of Special Interest (AESI) of cytokine release syndrome (CRS) or immune effector cell-
associated neurotoxicity syndrome (ICANS) should have a blood sample drawn as soon as possible upon learning of the AESI, in order to allow for the 
profiling of cytokine changes related to the event. 
11. Arm 2 Anti-PD-1 Administration: Participants randomized to Arm 2 should receive anti-PD-1 concurrently with lerapolturev while on study. 
Administration of the first anti-PD-1 dose should begin on C1D1 (+2 days). Where possible, participants should receive the same anti-PD-1 therapy 
that they previously failed prior to enrollment, dosed according to manufacturer’s prescribing information. The lerapolturev treatment cycle is Q4W for 
participants receiving nivolumab, whether nivolumab is given Q2 or Q4W.    
12. Lerapolturev Administration: Up to 6 lesions may be injected with lerapolturev injection volume proportional to lesion size as determined from 
Table 7. The same or different lesion(s) may be injected at each treatment visit, as described in Section 5.3.   
• 
After Cycle 3, lerapolturev should be administered Q4W in Arm 2 participants receiving nivolumab. If nivolumab is administered Q2W, lerapolturev 
should be continued Q4W. 
• 
NOTE: Participants previously treated with the Q3/4W lerapolturev schedule are allowed to receive the QW lerapolturev schedule per the 
guidance in Section 3.1.2.  
• 
Where possible, at least one target lesion should remain uninjected for as long as feasible while on study to facilitate the anti-tumor response 
assessment of non-injected target lesions 
13. Crossover from Arm 1 to Arm 2: Participants enrolled in the safety run-in or randomized to Arm 1 are allowed to crossover to Arm 2 following 
radiologic disease progression (per RECIST criteria), once a PR lasts ≥ 6 months, or after 26 weeks on study without progression or confirmed PR 
(per RECIST criteria). Where possible, participants should receive the same anti-PD-1 therapy on which they had disease progression prior to 
enrollment, which should be administered according to manufacturer’s prescribing information. The below assessments should be completed for 
participants at the time of crossover: 
• 
Tumor Imaging: All participants crossing over to Arm 2 should have a complete tumor assessment (ie, scans and ruler/caliper measurement of 
skin lesions with photography) within 28 days prior to the first cycle of the lerapolturev/anti-PD-1 combination. Scans and photographic 
ruler/caliper assessments performed to document disease progression prior to crossover are acceptable, provided they occur within 28 days prior 
to the initial treatment with the lerapolturev/anti-PD-1 combination. 
• 
Cutaneous and Subcutaneous Measurements and Imaging: For participants crossing over from Arm 1 to Arm 2, ruler/caliper measurement 
with photographs should be performed within 28 days prior to their first treatment with the lerapolturev/anti-PD-1 combination (along with scans).  
• 
Lerapolturev Administration: See Section 3.1.1 for guidance. 
• 
Tissue Biopsy: Prior to crossover, a mandatory tissue biopsy (injected lesions, noninjected lesions and draining lymph nodes) should be 
performed, within 1 week prior to the first cycle of the lerapolturev/anti-PD-1 combination (see Section 7.4); the biopsy taken at the time of PD can 
be used as the biopsy prior to the first crossover treatment cycle. Additional mandatory biopsies (injected lesions, noninjected lesions, and 
draining lymph nodes) should be performed 1 week (±2days) and 3 weeks (+7d) after Day 1 of crossover, and within 7 days of confirmed 
crossover PD. Any biopsy scheduled on same day as lerapolturev injection should be collected prior to treatment.  
14. Lerapolturev Viral Shedding:  
• 
The individual lesion receiving the largest injection volume of lerapolturev at C1D1, C1D15, and C2D8 should be designated for swabbing during 
that treatment cycle on the days indicated above (ie, the same lesion should be swabbed at each timepoint within a given cycle). Separate swabs 

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should be used to test each area in triplicate (ie, samples are not to be combined or pooled), as described. Following sample collection, the 
swabbed lesion should be wiped with alcohol, and redressed with an occlusive dressing as required.  
• 
The lesion injected with lerapolturev at C1D1, C1D15, and C2D8 should be swabbed at least 15 minutes, but less than 4 hours, after the injection 
site has been cleaned and bandaged post-lerapolturev injection, as described in Section 3.2. All other lesion swabbing timepoints have a ±1D 
window for collection, but those scheduled on the same day of a given treatment cycle must be collected prior to lerapolturev administration. 
• 
The injection site, as well as the inside and outside of the occlusive dressing should be swabbed independently (ie, samples are not to be 
combined or pooled into a single collection tube) in triplicate (ie, 3 swabs collected per area of interest), with the corresponding swab for each 
tested area labeled and placed into its own container of viral transport medium, according to the laboratory manual. The swabbed lesion should be 
cleaned and redressed with a new occlusive dressing once lesion swabbing has been completed, as described in Section 5.3.  
• 
Stool samples may be collected at the participant’s home up to 3 days prior to or after the C2D1 clinic visit, per the lab manual.   
15. End of Treatment Visit should be performed within 28 days after the last dose of study drug(s). The visit should include a focused and symptom-
directed physical assessment, cutaneous, subcutaneous, and nodal tumor measurements (including photographs), as well as radiographic tumor 
imaging.  
16. Survival Follow-up: Scans and cutaneous, subcutaneous, and nodal lesion measurements performed per SOC should still be collected for participants 
in post-EOT survival follow-up who discontinued study treatments for reasons other than disease progression. The collection of lesion measurement 
(cutaneous, subcutaneous and nodal and scans) performed per SOC should continue until confirmed progression or the start of the next anti-cancer 
therapy. Sites should continue to collect post-study therapies and survival status for follow-up duration. 

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1 
INTRODUCTION 
1.1 
Background 
Metastatic melanoma is often a fatal disease, with less than 28% of patients surviving 
5 years5. However, many patients are diagnosed with early-stage disease, where if well 
managed, the chance of cure can be quite high. Unfortunately, patients who recur or are 
diagnosed with advanced disease suffer a more aggressive disease course, making the 
likelihood of cure much less. For patients with Stage III disease, over 70% of patients’ 
first recurrence was regional/nodal or systemic8, meaning localized therapies (eg, surgery 
or isolated limb perfusion) are likely to have limited effect. Therefore, systemic therapies 
are often indicated, to mitigate further systemic spread and extend life.  
The past 10 years has seen an increase in the number of systemic therapies available to 
melanoma patients able to improve outcomes. Most notable among these were the FDA 
approval of immune therapies able to specifically target PD-1/L1 and CTLA-4, which can 
be used alone or in combination in the front-line setting. When used as a single-agent, 
less than 40% of patients respond to anti-PD-1 therapy (ie, more than 60% have primary 
PD-1 resistance)1,2. Of those who do respond, 25% or more go on to develop an acquired 
resistance3. While combining PD-1 and CTLA-4 blockade can increase the response rate 
to around 50%, this combination is associated with significant toxicity, with clinical studies 
demonstrating ~55% of patients experience Gr 3/4 AEs4. Beyond immunotherapies, 
treatment options are limited. Patients whose tumors harbor BRAF mutations have the 
option to receive targeted therapies against BRAF and the mitogen-activated protein 
kinase /extracellular signal-regulated kinase (MEK) pathway. Although BRAF/MEK based 
targeted therapy has been shown to improve survival, progression free survival is often 
less than 1 year and systemic toxicities are common9–11.  
Recently, there has been interest in determining whether there is any potential for clinical 
benefit from anti-PD-1 re-challenge in patients who previously progressed on anti-PD-
1/L1 or from treating beyond progression (TBP) in patients that are currently failing an 
anti-PD-1/L1. To the Sponsor’s knowledge, no study has formally addressed whether 
anti-PD-1 rechallenge following discontinuation is beneficial12, which may suggest this 
approach is not viable. For TBP, a pooled FDA analysis of melanoma clinical trials that 
allowed anti-PD-1 TBP has shown that continued anti-PD-1 beyond RECIST-defined 
progression can result in an ORR of up to 19%13. However, 66% of those treated beyond 
progression in this analysis were deemed to have progressed at their first post-treatment 
visit, and the median duration of TBP was only 1.41 months (IQR: 0.69–4.86 months). Of 
these patients with RECIST-defined PD at their first scan, approximately 36% 
discontinued due to the appearance of a new lesion without target lesion progression, 
which can be an immunoprogressive phenomenon that results in subsequent lesion 
contraction. In addition, the protocols allowing TBP within this pooled analysis had 
specific criteria to identify which patients were allowed to continue anti-PD-1, including 

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absence of clinical progression (including laboratory values), no decline in performance 
status, and absence of disease progression in areas requiring immediate medical 
treatment13. Given median time to response to anti-PD-1 is 2 to 3 months14,15, it is possible 
that TBP in this select, well-performing population allowed more patients time for 
treatment response to occur. In contrast, had the definition of anti-PD-1/L1 resistance 
from the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Task 
force been applied to the population of this study (ie, ≥6 weeks of therapy with 
confirmation of PD by repeat imaging at least 4 weeks later), many patients would not 
have been included7. Thus, one can estimate that the true ORR for anti-PD-1 treatment 
beyond progression in patients treated per the SITC Immunotherapy Resistance Task 
Force definition of anti-PD-1 resistance is no greater than 6%, as nearly two-thirds of 
patients included within the TBP cohort would be excluded because of discontinuation 
without confirmation of progression 4 weeks later.  
In addition, a recent study investigated ipilimumab alone or in combination with anti-PD-
1 in an anti-PD-1 refractory population. ORR in the combination arm was 31% vs 12% for 
ipilimumab alone, and OS at 1-year for the combination was also superior versus 
ipilimumab alone, suggesting that the addition of new immunotherapies to failing anti-
PD-1 therapy improves outcomes when compared to a switch strategy16. However, Grade 
3 or greater toxicities occurred in over 30% of the patients receiving ipilimumab, whether 
alone or in combination, meaning risk to patient safety remains a concern. Taken 
together, there is significant interest in the development of novel immunotherapeutic 
agents that can increase the anti-tumor response for the broad proportion of melanoma 
patients unable to benefit from currently approved options.  
Lerapolturev (formerly known as PVSRIPO) is a recombinant rhinovirus/polio virus 
chimera that may affect anti-tumor activity through two mechanisms: direct tumor cell 
killing and induction of a secondary anti-tumor immune response17. Lerapolturev has 
demonstrated clinical activity in patients with primary brain tumors18.   Preliminary data 
suggest lerapolturev has activity, either alone or in combination with an anti-PD-1 
inhibitor, in PD-1 refractory melanoma when injected intratumorally (summarized below). 
Therefore, this study is designed to further characterize lerapolturev activity in 
advanced/metastatic anti-PD-1/L1 refractory melanoma.  
1.2 
Rationale 
Even when accepting the risk for significant toxicity, most melanoma patients are unable 
to benefit from currently approved immunotherapy combinations, which suggests 
alterative mechanisms for immune activation are required to safely trigger an anti-tumor 
immune response. One alternative approach is the use of oncolytic viruses, which 
depending on the virus, can cause direct tumor cell killing and secondary anti-tumor 
immune response. Talimogene laherparepvec (T-VEC, Imlygic), a modified herpes 
simplex type 1 virus expressing human granulocyte macrophage colony-stimulating factor 
(GM-CSF), has been approved to treat melanoma based on increased DRR (defined as 

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the percent of patients with complete response (CR) or partial response (PR) maintained 
continuously for a minimum of 6 months) compared to GM-CSF alone: The DRR was 
16.3% in the IMLYGIC arm and 2.1% in the GM-CSF arm in the overall study population. 
There was no statistically significant difference in overall survival (OS) between the 
IMLYGIC and the GM-CSF arms; the median OS in the overall study population was 22.9 
months in the IMLYGIC arm and 19.0 months in the GM-CSF arm (p = 0.116)19.  
However, data from a Phase 1b trial investigating T-VEC (administered by intratumoral 
injection every 2 weeks) in combination with pembrolizumab in advanced anti-PD-1 naïve 
melanoma showed >60% of participants achieved an objective response, with multiple 
responses ongoing at the time of publication (median OS and progression-free survival 
not reached)20. Response to the combination was associated with increased CD8+ T-cell 
infiltration and increased expression of programmed death-ligand 1 (PD-L1; the 
immunosuppressive ligand of PD-1) following treatment, suggesting an oncolytic virus in 
combination with anti-PD-1 could potentially overcome mechanisms of anti-PD-1 
resistance.  
Although these data are encouraging, the follow-on randomized, placebo-controlled 
Phase 3 study failed to show a survival benefit and was halted for futility21, suggesting 
alternative approaches (such as optimized dosing schedules) may be required to 
translate apparent immune activation into clinical benefit – particularly in populations 
known to be refractory to anti-PD-1/L1-based therapies. In support of this hypothesis, 
preliminary data from an ongoing Phase 2 study investigating intratumoral injection of 
BO-112 (a non-coding double-stranded RNA formulated with the cationic carrier 
polyethylenimine and administered weekly x 7 followed by every 3-week maintenance) in 
combination with pembrolizumab has shown activity in anti-PD-1 refractory melanoma. 
BO-112 induces innate immunity through activation of RNA viral response sensors (eg, 
RIG-I and MDA5), which resulted in a 27% ORR when combined with pembrolizumab, 
suggesting a more persistent stimulation of innate immunity may be required to improve 
immune-mediated anti-tumor response.   
Given these data, it is hypothesized that weekly administration of lerapolturev in the 
setting of a vaccine-generated immune recall response will more effectively activate 
innate RNA viral response pathways when compared to oncolytic viruses like T-VEC or 
non-coding double-stranded RNA like BO-112. Lerapolturev is a live-attenuated, serotype 
1 poliovirus vaccine (Sabin) that was genetically modified by exchange of the cognate 
internal ribosomal entry site (IRES) with that of human rhinovirus type 2, thus eliminating 
its neurovirulence potential22. Infection of cells by lerapolturev is mediated via the 
poliovirus receptor (PVR), CD155--a cell adhesion molecule of the Ig-like superfamily that 
is broadly expressed in solid tumors, including melanoma23.  Upon infection, lerapolturev 
is directly cytotoxic to neoplastic cells, which offer ideal conditions for viral IRES-mediated 
ribosome recruitment due to the unhinged protein synthesis required in cancer cells24. In 
contrast, lerapolturev infection of antigen-presenting macrophages and dendritic cells 

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(DC) results in a non-lethal infection, and activation of innate interferon gamma (IFNγ) 
pathways to increase immune effector responses directed against tumor neoantigens17, 
thus driving a secondary immune response. As shown in Figure 1, lerapolturev infection 
resulted in death of breast and melanoma tumor cells without affecting DC viability. The 
principal elements determining lerapolturev tumor tropism, tumor-specific cell killing 
(Figure 1A & B), neuronal incompetence/safety, and immunogenicity are well established 
empirically17,25. Notably, lerapolturev infection in DCs significantly increased PD-L1 
expression (Figure 1C), suggesting lerapolturev in combination with anti-PD-1 blockade 
in the tumor is rational, as the combination could further enhance the immune system’s 
ability to specifically recognize and destroy tumor.  
 
Figure 1. Lerapolturev is directly lethal to breast and melanoma cell lines, yet 
lerapolturev infection of DCs is sublethal and induces sustained 
proinflammatory cytokine production. 
In further support of this rationale, data from an ongoing Phase 1 dose-finding study 
investigating lerapolturev in anti-PD-1 refractory melanoma (NCT03712358) suggests 
that lerapolturev is well-tolerated and has anti-tumor activity in this difficult to treat 
population. As of 23 March 2021, 12 participants were enrolled in the study, each 
receiving a single lerapolturev injection into a single lesion in up to 3 separate treatments. 
There were no SAEs noted; all AEs were Grade 1 or 2, with all but two lerapolturev-
related AEs (n=1 hot flash and n=1 fatigue; both Grade 1) localized to the injected 
cutaneous, subcutaneous or nodal lesion. Despite the limited number of treatments 
administered, four of the 12 participants achieved an objective response, including 2 PRs 
which were determined to be pathologic complete responses (pCR) upon biopsy 
(remaining lesions contained melanophages only, without evidence of melanoma). 
Among participants who received 3 lerapolturev injections (maximum number 
administered), objective responses were observed in 4/6 (67%) participants.  In addition, 
most participants were subsequently re-challenged with anti-PD-1 after lerapolturev, 

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which resulted in durable disease control in 3 additional participants, including a PR and 
a pCR6. Taken together, these data suggest lerapolturev is not only safe and well-
tolerated, but that lerapolturev could have direct anti-tumor activity in an anti-PD-1 
resistant melanoma population and could act synergistically in combination with anti-PD-
1.  
Given the safety and anti-tumor activity noted in Phase 1 following limited lerapolturev 
treatment, the purpose of LUMINOS-102 is to characterize the safety and efficacy of 
lerapolturev when injected into multiple tumors over time, as well as to assess the 
antitumor activity of lerapolturev in combination with anti-PD-1. This study was originally 
designed to test lerapolturev injection in up to 6 lesions (or max dose of 6 x 108 TCID50) 
given every 3 to 4 weeks, concurrent with or without anti-PD-1 antibody therapy, until 
progression. Despite a 6-fold increase in lerapolturev dose relative to the dose evaluated 
in the Phase 1 study, all AEs considered related to lerapolturev, or anti-PD-1 remain 
Grade 1 or 2; no dose-limiting toxicities (DLTs), treatment-related serious AEs (SAEs) or 
signs and symptoms of cytokine release syndrome were reported in the 17 participants 
treated as of the 10 December 2021 data cutoff (see Table 3 and Table 4). Therefore, 
based on the encouraging safety data generated with lerapolturev to date, together with 
the observation that more frequent administration of intratumoral therapies with similar 
mechanisms of action is tolerable and able to induce anti-tumor responses in patients 
with anti-PD-1 resistant melanoma, the safety and efficacy of lerapolturev given weekly 
for 7 weeks followed by administration every 3 or 4-weeks (maintenance) at a dose of up 
to 1.6 x 109 TCID50, as monotherapy and in combination with anti-PD-1 therapy will be 
tested.  
1.2.1 
Nonclinical Studies 
Refer to the lerapolturev Investigator's Brochure (IB) for details on nonclinical and 
preclinical studies. In animal tumor models, oncolytic PVs elicit efficient anti-neoplastic 
effects resulting in tumor regression and, eventually, destruction17. This includes 
histologic evidence for direct, virus-mediated tumor cell killing and indirect, host-mediated 
inflammatory responses directed against tumor.  
 
As described in the IB, a murine-specific version of lerapolturev called mRIPO was highly 
active in a melanoma mouse model26.  B16-F10.9-OVA-CD155 tumor cells were 
implanted in the flank of mice and treated with a single intratumoral injection of DMEM 
(control) or mRIPO (5x107 TCID50). mRIPO therapy significantly delayed tumor growth as 
measured by tumor volume (Figure 2B) and increased overall survival (Figure 2C). 
mRIPO therapy, but not the DMEM control, produced anti-tumor cytotoxic T lymphocytes 
(CTLs): cells harvested from draining inguinal lymph nodes exhibited cytotoxicity against 
EL4 thymoma cells expressing TRP-2 (B16-F10 melanoma antigen), OVA (B16-F10-OVA 
antigen), or B16-F10.9-OVA-CD155 cells themselves (Figure 2D). Effector T cells from 
control treated mice exhibited minimal cytotoxicity against any of the tested target cells 

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(Figure 2D). Analysis of cytokines in supernatant revealed increased granzyme B, IFN-γ, 
and TNF-α secretion only in the mRIPO-treated group (Figure 2E), which corroborates 
CTL activity observed in Figure 2D.  
 
Systemic T cell activation also occurred in spleens harvested 14 days after mRIPO 
treatment. Splenocytes were co-cultured with B16-F10.9-OVA-CD155 cells for 2 days and 
supernatant was assessed for T cell effector cytokines and granzyme B. Splenocytes 
from mRIPO-treated tumor-bearing mice exhibited T cell effector function against B16-
F10.9-OVA-CD155 cells (Figure 2F). 
 
 
Figure 2. 
Lerapolturev restricts tumor growth and produces antigen-specific 
anti-tumor immunity25 
A. Cytotoxicity characteristics of mRIPO in murine melanoma B16-F10.9-OVA-CD155 cells. B., C. 
Subcutaneous B16-F10.9-OVA-CD155 tumors were implanted in C57BL/6-CD155 mice and treated when 
the volume was ~50-100 mm3 (~15-18 days post tumor implant). Tumors were injected with either control 
(DMEM) or mRIPO in a volume of 20 µl. Tumor volume was measured (n = 11 per group) on the days 
indicated. Mice were sacrificed when the tumor volume reached 1000 mm3, data from two pooled 
experiments are shown. D. Tumor draining inguinal lymph nodes were harvested from mice (n=4) 7 days 
post treatment with control DMEM/mRIPO and re-stimulated with antigen expressing cells for 5 days. Re-
stimulated cells were harvested, washed, and tested for lytic activity against B16-F10.9-OVA cells or EL4 

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cells electroporated with RNA encoding: GFP (control), TRP-2 (melanoma antigen), or OVA.  E. 
Supernatant from the CTL assay in D. was tested for markers of T cell activation and lytic activity by ELISA. 
F. B16-F10.9-OVR-CD155 tumor bearing mice were treated with control DMEM/mRIPO and spleens were 
harvested 14 days after treatment (n=4). Splenocytes from individual mice were co-cultured with B16-
F10.9-OVA-CD155 cells (5:1 ratio) (48h). Supernatant was harvested and tested for markers of T cell 
activation and lytic activity by ELISA. G. Tumor draining inguinal lymph nodes were harvested following 
treatment with control DMEM/mRIPO and individually re-stimulated in vitro. After 5 days, re-stimulated cells 
were harvested and analyzed for CD4 and CD8 T cells by flow cytometry. Melanoma antigen TRP-2 specific 
response was assessed using a H-2Kb TRP-2 tetramer (right panel). TRP-2 specific responses were 
compared using student t test and p<0.05. 
 
Istari and collaborators have conducted preclinical studies to support lerapolturev plus 
anti-PD1 therapy in this setting, which in summary have produced the following results: 
• Up-regulation of PD-L1 expression in lerapolturev infected macrophages and 
dendritic cells, suggesting lerapolturev in combination with anti-PD-1 blockade in 
the tumor is rational17,26. 
• Lerapolturev infection of tumor-associated macrophages (TAMs), and type-I/III 
interferon dominant antiviral inflammation of the nonmalignant tumor 
microenvironment (TME), instigate polyfunctional antitumor CD8 T cell 
responses27.  This leads to upregulation of the PD1 immune checkpoint on 
tumor-infiltrating T cells.  Thus, lerapolturev’s mechanism of action is synergistic 
with blockade of PD-1/L1 interaction. 
• Synergy of lerapolturev and anti-PD-1 therapy has been demonstrated in a 
mouse glioma model (refer to lerapolturev IB). 
Lerapolturev was subjected to extensive dose-range finding, toxicology, biodistribution, 
shedding and neutralizing antibody tests with intrathalamic inoculation of up to 5 x 109 
TCID50 of lerapolturev in M. Fascicularis28. These revealed: (i) absence of morbidity and 
mortality; (ii) absence of neuropathological signs consistent with virus-induced central 
nervous system (CNS) damage; (iii) absence of virus dissemination from the brain or 
viremia; (iv) absence of extraneural replication; (v) absence of shedding with saliva, urine 
or stool; (vi) presence of a neutralizing antibody response. 
1.2.2 
Clinical Studies 
1.2.2.1 
 Lerapolturev in patients with recurrent glioblastoma (rGBM) 
The safety and efficacy of lerapolturev monotherapy and lerapolturev in combination with 
pembrolizumab in patients with recurrent glioblastoma multiforme (rGBM) is currently 
under investigation. Lerapolturev monotherapy has been administered intratumorally to 
more than 190 rGBM participants via convection enhanced delivery (CED). The first-in-
human Phase I (NCT01491893) evaluated 7 lerapolturev doses, ranging from 1 x 107 and 

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1 x 1010 TCID5018. Across all doses tested, one dose limiting toxicity (DLT) of intracranial 
hemorrhage due to removal of the infusion catheter post infusion was observed in a single 
participant. No other DLTs were reported. The most commonly (≥30% of total 
participants) reported treatment-related AEs were consistent with the signs and 
symptoms expected to be observed with increased peritumoral edema resulting from 
lerapolturev induced inflammation after intratumoral infusion of the brain tumor. There 
was no evidence of viral encephalomyelitis, poliomyelitis, meningitis, or systemic 
autoimmune reactions in any participant treated at any dose level.  
 
For the follow-on Phase 2 study of lerapolturev monotherapy in rGBM (NCT02986178), 
a dose of 5 x 107 TCID50 delivered via CED was selected. The most commonly (≥30% of 
total participants) reported treatment-related AEs were headache (62.0%), hemiparesis 
(57.9%), seizure (40.5%), and aphasia (30.6%). This AE profile is consistent with the 
treatment-related AEs observed during Phase 1, which are signs and symptoms expected 
to be observed with increased peritumoral edema resulting from lerapolturev-induced 
inflammation after intratumoral infusion of the brain tumor. With a median follow-up of 
17.1 months (range: 13.1 to 46), six participants had PRs per investigator determination 
and median OS was 12.0 months. Landmark OS at 12 and 24 months were 50% and 
17%, which taken together is consistent with the efficacy results observed in Phase 1.  
 
LUMINOS-101 (NCT04479241) is an ongoing single-arm Phase 2 study investigating the 
safety and efficacy of a single intratumoral infusion of lerapolturev (5 x 107 TCID50) in 
combination with intravenous pembrolizumab (200mg every three weeks) in adults with 
rGBM. No DLTs were reported during the safety run-in (n=3). As of 16 September 2021, 
15 participants were enrolled and the most common AEs (≥25% of total participants) 
regardless of relatedness were headache (66.7%), nausea (33.3%), fatigue (26.7%), and 
peritumoural oedema (26.7%). The most common lerapolturev-related AEs (≥15% of total 
participants) were headache (66.7%), peritumoural oedema (26.7%), cognitive disorder 
(20%), dizziness (20.0%), fatigue (20.0%), and hemiparesis (20.0%). These data suggest 
that the addition of anti-PD-1 therapy (ie, pembrolizumab) does not significantly affect the 
safety profile of lerapolturev, and the combination of lerapolturev and anti-PD-1 therapy 
is tolerable.  Furthermore, there was no evidence of viral encephalomyelitis, poliomyelitis, 
meningitis, or systemic autoimmune reactions in any participant receiving lerapolturev 
combined with pembrolizumab. For more information, consult the IB.  
 
1.2.2.2 
Lerapolturev in patients with melanoma  
Lerapolturev has been administered via intratumoral injection (1 x 108 TCID50 per lesion 
per visit) to 12 participants in a Phase 1 open-label study with unresectable and/or 
metastatic anti-PD-1 refractory melanoma (as defined by the investigator) as of 23 March 
2021 (NCT03712358). No serious adverse events (SAEs) or dose-limiting toxicities 
(DLTs) were observed, and administration of 1 x 108 TCID50 lerapolturev to one lesion/visit 

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for up to three successive visits was well tolerated. This included 5 participants that 
received 3 injections of lerapolturev who had received prior anti-PD-1 therapy within 30 
days prior to administration of lerapolturev (and thus had anti-PD1 therapy on board 
during lerapolturev); none of these participants experienced systemic toxicities. All AEs 
were Grade 1 or 2 in severity (pruritis [58%] and erythema [50%]) and primarily localized 
to the injected lesion(s).  
 
Based on the favorable tolerability profile, and encouraging preliminary anti-tumor activity 
(33% ORR per irRC) noted in Phase 1, this study (NCT04577807) was designed to test 
the safety and efficacy of lerapolturev alone or in combination with anti-PD-1 therapy, in 
participants with unresectable melanoma who meet the more rigorous and objective 
definition for anti-PD-1 resistance, as described in the SITC Immunotherapy Resistance 
Task Force Guidance7. Despite a 6-fold increase in the total maximum lerapolturev dose 
relative to Phase 1 (ie, 6 x 108 TCID50 versus 1 x 108 TCID50 in Phase 1) and/or injection 
of up to 6 lesions per treatment visit (compared to 1 lesion/visit in Phase 1), lerapolturev 
remains well tolerated, whether given alone or when combined with anti-PD-1 therapy.  
As summarized in Table 3 and Table 4, 17 participants were treated with lerapolturev 
monotherapy (n=11) or lerapolturev combined with anti-PD-1 therapy (n=6) as of the 10 
December 2021 data cutoff. Additionally, 7 lerapolturev monotherapy participants 
crossed over to receive the lerapolturev/anti-PD-1 combination.  
 
An overall summary of AEs can be found in Table 3. No DLTs, lerapolturev AEs of special 
interest, treatment-related Grade ≥3 AEs, treatment-related SAEs, or Grade 5 AEs 
regardless of relationship were reported. The most common (of total participants) AEs 
regardless of relationship were vomiting (17.6%), constipation (11.8%), fatigue (11.8%), 
hypertension (11.8%), nausea (11.8%), pain in extremity (11.8%), pyrexia (11.8%), and 
tumour pain (11.8%). The only AE related to lerapolturev that was reported in more than 
1 participant was fatigue, which was observed in 2 participants (11.8%) (Table 4). There 
were no Grade ≥3 AEs that occurred in more than 1 participant and none were related to 
either lerapolturev or anti-PD-1 therapy. No participant reported symptoms of CRS or 
immune effector cell associated neurotoxicity syndrome (ICANS). (Table 3). With regards 
to efficacy, the best anti-tumor responses observed as of the data cutoff have been stable 
disease. Together, these data suggest further optimization of the lerapolturev dose and/or 
schedule may be required to rekindle immunotherapy responsiveness in the truly 
refractory population. For more information, consult the IB. 

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Table 3. 
LUMINOS-102 Overall Summary of Adverse Events as of 10DECEMBER2021 
 
Summary 
Lerapolturev 
Monotherapy, 
Safety Run-in1 
(N=6) 
Lerapolturev 
Monotherapy 
(Arm 1)1 
(N=5) 
All 
Lerapolturev 
Monotherapy
1 
(N=11) 
Lerapolturev/ 
Anti-PD-1 
(Arm 2) 
(N=6) 
All 
Participants1 
(N=17) 
Crossover2 
Lerapolturev 
Monotherapy to 
Lerapolturev/Anti-
PD-1 
(N=7) 
All 
Lerapolture
v/ Anti-PD-1 
(N=13) 
Participants with one or more AEs, 
 n (%) 
6 (100.0%) 
2 (40.0%) 
8 (72.7%) 
2 (33.3%) 
10 (58.8%) 
5 (71.4%) 
7 (53.8%) 
Participants with one or more 
treatment-related3 AEs, n (%)  
    Lerapolturev-related AEs, n (%)  
    Anti-PD-1-related AEs, n (%) 
4 (66.7%) 
 
4 (66.7%)  
NA 
1 (20.0%) 
 
1 (20.0%)  
NA 
5 (45.5%) 
 
5 (45.5%)  
NA 
2 (33.3%) 
 
1 (16.7%)  
1 (16.7%) 
7 (41.2%) 
 
6 (35.3%)  
1 (5.9%) 
2 (28.6%) 
 
2 (28.6%)  
2 (28.6%) 
4 (30.8%) 
 
3 (23.1%)  
3 (23.1%) 
Participants with one or more serious 
AEs, n (%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (16.7%) 
1 (5.9%) 
0 (0.0%) 
1 (7.7%) 
Total number of serious AEs, n 
0 
0 
0 
3 
3 
0 
3 
Participants with one or more 
treatment-related3 serious AEs, n (%)  
    Lerapolturev-related serious AEs,   
        n (%) 
    Anti-PD-1-related serious AEs, 
        n (%) 
0 (0.0%) 
 
 
0 (0.0%)  
 
NA 
0 (0.0%) 
 
 
0 (0.0%)  
 
NA 
0 (0.0%) 
 
 
0 (0.0%)  
 
NA 
0 (0.0%) 
 
 
0 (0.0%)  
 
0 (0.0%) 
0 (0.0%) 
 
 
0 (0.0%)  
 
0 (0.0%) 
0 (0.0%) 
 
 
0 (0.0%)  
 
0 (0.0%) 
0 (0.0%) 
 
 
0 (0.0%)  
 
0 (0.0%) 
Total number of treatment-related3 
serious AEs, n  
    Lerapolturev-related serious AEs,   
        n  
    Anti-PD-1-related serious AEs, n 
0 
 
0  
 
NA 
0 
 
0  
 
NA 
0 
 
0  
 
NA 
0 
 
0  
 
0 
0 
 
0  
 
0 
0 
 
0  
 
0 
0 
 
0  
 
0 
Participants with one or more dose-
limiting toxicities AEs, n (%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Participants with one or more Grade 
3 or 4 AEs, n (%) 
2 (33.3%) 
0 (0.0%) 
2 (18.2%) 
1 (16.7%) 
3 (17.6%) 
1 (14.3%) 
2 (15.4%) 
Participants with any Grade 3 or 4 
Treatment-related3 AE, n (%)  
    Lerapolturev-related Grade 3 or 4 
         AEs, n (%)  
    Anti-PD-1-related Grade 3 or 4 
         AEs, n (%) 
0 (0.0%) 
 
0 (0.0%) 
 
NA 
0 (0.0%) 
 
0 (0.0%) 
 
NA 
0 (0.0%) 
 
0 (0.0%) 
 
NA 
0 (0.0%) 
 
0 (0.0%) 
 
0 (0.0%) 
0 (0.0%) 
 
0 (0.0%) 
 
0 (0.0%) 
0 (0.0%) 
 
0 (0.0%) 
 
0 (0.0%) 
0 (0.0%) 
 
0 (0.0%) 
 
0 (0.0%) 
Participants with one or more Grade 
5 AEs, n (%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 

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Summary 
Lerapolturev 
Monotherapy, 
Safety Run-in1 
(N=6) 
Lerapolturev 
Monotherapy 
(Arm 1)1 
(N=5) 
All 
Lerapolturev 
Monotherapy
1 
(N=11) 
Lerapolturev/ 
Anti-PD-1 
(Arm 2) 
(N=6) 
All 
Participants1 
(N=17) 
Crossover2 
Lerapolturev 
Monotherapy to 
Lerapolturev/Anti-
PD-1 
(N=7) 
All 
Lerapolture
v/ Anti-PD-1 
(N=13) 
Participants with any Grade 5 
treatment-related3 AE, n (%)  
    Lerapolturev-related Grade 5  
        AEs, n (%) 
    Anti-PD-1-related Grade 5 AEs,  
        n (%) 
0 (0.0%) 
 
0 (0.0%)  
 
NA 
0 (0.0%) 
 
0 (0.0%)  
 
NA 
0 (0.0%) 
 
0 (0.0%)  
 
NA 
0 (0.0%) 
 
0 (0.0%)  
 
0 (0.0%) 
0 (0.0%) 
 
0 (0.0%)  
 
0 (0.0%) 
0 (0.0%) 
 
0 (0.0%)  
 
0 (0.0%) 
0 (0.0%) 
 
0 (0.0%)  
 
0 (0.0%) 
Participants with one or more 
lerapolturev AESIs 
    Participants with one or more AEs  
        with an ISR 
    Participants with one or more AEs  
        with signs of CRS/ICANs 
0 (0.0%) 
 
0 (0.0%) 
 
0 (0.0%) 
0 (0.0%) 
 
0 (0.0%) 
 
0 (0.0%) 
0 (0.0%) 
 
0 (0.0%) 
 
0 (0.0%) 
0 (0.0%) 
 
0 (0.0%) 
 
0 (0.0%) 
0 (0.0%) 
 
0 (0.0%) 
 
0 (0.0%) 
0 (0.0%) 
 
0 (0.0%) 
 
0 (0.0%) 
0 (0.0%) 
 
0 (0.0%) 
 
0 (0.0%) 
AESI = adverse event of special interest; CRS = cytokine release syndrome; ICANS = immune effector cell associated neurotoxicity syndrome; ISR = injection site 
reaction; NA = not applicable; PD-1 = programmed cell death protein 1; AE = adverse event 
1 Data shown do not include data collected during crossover. 
2 Crossover starts with first administration of first crossover cycle. Pooled data presented for all crossover participants. 
3 Treatment-related based on definite, possible, and probable relatedness to lerapolturev and/or anti-PD-1. 

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Table 4. 
LUMINOS-102 Lerapolturev-Related Adverse Events by Preferred Term in Descending Frequency as 
of 10DECEMBER2021 
 
Summary 
Lerapolturev 
Monotherapy, 
Safety Run-in1 
(N=6) 
Lerapolturev 
Monotherap
y (Arm 1)1 
(N=5) 
All Lerapolturev 
Monotherapy1 
(N=11) 
Lerapolturev/ 
Anti-PD-1 
(Arm 2) 
(N=6) 
All 
Participants1 
(N=17) 
Crossover2 Lerapolturev 
Monotherapy to 
Lerapolturev/Anti-PD-1 
(N=7) 
All 
Lerapolture
v/ Anti-PD-1 
(N=13) 
Participants with one or 
more Lerapolturev-
Related3 AEs, n (%) 
4 (66.7%) 
1 (20.0%) 
5 (45.5%) 
1 (16.7%) 
6 (35.3%) 
2 (28.6%) 
3 (23.1%) 
Preferred term, n (%) 
     Fatigue 
     Anaemia 
     Decreased appetite 
     Dyspnoea 
     Groin pain 
     Hyperglycaemia 
     Hypoalbuminaemia 
     Hypochloraemia 
     Hyponatraemia 
     Lymphadenopathy 
     Nausea 
     Oncologic complication 
     Pain in extremity 
     Paraesthesia 
     Peripheral swelling 
     Pyrexia 
     Tumour pain 
     Vomiting 
     Wound haemorrhage 
     Headache 
     Pruritus 
  
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
0 (0.0%) 
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
  
1 (20.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
  
2 (18.2%) 
1 (9.1%) 
1 (9.1%) 
1 (9.1%) 
0 (0.0%) 
1 (9.1%) 
1 (9.1%) 
1 (9.1%) 
1 (9.1%) 
1 (9.1%) 
1 (9.1%) 
1 (9.1%) 
1 (9.1%) 
1 (9.1%) 
1 (9.1%) 
1 (9.1%) 
1 (9.1%) 
1 (9.1%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
  
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
  
2 (11.8%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
1 (5.9%) 
0 (0.0%) 
0 (0.0%) 
  
1 (14.3%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (14.3%) 
1 (14.3%) 
  
1 (7.7%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (7.7%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (7.7%) 
1 (7.7%) 
, PD-1 = programmed cell death protein 1; AE = adverse event 
1 Data shown do not include data collected during crossover. 
2 Crossover starts with first administration of first crossover cycle. Pooled data presented for all crossover participants. 
3 Includes AEs considered definitely, probably or possibly related to lerapolturev.

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1.3 
Benefit/Risk Assessment 
1.3.1 
Known Potential Risks 
Risks related to lerapolturev administration: For detailed risks regarding use of 
lerapolturev, refer to the IB. Based on available data from ongoing Phase 1 and Phase 2 
trials in rGBM, lerapolturev infusion into CNS tumors can result in peritumoral edema 
during the first 12 months post-infusion. This peritumoral inflammation can manifest as 
transient neurologic changes or exacerbate existing neurologic signs and symptoms, 
which are best managed with low dose dexamethasone and/or bevacizumab. In contrast, 
lerapolturev injection into solid tumors outside the brain has resulted in treatment-related 
AEs that are only Grade 1 or 2. For the Phase 1 melanoma study in anti-PD-1 refractory 
melanoma, lerapolturev-related AEs were primarily localized to the injected lesion(s), with 
pruritis (45.5%) and erythema (27.3%) at the injection site most commonly reported. As 
discussed in Section 1.2.2, all treatment-related AEs in participants enrolled in this study 
as of the 10 December 2021 data cutoff continue to be Grade 1 or 2, whether lerapolturev 
is given as monotherapy or in combination with anti-PD-1 therapy. Fatigue was the only 
lerapolturev-related AE reported in >10% of participants (11.8%).    
After oral uptake, poliovirus replicates in the gastrointestinal tract and is excreted by 
infected individuals in stool. Per the Istari IB, analysis of viral shedding in non-human 
primates have shown that excretion of lerapolturev does not occur after intracerebral 
administration, implying the absence of dissemination and subsequent gastrointestinal 
replication. In addition, prior immunization against poliovirus, as well as administration of 
a poliovirus booster 1 to 6 weeks prior to lerapolturev administration, is required for study 
participation. Immunity to poliovirus following proper immunization is believed to be 
lifelong29, which is supported by a study from Rumke et al, who showed that 92% (22 of 
24) of participants previously immunized against poliovirus with an undetectable 
poliovirus titer had a four-fold increase in neutralizing antibodies within 1 week of DT-IPV 
administration30. Therefore, lerapolturev dissemination in participants treated with 
lerapolturev is less likely given the high-titer immune response to poliovirus that is present 
following immunization and pre- lerapolturev boosting with the Salk poliovirus vaccine 
(Istari data on file). Lerapolturev has not been detected in the stool of participants with 
rGBM treated with intratumoral injection. However, lerapolturev excretion within stool 
following subcutaneous injection of melanoma tumors cannot be categorically excluded, 
although viral shedding data from the Phase 1 melanoma study indicate lerapolturev was 
undetectable in the stool of the tested melanoma participants treated with lerapolturev 
(Istari data on file).  Again, high-titer poliovirus immunity was demonstrated both pre- and 
post-IPOL® vaccination in these participants.  Stool specimens and swabs of injected 
lesions and dressings will be collected in the current study following lerapolturev 
administration to further rule out risk of virus transmission, systemic dissemination, and 
gastrointestinal excretion during the study.  

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Given current clinical and non-clinical data demonstrate the lack of systemic 
dissemination or replication and the absence of virus shedding through stool, the 
likelihood of unintended exposure of participant household contacts is low. If accidental 
exposure occurred, it would equal the risk of exposure to any type 1 Sabin vaccine virus 
or vaccine virus derivatives. Thus, exposure to lerapolturev is equal to oral immunization 
with a safer version of type 1 Sabin. Because type 1 Sabin vaccine virus or vaccine virus 
derivatives have to be considered part of the human environment, exposure to 
lerapolturev would not represent an added risk beyond the possibility for exposure that 
already exists. Study participants will be advised of the risks of exposure to unvaccinated 
household contacts (such as babies), or those who might be immunocompromised.  
Risks related to modifying the dose/schedule of lerapolturev: Review of all available 
safety data for this study (Section 1.2.2.2) indicates that lerapolturev injected into multiple 
lesions/visit up to a maximum dose of 6 x 108 TCID50 every 3 weeks is safe and tolerable 
when administered as monotherapy or in combination with anti-PD-1 therapy. In addition, 
review of the published literature (Table 5) for other innate immune agonists (including 
oncolytic viruses) delivered by intratumoral injection, indicates that increasing the 
maximum possible dose of lerapolturev to 1.6 x 109 TCID50 and changing the schedule of 
administration to an “induction” phase of weekly injections x 7 followed by a maintenance 
phase of less frequent administration is a common approach that is safe and tolerable 
and not predicted to substantially change the safety profile of the drug.  
 
 
 
 
 
 
 
 
 
 
 
 

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Table 5. 
Oncolytic Virus Doses and Schedules 
Innate Immune 
Agonist 
Total maximum 
dose delivered 
by intratumoral 
injection 
Schedule 
Safety 
Reference 
BO-112  
(double-stranded 
RNA in carrier) 
2mg 
Weekly x 7 
followed by every 
3 week 
maintenance 
No treatment-
related Grade ≥3 
AEs 
Marquez-Rodas et al 
202131 
Vidutolimod 
(TLR9 agonist in 
virus-like particle) 
10mg 
Weekly x 7 
followed by every 
3 week 
maintenance 
No treatment-
related Grade ≥4 
AEs 
Kirkwood et al 202132 
CAVATAK 
(coxsackievirus) 
3 x 108 TCID50 
Day 1, 3, 5, 8, and 
22 followed by 
every 3 week 
maintenance 
No DLTs or 
treatment-related 
Grade ≥3 AEs 
Andtbacka et al 
202133 
ONCOS-102 
(adenoviral vector 
with payload) 
3 x 1011 viral 
particles 
Day 1, 4, 8, 15, 
and 19 followed 
by every 4 week 
maintenance 
No DLTs 
Ranki et al 201634 
NG-350A 
(adenoviral vector 
with payload) 
2 x 1012 viral 
particles 
Weekly x 4 
No DLTs 
Nain et al 202135 
ORCA-010 
(adenoviral 
vector) 
1.5 x 1012 viral 
particles 
One dose 
No DLTs or 
treatment-related 
Grade ≥3 AEs  
Brachtlova et al 
202136 
ONCR-177  
(HSV-1 vector 
with payload) 
4 x 108 pfu 
Every 2 weeks 
No DLTs or 
treatment-related 
Grade ≥3 AEs 
Park et al 202137 
IMLYGIC (HSV-1 
vector with 
payload) 
4 x 108 pfu 
Every 2 weeks 
No DLTs 
Hu et al 200638 
 
 Risks related to anti-PD-1 administration: Anti-PD-1 administration carries the risk of 
immune-related AEs (irAEs) in various organ systems, including the skin. Consult the 
current pembrolizumab or nivolumab package insert for the most current information 
related to administration and safety, such as AE management and dose modifications. 
Per the respective package inserts for nivolumab and pembrolizumab, administration of 
either anti-PD-1 can be associated with rash, and pruritis has been reported in melanoma 
patients treated with nivolumab. Given lerapolturev’s mechanism of action, and the 
monotherapy safety profile observed in melanoma participants treated to date, it is 
possible that concurrent use of lerapolturev with anti-PD-1 therapy could increase the 
frequency or severity of cutaneous irAEs like rash or pruritis.  However, review of the 
available safety data for participants treated with the combination of lerapolturev and anti-
PD-1 therapy in this study suggests there is not an increased risk of cutaneous irAEs for 

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the combination (Table 3 and Table 4). Because co-administration of lerapolturev with 
anti-PD-1 therapy has a theoretical risk for CRS and/or immune effector cell-associated 
neurotoxicity syndrome (ICANS)20, this study will monitor participants for such events, 
and will obtain blood samples to determine the cytokine profile associated with any such 
events (if applicable) in order to inform treatment algorithms in subsequently treated study 
participants.  In addition, the study will employ a safety run-in (Section 3.1.2) to establish 
the safety of multiple lerapolturev intratumoral injections prior to proceeding the 
randomized portion of the trial. 
 
1.3.2 
Known Potential Benefits 
Lerapolturev has demonstrated evidence of meaningful anti-tumor response in patients 
with rGBM, which is a nearly universally fatal disease. For participants treated with 
lerapolturev in the Phase 1 study, based on an interim data summary, overall survival 
reached a plateau of 21% (95% CI: 11 to 33) at 24 months that was sustained at 36 
months; this was a significant improvement relative to criteria-matched historical 
controls18. Lerapolturev monotherapy is currently being investigated in an ongoing multi-
center Phase 2 in rGBM, with preliminary evidence supporting the observations seen in 
Phase 1. Lerapolturev is also being evaluated in combination with pembrolizumab in 
participants with rGBM (LUMINOS-101); the data from this study further suggest the 
combination of lerapolturev and anti-PD-1 therapy is safe and well tolerated. 
Lerapolturev has also shown anti-tumor activity in participants with anti-PD-1 refractory 
melanoma in a Phase 1 study. Four of twelve participants with anti-PD-1 refractory (and 
BRAF/MEK refractory, for those with BRAF-mutated melanoma) treated with intratumoral 
lerapolturev achieved an objective response with lerapolturev, despite dosing being 
limited to one injection of a single lesion/visit every three weeks for a maximum of three 
visits. Of those who received 3 lerapolturev injections (maximum dose administered), 
responses were observed in 4/6 (67%). Responses included two participants with in-
transit melanoma who had complete pathologic responses.  

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The current study was designed to test the safety and efficacy of lerapolturev 
administered as monotherapy and in combination with anti-PD-1 therapy where the dose 
of lerapolturev was increased relative to the Phase 1 study by varying the injected volume 
with the lesion size, and increasing the number of injected lesions/visit.  While this 
approach has been shown to be safe and tolerable (Section 1.2.2.2), the level of clinical 
activity observed in the Phase 1 study has not been duplicated. The most likely 
explanation for this observation is differences in the enrolled patient populations ie, the 
LUMINOS-102 protocol includes a more rigorous definition of anti-PD-1 resistance than 
what was implemented for the Phase 1 study.  Therefore, to improve the probability of 
participant benefit and the resultant benefit/risk profile, both the eligibility criteria and 
dosing regimen are being updated in this amendment.  The changes in eligibility criteria 
will exclude those patients with a lower probability of receiving benefit (eg, patients with 
mucosal melanoma or who are more heavily pretreated) while maintaining the more 
clinically relevant and rigorous definition of anti-PD-1 resistance.  
In addition, both the schedule and dose of lerapolturev injections will be altered to 
potentially improve the probability of response in this more anti-PD-1 resistant patient 
population (compared to the Phase 1).  Both the change in schedule frequency, and 
increase in dose, were chosen based on review of published literature for other innate 
immune agonists (including oncolytic viruses). For example, as outlined in Table 5, the 
majority of innate immune agonists employ an “induction/maintenance” type of approach 
to the schedule of injections where more frequent injections are given in the first 1 to 
2 months of the treatment period to ignite the immune system, followed by transition to a 
less frequent schedule where the goal is to maintain the immune response. It is expected 
that the increase in injection frequency will result in an improvement in participant 
response without a significant increase in toxicity. 
The data summarized in Table 5 also indicates that virus doses of ≈108 TCID50 or pfu are 
safe and well tolerated with no dose limiting toxicities when delivered by intratumoral 
injection.  Given anti-PD-1 refractory melanoma participants have received up to 
6 x 108 TCID50 lerapolturev without clinically significant toxicity, and that all participants 
will have high levels of circulating neutralizing anti-poliovirus antibodies after being 
boosted prior to enrollment, the proposed study dose of up to 1.6 x 109 TCID50 
lerapolturev is not expected to cause clinically significant increases in toxicity.    
With respect to the potential benefits of combining with anti-PD-1 therapy, the nonclinical 
data summarized in Section 1.2.1 suggest that lerapolturev injection upregulates the 
compensatory anti-PD-1/L1 pathway, such that concurrent blockade of that pathway is 
predicted to increase the potential benefit to patients. This hypothesis has been tested in 
nonclinical experiments where the combination of a mouse adapted version of 
lerapolturev (mRIPO) administered in combination with a murine anti-PD-1 antibody 
results in more significant effects on tumor growth as compared to either drug alone (see 
lerapolturev IB).  

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1.3.3 
Benefit-Risk Summary 
Clinical evidence gathered to date suggests that intratumoral injection of lerapolturev in 
patients with cutaneous, subcutaneous, or nodal unresectable melanoma is well 
tolerated. Lerapolturev has been associated with clinically relevant peritumoral edema 
when administered to patients with rGBM. However, AEs related to injection of 
lerapolturev into melanoma lesions have been mainly local, and remain Grade 1 or 2 in 
severity in all participants treated to date, regardless of treatment group. This suggests 
that systemic dissemination of lerapolturev does not occur (likely due to pre-existing anti-
polio immunity and CD155 tropism), which distinguishes lerapolturev from other oncolytic 
viruses such as T-VEC that are associated with systemic dissemination and systemic AEs 
such as CRS.  
Given that all currently available safety data indicate that lerapolturev-related AEs in 
participants with melanoma are mild to moderate despite administration of a lerapolturev 
dose of up to 6 x 108 TCID50 (alone and when combined with anti-PD-1 therapy), it is 
reasonable to assume a lerapolturev dose of up to 1.6 x 109 TCID50, and a weekly dosing 
regimen following by Q3/4W maintenance dosing would not result in DLT. In addition, 
because participants receiving lerapolturev monotherapy are allowed to crossover to the 
combination regimen, those participants randomized to lerapolturev monotherapy have 
an opportunity to maximize their potential benefit upon crossover.   
 
 

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2 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives and Endpoints 
Objectives 
Endpoints/Evaluation Criteria 
Primary  
To evaluate the anti-
tumor activity of 
lerapolturev with and 
without anti-PD-1, in 
participants who have 
failed anti-PD-1/L1-
based therapy 
• Overall Response Rate (ORR): the proportion of 
participants achieving confirmed complete (CR) or 
partial response (PR), per RECIST 1.1 criteria. 
To evaluate the 
safety/tolerability of 
lerapolturev with and 
without anti-PD-1, in 
participants who have 
failed anti-PD-1/L1-
based therapy  
• The frequency and severity of treatment-emergent 
adverse events (AE) via Common Terminology Criteria 
for Adverse Events (CTCAE, v5.0) 
• Changes in laboratory (hematology, chemistry) and 
vital sign parameters 
• Lerapolturev AESIs 
• Anti-PD-1 irAEs 
• Study treatment discontinuation due to AEs 
To evaluate the effect of 
lerapolturev on the TME 
of injected and non-
injected lesions when 
administered with and 
without anti-PD-1 
therapy 
• Changes from baseline in the number of CD8+ tumor 
infiltrating lymphocytes (TILs)  
• Changes from baseline in PD-L1 expression 
Secondary 
To evaluate survival and 
disease control 
outcomes of lerapolturev 
with and without anti-PD-
1, in participants who 
have failed anti-PD-1/L1-
based therapy 
• Overall survival (OS): time from treatment group 
assignment until death from any cause 
• Duration of Response (DOR): time from confirmed 
objective response (CR or PR per RECIST 1.1) until 
unequivocal disease progression or death, whichever 
occurs first 
• Disease control rate (DCR): the proportion of 
participants achieving confirmed CR, confirmed PR, or 
stable disease (SD) per RECIST 1.1, as best response  
• Disease control rate-6months (DCR-6mo): the 
proportion of participants achieving confirmed CR (any 
duration), confirmed PR (any duration), or SD (≥ 6 
months) per RECIST 1.1 as best response  
• Durable Response Rate (DRR): the proportion of 
participants with confirmed CR or PR (per RECIST 1.1) 
lasting at least 6 months 

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• Progression-free survival (PFS): time (number of 
months) from treatment group assignment until date of 
documented radiologic disease progression per 
RECIST 1.1 or death due to any cause, whichever 
comes first  
Exploratory: 
To explore lerapolturev 
mechanism of action and 
predictors of response to 
lerapolturev with or 
without anti-PD-1 in 
participants who have 
failed anti-PD-1/L1-
based therapy 
• Assessment and identification of genetic, cytologic, 
histologic and/or other markers in tumor biopsies and 
PBMC samples that may correlate with response. 
• Assessment of changes over time in immune markers, 
including, but not limited to, immune cell density, T cell 
receptor repertoire, and chemokine and/or cytokine 
profile in blood samples and/or tissue 
To evaluate anti-tumor 
response to lerapolturev 
with and without anti-PD-
1, based on iRECIST 
criteria in participants 
who have failed anti-PD-
1/L1-based therapy 
• ORR/DOR, DRR, DCR, and DCR-6mo based on 
iRECIST criteria 
To evaluate anti-tumor 
response outcomes to 
lerapolturev with and 
without anti-PD-1, based 
on subgroup in 
participants who have 
failed anti-PD-1/L1-
based therapy 
• ORR, DOR, DRR, DCR, and DCR-6mo in the following 
subgroups: 
o Acquired versus primary PD-1/L1 resistance, as 
defined by Kluger, et al14 
o BRAF wild type and mutant 
o LDH levels at baseline 
o Time since last dose of anti-PD-1/L1 therapy 
prior to randomization (≤ or > 6 weeks) 
o Crossover to combination arm from lerapolturev 
monotherapy 
To evaluate survival 
outcomes to lerapolturev 
with and without anti-PD-
1, based on subgroup in 
participants who have 
failed anti-PD-1/L1-
based therapy 
• OS and PFS in the following subgroups: 
o According to treatment arm and AJCC stage at 
baseline 
o Primary versus acquired resistance, as defined 
by Kluger et al14 
o BRAF wild type and mutant 
o LDH levels at baseline 
o Time since last dose of anti-PD-1/L1 therapy 
prior to randomization (≤ or > 6 weeks) 
o Crossover to combination from lerapolturev 
monotherapy 
2.2 
Hypothesis 
Efficacy: Lerapolturev administered in combination with anti-PD-1 therapy using the 
induction/maintenance schedule of injections (weekly x 7 followed by injections every 3 to 

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4 weeks concurrent with anti-PD-1 therapy) to participants with anti-PD-1 refractory 
melanoma will result in an ORR of ≥ 33%.   
Translational: Lerapolturev administered in combination with anti-PD-1 therapy will result 
in an increase in CD8+ T cells and PD-L1 expression in TME. 
3 
TRIAL DESIGN 
3.1 
Overall Design 
The purpose of this randomized, multicenter, open-label Phase 2 study is to test the safety 
and efficacy of lerapolturev alone and in combination with anti-PD-1 therapy in 
participants with unresectable advanced anti-PD-1/L1 refractory melanoma. Participants 
will be randomized 1:1 to receive lerapolturev alone (Arm 1) or lerapolturev and an FDA-
approved anti-PD-1 therapy (Arm 2). Prior to starting the randomized portion of the study, 
a safety run-in cohort of at least six participants treated with lerapolturev monotherapy 
was to have been enrolled to demonstrate the safety and tolerability of the administration 
of multiple lerapolturev injections per visit.   
As of July 2021, the safety run-in portion of the study has been completed. Six participants 
were enrolled and received total lerapolturev doses ranging from 1 x 108 to 6 x 108 TCID50 
injected into between 1 and 6 lesions/visit. The schedule of administration was for 
participants to receive a single lerapolturev injection into the largest lesion on Day 1 
followed by initiation of multiple lesion injections/visit on Day 10.  For participants in Arm 
2, anti-PD-1 therapy was started on Day 10 concurrent with initiation of multiple 
lerapolturev injections. Upon initiation of multiple injections on Day 10, the timing of future 
injections was dependent upon anti-PD-1 dosing, ie, for pembrolizumab the schedule was 
every 3 weeks starting from Day 10, and for nivolumab the schedule was every 4 weeks 
starting from Day 10. For participants in Arm 1, the timing of future injections was every 
3 weeks. This schedule of injections will be abbreviated as the Q3/4W schedule.  
Upon review of the safety profile for lerapolturev administered as monotherapy or in 
combination with anti-PD-1 therapy (Section 1.2.2), and in agreement with the DSMC, the 
total lerapolturev dose to be administered will be a maximum of 1.6 x 109 TCID50/visit, 
and the maximum number of lesions injected/visit will remain 6. The schedule of 
administration will include weekly injections x 7 followed by either Q3W dosing 
(lerapolturev monotherapy or in combination with pembrolizumab) or Q4W dosing 
(combination with nivolumab); this schedule of injections will be abbreviated as the QW 
schedule.  
Participants receiving the Q3/4W schedule of injections will be given the option to change 
to the QW schedule (Section 3.1.2). Upon commencement of enrollment using the QW 
schedule, the DSMC will continue to review all available safety data at a minimum of 
every 4 months to ensure independent oversight of the safety of participants enrolled in 

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this study (Section 9.1.5). This includes a meeting to review all safety data once the first 
12 participants receiving the new lerapolturev dose and QW schedule of injections clear 
the DLT period. 
Participants randomized to receive the Q3/4W schedule of injections were stratified based 
on time since prior anti-PD-1/L1 exposure (≤6 weeks versus >6 weeks) and baseline LDH 
levels (normal vs >ULN). With the change in eligibility criteria, participants randomized to 
the QW dosing schedule will be stratified based on the type of anti-PD-1/L1 resistance 
(primary versus secondary as defined in Kluger et al7), while the baseline LDH (normal 
versus >ULN) stratification factor will be retained.   
3.1.1 
Crossover 
Participants receiving lerapolturev monotherapy (Safety Run-In Cohort or Arm 1) may 
crossover to combination (lerapolturev and anti-PD-1) therapy if any of the following 
criteria are met 
o radiologic disease progression per RECIST v1.1 (progression does not need 
to be confirmed prior to crossover) 
o have not had progression or confirmed partial response per RECIST v1.1 by 
week 26 on study 
o partial response ≥ 6 months in duration 
All participants crossing over to combination therapy should have a complete assessment 
of tumor burden (ie, scans and caliper/ruler measurement of skin lesions with 
photographic documentation) ≤ 28 days prior to starting the combination. The dose of 
lerapolturev administered in combination will be the same as monotherapy and is detailed 
in Table 7. The schedule of lerapolturev injections at the time of initiation of combination 
therapy will depend on the timing of crossover (Table 6).  
 
 
 
 
 

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Table 6. 
Lerapolturev Injection Schedule After Crossover 
Schedule of lerapolturev 
monotherapy injections at the 
time of crossover 
Timing of when criteria for 
crossover are met 
Recommended lerapolturev 
dosing schedule for 
combination 
Participant is receiving weekly 
injections 
< 6 months from Cycle 1 Day 1 
Continue weekly injections for a 
total of 7 (monotherapy + 
combination) followed by every 
3 week dosing (pembrolizumab) 
or every 4 week dosing 
(nivolumab)* 
Participant is receiving injections 
every 3 weeks (pembrolizumab) 
or every 4 weeks (nivolumab)  
< 6 months from Cycle 1 Day 1 
Continue concurrent dosing 
schedule 
Participant is receiving injections 
every 3 weeks (pembrolizumab) 
or every 4 weeks (nivolumab) 
≥ 6 months from Cycle 1 Day 1 
Weekly x 7 followed by every 3 
week dosing (pembrolizumab) 
or every 4 week dosing 
(nivolumab) 
 
*NOTE: Anti-PD-1 dosing begins Day 1 of crossover. Following the 7th weekly injection, lerapolturev should be 
administered Q3w when in combination with pembrolizumab (given Q3 or 6w), or Q4w when in combination with 
nivolumab (given Q2 or 4w).  
  
3.1.2 
Considerations for Modification of Dose and/or Dosing Schedule for 
Participants receiving the Q3/4W Schedule of Injections. 
Lerapolturev Dose: All participants receiving lerapolturev on the Q3/4W schedule will 
have their lerapolturev dose adjusted as described in Section 5.3.  
 
Lerapolturev Schedule: Participants receiving treatment using the Q3/4W schedule will 
have the option to receive the “induction” series of weekly x 7 injections (ie, QW 
schedule). If the participant chooses to receive the weekly x 7 injections, the timing and 
schedule of assessments as shown in Table 1 (or Table 2 if receiving lerapolturev + 
nivolumab) beginning with Cycle 1, Day 1 should be followed. Note that the on-study 
biopsy and blood collection timepoints outlined in the Table 1 and Table 2 will remain 
mandatory for those participants who choose to undergo “induction” injections.  
 
Participants who choose not to receive the “induction” injections will continue on the every 
3 week (pembrolizumab) or every 4 week (nivolumab) schedule of injections.   
3.1.3 
Determination of the Recommended Lerapolturev Dose 
As a primary endpoint of this Phase 2 study, the safety and tolerability of lerapolturev 
alone or in combination with anti-PD-1 will be continually assessed.  

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Lerapolturev Dose, Q3/4W Schedule To more fully characterize the safety and tolerability 
of lerapolturev monotherapy, the Sponsor will enroll a safety run-in cohort of 
6 participants. Participants enrolled in the cohort will receive a lerapolturev injection into 
a maximum of 6 lesions (maximum dose of 6 x 108 TCID50) on Day 10 (or after, depending 
on resolution of treatment-limiting AEs) following the single lesion “test” injection. The 
decision to adjust the lerapolturev dose upon completion of the cohort will be based on 
the presence of dose-limiting toxicities (DLTs) observed during the 21 days following 
administration of Cycle 2, in consultation with the independent DSMC.  
Provided the DLT rate for the safety run-in cohort is ≤33%, it will be considered that the 
maximum tolerated dose (MTD) for lerapolturev has not been exceeded. However, should 
the DLT rate in the safety run-in cohort be >33%, then the recommended dose for 
single-agent lerapolturev will be the maximum number of lesions injected (and/or TCID50 
dose) where the DLT rate is ≤33%. If needed, the number of participants enrolled in the 
safety run-in cohort may be increased up to a maximum of 18 to establish the 
recommended lerapolturev dose prior to starting the randomized portion of the study.  The 
recommended lerapolturev dose from this cohort will be used in both arms of the 
randomized portion of the trial (ie, single-agent lerapolturev or lerapolturev in combination 
with anti-PD-1). Once 12 participants have been treated and on study approximately 31 
days (ie, once 6 participants have completed the first cycle of multi-lesion lerapolturev 
injection with concurrent anti-PD-1), the DSMC will perform an additional safety review to 
evaluate the prevalence of any untoward safety signals in either treatment arm. Should 
an excessive DLT rate (ie, >33%) be detected, the lerapolturev dose (ie, the maximum 
number of lesions and/or maximum TCID50 dose) may be decreased in one or both 
treatment arms, in conjunction with DSMC recommendations. See Section 3.1.4 for the 
DLT definitions. 
Any participant from the safety run-in cohort is allowed to crossover to combination 
therapy after completion of the safety run-in, as described in Section 3.1.1. However, 
these participants will be analyzed separately, and will not contribute to the population 
enrolled to establish the anti-tumor activity of the lerapolturev/anti-PD-1 regimen.   
Lerapolturev Dose, QW Schedule: Given the slight increase in the lerapolturev dose and 
increased frequency of dosing during the first 2 months on treatment, the DSMC will 
review all safety data once 12 participants have started the weekly x 7 “induction” series 
of injections (ie, n=6 monotherapy and n=6 combination with anti-PD-1) and have cleared 
the DLT evaluation period (ie, 21 days after Cycle 1, Day 1). Applying the same rules as 
used for the original safety run-in, should an excessive DLT rate (ie, >33%) be detected, 
the lerapolturev dose (ie, the maximum number of lesions and/or maximum TCID50 dose) 
and/or the number of weekly injections may be decreased in one or both treatment arms, 
based on DSMC recommendations. See Section 3.1.4 for the DLT definitions.   

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NOTE: For Arm 2 (lerapolturev/anti-PD-1 combination), AEs should only be considered a 
DLT if judged by the investigator to be related to lerapolturev and of increased 
severity/frequency compared to what is expected with administration of single-agent anti-
PD-1 therapy in this population, or if it is refractory to common management practices 
due to lerapolturev.  
3.1.4 
Definition of Dose-Limiting Toxicity 
The DLT evaluation period begins on the day of first lerapolturev injection (ie, Cycle 1, 
Day 1) and ends 21 days later. The definition of a DLT includes any of the following 
treatment-emergent events that are deemed at least possibly related to lerapolturev 
administration:     
• Any Grade 4 non-hematologic toxicity (not laboratory) 
• Any Grade 3 non-hematologic toxicity (not laboratory), EXCEPT:  
o Grade 3 fatigue lasting ≤3 days or Grade 3 fatigue in a participant with 
Grade 1 fatigue at baseline  
o Grade 3 diarrhea, nausea, or vomiting without use of anti-emetics or anti-
diarrheals per standard of care  
o Grade 3 adrenal insufficiency, hypothyroidism, or Type 1 diabetes mellitus 
due to suboptimal hormone replacement therapy  
o Grade 3 rash without use of corticosteroids or anti-inflammatory agents per 
standard of care 
•  Grade 3 or Grade 4 non-hematologic laboratory values ONLY if: 
o Clinically significant medical intervention is required to treat the participant, 
or 
o The abnormality leads to hospitalization, or 
o The abnormality persists for >1 week after intervention 
o The abnormality results in a diagnosis of drug-induced liver injury (DILI)  
o Exceptions: Clinically nonsignificant, treatable, or reversible laboratory 
abnormalities including liver function tests, uric acid, etc. 
• Any Grade 4 hematologic toxicity lasting ≥7 days, EXCEPT: 
o Grade 4 thrombocytopenia of any duration 
o Grade 3 thrombocytopenia associated with bleeding that requires a platelet 
transfusion 
• Febrile neutropenia Grade 3 or Grade 4 ONLY if: 
o Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 
°C (101 °F) or a sustained temperature of ≥38 °C (100.4 °F) for more than 
1 hour 
o Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 
°C (101 °F) or a sustained temperature of ≥38 °C (100.4 °F) for more than 
1 hour, with life-threatening consequences and urgent intervention 
indicated 
• Prolonged delay (>2 weeks) in initiating the second cycle of anti-PD-1 therapy 
while on study due to lerapolturev-related toxicity. 
• Prolonged delay (> 15 weeks) in initiating the second cycle of anti-PD-1 therapy 
while on study due to anti-PD-1-related toxicity (12 weeks for recovery to ≤ Grade 

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1 and up to an additional 3 weeks for steroid taper of oral prednisone or equivalent 
to ≤ 10 mg/day) 
• Any treatment-related toxicity that causes the participant to discontinue treatment 
during the DLT evaluation period 
• 
Grade 5 treatment-related toxicity   
3.2 
Evaluation of Lerapolturev Shedding  
As described in Section 1.2.1 and in the IB, lerapolturev has been subjected to extensive 
non-clinical and clinical viral shedding studies. Non-human primate studies in 
Cynomolgus macaques were unable to detect lerapolturev in saliva, stool or urine up to 
56 days post intracerebral inoculation, with a lerapolturev dose of 5 x 109 TCID5028. 
Likewise, lerapolturev shedding was undetected in the stool (the main excretory pathway 
for polio) of participants treated with lerapolturev for rGBM following administration of 
intracerebral doses of up to 1 x 1010 TCID50 or in melanoma participants receiving 
3 telerapolturev injections (1 x 108 TCID50 each). These results combined with the 
requirement that all participants must receive a CDC-recommended immunizing 
vaccination against PV, as well as a PV booster prior to study entry (which has resulted 
in extremely high levels of neutralizing anti-PV antibodies in patients tested to date) the 
risk of extra-tumoral lerapolturev dissemination and shedding is predicted to be extremely 
low.  
However, because lerapolturev shedding in melanoma participants receiving repeat 
injections of lerapolturev at the dose levels allowed in this study has not been fully 
characterized, the Sponsor will test for the presence of lerapolturev in stool and on the 
surface of lerapolturev-injected lesions (as well as on the internal and external surfaces 
of any occlusive dressings applied post-lerapolturev injection) for up to 25 participants 
who received lerapolturev injections using the Q3/4W dosing schedule. For those 
participants enrolled using QW schedule of lerapolturev injections, viral shedding studies 
will be done in up to 25 participants as described in the appropriate SOA (Table 1 or 
Table 2 [Arm 2: lerapolturev + nivolumab]).  
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. 
 
3.3 
Justification for Lerapolturev Dose and Schedule 
The initial dose of lerapolturev evaluated in this trial was selected based on IND-directed 
toxicity studies and experience from ongoing studies in participants with rGBM or anti-
PD-1 refractory melanoma (Section 1.2.2). Dose-range finding and toxicology studies in 
non-human primates documented the absence of viral encephalomyelitis, poliomyelitis 
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In the adult Phase 1 rGBM study, 4 participants were dosed at the maximum intended 
dose of 1010 TCID50, injected intracerebrally, without signs of viral encephalomyelitis, 
poliomyelitis, or meningitis. However, due to persistent peri-tumoral inflammation and the 
continuing requirement for steroids in all participants, the recommended intracerebral 
dose was eventually reduced to 5 x 107 TCID50.  
In subcutaneous melanoma, the effect of inflammation is not expected to be as significant 
because cutaneous swelling is more easily managed than edema within the confines of 
the brain/skull. Data from the Phase 1 trial in anti-PD-1 refractory melanoma, as well as 
the currently available data generated during this study, has shown that a lerapolturev 
dose of up to 6 x 108 TCID50 is very well tolerated when given alone or in combination 
with anti-PD-1 therapy. All treatment-related AEs remain Grade 1 or 2, with no treatment-
related SAEs, DLTs or evidence of CRS or ICANS in participants treated at any dose 
level (Section 1.2.2.2).   
Therefore, this study has been amended to explore an approximately 2-fold higher 
lerapolturev dose using a dosing schedule (QW) with more frequent injections during the 
first 2 months of treatment followed by transition to a less frequent “maintenance” 
schedule. The rationale and data supporting this change are summarized in Section 1.3. 
3.4 
End of Study Definition 
The study is considered completed with the last study assessment for the last participant 
participating in the study. The final data from the site will be sent to the Sponsor after 
completion of the final participant assessment at that study site, in the time frame 
specified in the clinical trial agreement. 
4 
STUDY POPULATION 
The inclusion and exclusion criteria for enrolling participants in this study are described 
below. If there is a question about these criteria, the investigator must consult with the 
Sponsor or designee to resolve any issues prior to enrollment.  
Screening for eligible participants will be completed within 28 days prior to Day 1. Refer 
to Section 4.3 for conditions under which repeat screening procedures are permitted. 
4.1 
Inclusion Criteria 
1. ≥ 18 years of age 
2. Prior CDC-recommended vaccination series against poliovirus (PV), and has 
received a boost immunization with trivalent IPOL® (Sanofi-Pasteur SA) at least 1 
week, but less than 6 weeks, prior to Day 1  
a. NOTE: Patients who are unsure of their vaccination status must provide 
evidence of anti-PV immunity prior to enrollment, as applicable 

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3. Has biopsy proven unresectable cutaneous melanoma and is willing to undergo 
tumor biopsy prior to the first dose of study drug(s) and at prespecified intervals 
during the study. Note the following details: 
a. Patients with ocular, acral or mucosal melanoma are not eligible 
b. Patients with M1c or M1d disease are NOT eligible 
c. Submission of an archival biopsy sample is allowed in lieu of the baseline 
tumor biopsy, provided the tissue is ≤4 months old and the participant 
received no intervening systemic/intratumoral anti-cancer therapy since the 
biopsy was acquired. 
d. Must have at least 1 lesion that is amenable to biopsy. The lesion must be 
safely accessible as determined by the investigator and should not be 
located at sites that require significant risk procedures to biopsy. Examples 
of sites considered to be of significant risk include but are not limited to the 
following: the brain, lung, mediastinum, pancreas, or endoscopic 
procedures extending beyond the esophagus, stomach, or bowel wall. 
 
4. Has ≥ 2 melanoma lesions that are accurately measurable by caliper or a 
radiological method according to RECIST 1.1 criteria 
a. One lesion must be injectable--defined as a visible or palpable cutaneous, 
subcutaneous, or nodal melanoma lesion ≥ 10mm in longest diameter or 
multiple injectable melanoma lesions which in aggregate have a longest 
diameter of ≥ 10mm and where the minimal lesion size is ≥ 5mm.   
b. Note that visceral lesions (eg, liver, lung, retroperitoneal, subpleural 
lesions) are not considered injectable for the purposes of this trial. 
5. Has had confirmed progression of disease (PD) while receiving at least 6 weeks 
(> 1 dose) of an FDA-approved anti-PD-1/L1 therapy (as monotherapy or in 
combination) for the treatment of melanoma.  Note the following details:   
a. Initial PD as defined by RECIST v1.1 
b. Confirmation of PD per iRECIST must occur by repeat assessment ≥ 4 
weeks from initial evidence of PD, in the absence of rapid clinical 
progression.  
c. Those who discontinue anti-PD-1/L1 therapy after at least 6 weeks (> 1 
dose) and have confirmed PD per iRECIST within 12 weeks of their last 
anti-PD-1/L1 dose are also eligible, provided the anti-PD-1/L1 was not 
stopped due to toxicity requiring permanent discontinuation 
d. Those treated with anti-PD-1/L1 in the adjuvant setting and who have 
biopsy-confirmed progression either while receiving anti-PD-1/L1-based 
therapy or ≤ 12 weeks after their last dose of anti-PD-1/L1 therapy are 
allowed 

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NOTE: Adjuvant is defined as therapy received after surgical resection of disease such 
that the patient has no evidence of disease when the anti-PD-1/L1 therapy is initiated. 
Patients with known BRAF mutation must have also failed or refused to receive BRAF-
targeted therapy (alone or in combination with MEK inhibitor) to be eligible  
6. Eastern Cooperative Oncology Group (ECOG) status of 0-1 
7. Serum lactate dehydrogenase (LDH) levels ≤3 x upper limit of normal (ULN) 
8. Adequate bone marrow, liver and renal function as assessed by the following: 
a. Hemoglobin ≥9.0 g/dl, patients may be transfused  
b. Lymphocyte count ≥0.5 x 109/L (500 µL) 
c. Absolute neutrophil count (ANC) ≥1.5 x 109/L (1500 µL) 
d. Platelet count ≥100 x 109/L (100,000 µL) without transfusion 
e. AST, ALT, and alkaline phosphatase (ALP) ≤2.5 x upper limit of normal 
(ULN), with the following exceptions: 
i. Patients with documented liver metastases:  AST and ALT ≤5 x ULN 
ii. Patients with documented liver or bone metastases:  ALP ≤5 x ULN 
f. Serum bilirubin ≤1.5 x ULN with the following exception: 
i. Patients with known Gilbert disease:  serum bilirubin level ≤3 x ULN 
g. Measured or calculated (per institutional standards) creatinine clearance 
≥30 ml/min (GFR can also be used in place of creatinine clearance) 
h. For patients not receiving therapeutic anticoagulation:  INR, PT, PTT (or 
aPTT) ≤1.5 x ULN 
9. Life expectancy of >12 weeks 
10. Signed informed consent form (ICF) indicating that participant understands the 
purpose of, and procedures required for the study, and is willing/able to 
participate in the study  
4.2 
Exclusion Criteria 
1. Has biopsy-proven ocular, acral or mucosal melanoma 
2. Has M1c or M1d disease 
3. No more than one prior systemic anti-cancer regimen (monotherapy or 
combination) for management of melanoma. Additional details noted below: 
a. Adjuvant anti-cancer therapy administered ≥ 6 months prior to the first 
injection of lerapolturev does NOT count as a line of treatment.  
b. Patients with BRAF mutant melanoma may enroll if they have received ≤ 2 
prior lines of systemic anti-cancer therapy only if one of those lines of 
therapy was a BRAF-targeted regimen (alone or in combination with MEK 
inhibitor).  
c. A line of therapy is defined as a regimen in which at least 2 doses of 
systemic anti-cancer therapy (monotherapy or combination) was 
administered, and the regimen was discontinued because of progressive 
disease. 

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4. Uncontrolled tumor-related pain.  Participants requiring pain medication must be 
on a stable regimen at study entry 
a. Symptomatic lesions amenable to palliative radiotherapy (eg, bone 
metastases or metastases causing nerve impingement) should be treated 
prior to enrollment.  Patients should be recovered from the effects of 
radiation.  There is no required minimum recovery period 
b. Asymptomatic metastatic lesions that would likely cause functional deficits 
or intractable pain with further growth (eg, epidural metastasis that are not 
currently associated with spinal cord compression) should be considered 
for loco-regional therapy if appropriate prior to enrollment 
5. Grade ≥2 pleural effusion, pericardial effusion, or ascites  
6. Active or history of autoimmune disease or immune deficiency within previous 2 
years, with the following exceptions: 
a. History of autoimmune-related endocrinopathy (e.g. adrenal insufficiency, 
hypothyroidism, Type 1 diabetes mellitus, etc.) that is managed by hormone 
replacement therapy (e.g. hydrocortisone, thyroid hormone, insulin, etc.) 
b. Eczema, psoriasis, or lichen simplex chronicus with dermatologic 
manifestations only (eg, patients with psoriatic arthritis are excluded), 
provided all of the following conditions are met: 
i. Rash must cover <10% of body surface area 
ii. Disease is well-controlled at baseline and requires only low-potency 
topical corticosteroids 
iii. No occurrence of acute exacerbations of the underlying condition 
requiring psoralen plus ultraviolet A radiation, methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors, or high potency 
or oral corticosteroids within 12 months of Day 1 
7. History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis 
obliterans), drug-induced or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan 
a. History of radiation pneumonitis in the radiation field (fibrosis) is allowed 
8. History of a positive HIV RNA test (HIV 1 or 2 RNA by PCR) 
9. Known active hepatitis B virus (HBV) infection (chronic or acute) 
a. NOTE: Participants with a negative HBsAg test and a positive total hepatitis 
B core antibody (HBcAb) test are allowed  
10. Known active hepatitis C virus (HCV) infection 
a. NOTE: History of a positive HCV antibody test, but negative HCV RNA test, 
is allowed 
11. Active tuberculosis 

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12. Significant cardiovascular disease, such as New York Heart Association Class II 
or greater cardiac disease, myocardial infarction, or cerebrovascular accident 
within 3 months of Day 1, unstable arrhythmia, or unstable angina  
13. Has received prior systemic anti-cancer therapy including investigational agents 
within 4 weeks or 5 elimination half-lives—whichever is shorter—prior to treatment 
or has not recovered from all AEs due to previous therapies to ≤Grade 1 or 
baseline. Participants with ≤Grade 2 neuropathy are eligible 
a. Note: Anti-PD-1/L1 within 4 weeks prior to Day 1 is allowed  
b. If participant received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention 
prior to starting study treatment 
14. History of other malignancy within 2 years prior to Day 1, with the exception of 
those with a negligible risk of metastasis or death (eg, resected cutaneous basal 
cell carcinoma, or other cancers with 5-year OS of >90%) 
15. Severe infection within 4 weeks prior to Day 1, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
a. Prophylactic antibiotics (eg, to prevent a urinary tract infection or chronic 
obstructive pulmonary disease exacerbation) are allowed 
16. Prior allogeneic stem cell or solid organ transplantation 
17. Treatment with a live, attenuated vaccine within 4 weeks prior to Day 1 
18. Treatment with systemic immunosuppressive medication within 4 weeks prior to 
Day 1, with the following exceptions: 
a. Participants who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (eg, 48 hours of corticosteroids for a contrast allergy) are eligible  
b. Patients receiving mineralocorticoids (eg, fludrocortisone), or systemic 
prednisone equivalent corticosteroid doses of <10mg per day are eligible 
for the study 
19. Known hypersensitivity to pembrolizumab, nivolumab, or any of the respective 
excipients  
20. Requires therapeutic anticoagulation and cannot discontinue anticoagulation 
safely during the day prior, day of, and day after each lerapolturev injection 
a. NOTE: Participants receiving anticoagulation with warfarin at the time of 
study entry are allowed if they can be transitioned to an alternative 
anticoagulant (eg, low molecular weight heparin or direct oral 
anticoagulants) prior to the first dose of lerapolturev. Anyone transitioned 
from warfarin to an oral anticoagulant prior to the first dose of lerapolturev 
should have an INR <1.5x upper limit of normal in order to participate. 
Antiplatelet agents (eg, aspirin, clopidogrel, etc.) are not considered 
anticoagulants for the purposes of this study (ie, are allowed) 

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21. A pregnant or nursing female, or women of child-bearing potential and men who 
are sexually active and not willing/able to use medically acceptable forms of 
contraception starting from signed ICF through 150 days after last anti-PD-1 
dose 
22. History of human serum albumin allergy 
23. History of neurological complications due to polio virus infection 
24. History of agammaglobulinemia 
25. Concurrent participation in a separate interventional clinical trial during this study 
26. Any underlying medical condition for which, in the opinion of the investigator, 
participation would not be in the best interest of the participant (eg, compromises 
the participant’s well-being) or that could prevent, limit, or confound protocol-
specified assessments 
 
4.3 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled. A minimal set of screen failure information 
(demography, screen failure details, eligibility criteria, and any SAEs) will be collected to 
ensure transparent reporting. 
Individuals who do not meet the criteria for participation in this study may be rescreened. 
Rescreening is at the discretion of the Investigator.  Participants who are to be rescreened 
based on a laboratory exclusion are not required to reconsent. Otherwise, a new ICF is 
required before rescreening and the participant must be assigned a new participant 
number.  
5 
STUDY DRUG (LERAPOLTUREV, NIVOLUMAB OR PEMBROLIZUMAB) 
5.1 
Lerapolturev: Packaging, labeling and how supplied  
Lerapolturev is a modified version of the serotype 1 live-attenuated (Sabin) PV vaccine 
(PV1S) and is classified as an oncolytic viral immunotherapeutic.  
Lerapolturev is formulated in 50 mM sodium phosphate in 0.9% sodium chloride, pH 7.4 
with 0.2% human serum albumin (HSA) in phosphate buffered saline (PBS). Lerapolturev 
is provided in sterile, single use glass vials with a flip off top containing approximately 
0.5 mL of stock lerapolturev (2.24 x 109 TCID50).  
5.2 
Preparation/Handling/Storage/Accountability 
For complete lerapolturev storage, handling, and preparation instructions, please refer to 
the pharmacy manual. Lerapolturev preparation with Sponsor-supplied vehicle must 
occur in a biosafety cabinet or similarly contained environment in the institution’s 

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investigational pharmacy or equivalent. All handling of the study agent should occur under 
appropriate biosafety measures.  
Any materials in contact with the study agent, eg, pipettes, vials, etc., should be disposed 
of as biological waste. The minimum final desired volume of the study agent for injection 
is 0.5 ml, and the maximum volume will be 3.0 ml. The final volume should be drawn into 
the intended delivery device(s) (See pharmacy manual for list of needles/syringes that 
are acceptable for lerapolturev administration).  
5.3 
Lerapolturev Dose, Schedule, and Administration 
Dose: Lerapolturev should be administered at a fixed concentration of 5.33 x 108 
TCID50/ml in accordance with the pharmacy manual (PM). Please refer to the PM for 
complete information regarding lerapolturev administration. The maximum volume 
injected at an individual treatment visit will be 3 ml, which is dependent on the number 
and size of injectable lesions. This corresponds to a maximum lerapolturev dose of 
1.6 x 109 TCID50. The minimum injection volume is 0.5 ml (ie, minimum lerapolturev dose 
2.67 x 108 TCID50). Up to 6 lesions may be injected at an individual treatment visit. It is 
possible that more than 1 syringe may be required to treat a single lesion, due to large 
lesion size. See Table 7 for recommended lerapolturev injection volumes. See 
Section 3.1.2 for instructions regarding lerapolturev dose for participants receiving the 
Q3/4W schedule of injections.  

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Table 7. 
Recommended Lerapolturev Injection Volumes 
Lesion Size (longest 
dimension [cm]) 
Maximum Injection Volume 
Per Lesion (ml) 
Lerapolturev 
Concentration 
(TCID50/ml) 
≥ 5  
3.0  
5.33 x 108 
≥ 4 and < 5  
2.0 
≥ 3 and < 4  
1.5  
≥ 2 and < 3 
1.0 
0.5 to <2.0 
0.5 
Schedule: Participants will receive lerapolturev injections using the QW schedule which 
is defined as weekly x 7 followed by every 3 weeks (pembrolizumab) or every 4 weeks 
(nivolumab).  See Section 3.1.1 for instructions of what injection schedule to use upon 
crossover.  See Section 3.1.2  for instructions of what injection schedule to use for 
participants receiving the Q3/4W schedule.  
Key Considerations Regarding Lerapolturev Injection:  
• Where possible, at least one RECIST1.1/iRECIST target lesion should remain 
uninjected for as long as feasible while on study to facilitate the anti-tumor 
response assessment of non-injected target lesions.  
• Participants with lesions known to be sensitive to intratumoral injection (ie, are 
painful, such as in transit lesions with limited subcutaneous tissue on the shin) may 
receive reduced injection volumes relative to the recommended volume for a given 
tumor size, per investigator’s discretion, to manage tumor-related pain. However, 
the minimum allowable injection volume for a given lesion is 0.5 ml. 
• Any lesion that is visible or palpable may be injected; lesions located in sites 
considered to be of more significant risk for complications from lerapolturev 
injection and associated inflammation (eg brain, lung, mediastinum, liver, 
pancreas, other visceral organs, lesions subjected to curative levels of radiation 
where radiation-associated toxicity has not healed, lesions encasing or 
immediately adjacent to major blood vessels including the carotid artery) are not 
to be injected in this study. Ultrasound may be used to better visualize the lesion 
during lerapolturev injection to optimize participant safety. 
• Participants may stop receiving lerapolturev injections upon confirmation of CR or 
upon resolution of all injectable lesions (participants in Arm 2 should continue anti-
PD-1 maintenance per manufacturer’s prescribing instructions) and should be 
observed until progression/recurrence, at which point retreatment with lerapolturev 
is allowed. This process of injection, discontinuing injections and retreatment with 
injection may occur for a maximum of three times. 
o Participants receiving single-agent lerapolturev with a CR or complete 
resolution of all injectable disease (ie, other non-injectable disease persists) 
can crossover to Arm 2 upon progression. If upon progression, there are no 

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injectable lesions, the participant should begin anti-PD-1 therapy 
monotherapy upon crossover.  
• Lerapolturev injections should be administered concurrently with anti-PD-1 therapy 
during the “maintenance” schedule, (ie, Q3W for pembrolizumab and Q4W for 
nivolumab). Note that lerapolturev should be continued Q3W in the event 
pembrolizumab is administered on a Q6W cycle or Q4W in the event nivolumab is 
administered on a Q2W cycle.  
• Where possible, participants should receive the same anti-PD-1 that they failed 
prior to study entry, administered in accordance with the respective package insert 
with respect to length of exposure and/or management (eg, dose delay or 
discontinuation) of irAEs.  
Administration: Lerapolturev administration should be performed in accordance with the 
Pharmacy Manual. Anticoagulant and antiplatelet medications will be managed by the 
treating physician, per local institutional guidelines, to optimize the safety of intratumoral 
injection of lerapolturev. 
5.4 
Prior/Concomitant Therapy 
There are no currently known contraindications or drug-drug interactions for lerapolturev 
(per the IB), pembrolizumab, or nivolumab as per FDA-approved package labeling. All 
medical conditions should be treated by the investigator per current standard of care. 
Participants may also receive medications for symptomatic relief (ie, analgesics, 
laxatives, anti-emetics).  
• NOTE: Lerapolturev administration in combination with an anti-PD-L1 therapy is 
not allowed during this study  
Medications the participant has received within 28 days of Day 1 until 30 days after the 
last dose of study drug(s) should be recorded in the eCRF. This includes, but is not limited 
to, prescription medications, over-the-counter medications, injected medications, 
natural/herbal remedies, biological products, blood products, imported drugs, or “street” 
drugs.  Subsequent anticancer therapy should be collected until the end of study. 
Prohibited Therapies:  
Concomitant treatments that could prevent or mask potential AEs related to the 
investigational treatment or confound the assessment of its anti-tumor efficacy are not 
permitted, as far as the participant’s safety is protected.  
 
Administration of other systemic concomitant non-protocol anticancer therapies prior to 
progression is not permitted while on this study, with the exception of adjuvant endocrine 
therapy for breast cancer or prostate cancer defined as M0 disease or PSA 
persistence/recurrence without metastatic disease. Local treatment of isolated lesion(s) 
with palliative radiation therapy or surgery is permitted to control disease symptoms but 

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not to aid in the response of the tumor. If the lesion(s) treated is being followed for 
evaluation by RECIST (target or nontarget lesion), then “not evaluable” should be 
reported in the eCRF for this lesion at subsequent disease assessments following 
palliative radiotherapy or surgery. Participants requiring palliative radiation may continue 
receiving study drug until documented disease progression (radiographic or clinical) if, in 
the Investigator’s opinion, the participant is continuing to receive clinical benefit and they 
meet the requirements described in Section 6.2. However, for participants who have not 
had disease progression at the time of the need for palliative radiation therapy or surgery, 
the requirement for intervention will be regarded as disease progression in the study’s 
analyses and will be entered as such in the eCRF. 
 
The following medications are also not permitted: 
• Non-protocol specified investigational drugs. 
• Use of topical corticosteroids with occlusive dressings. 
• Anticoagulant use the day prior to, day of and the day following lerapolturev 
injection. Warfarin use is not allowed at any time during study participation. 
Antiplatelet agents, such as aspirin, clopidogrel, etc., are not considered 
anticoagulants for the purposes of this study and are allowed.  
• Live virus vaccines (beyond lerapolturev)  
o Examples of live virus vaccines include, but are not limited to, measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, and typhoid vaccine.  
o Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are 
live attenuated vaccines and are not allowed. 
COVID-19 Vaccination: 
Vaccination against COVID-19 is allowed on study, provided the vaccine is not based on 
a live virus (eg, the Johnson and Johnson single-dose vaccine or AstraZeneca vaccine). 
While on study, it is recommended that participants vaccinated with non-live virus 
vaccines (eg, mRNA-based vaccines) receive the vaccine at least 14 days before or after 
lerapolturev administration, if possible. The COVID-19 vaccine should be given in an 
anatomic area as far as possible from melanoma lesions that were recently injected with 
lerapolturev or that are planned for future injection. Participants receiving a COVID-19 
vaccine based on a live virus may begin Cycle 1, Day 1, once they are at least 4 weeks 
removed from vaccine administration.   
5.5 
Dose Modification/Toxicity Management Guidelines 
5.5.1 
Lerapolturev 
For AEs related to lerapolturev, lerapolturev may be withheld or permanently 
discontinued based on the severity of the adverse reaction. 
 

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Holding Lerapolturev Dosing  
If a participant experiences any of the following toxicities deemed related to lerapolturev, 
lerapolturev administration should be held until the toxicity has resolved to at least CTCAE 
Grade 1 or has returned to baseline: 
• Grade 2 or greater irAE, with the exception of vitiligo 
• Grade 2 or greater allergic reactions 
• any other Grade 3 or greater hematologic or non-hematologic toxicity 
For participants receiving concurrent lerapolturev and anti-PD-1 therapy, lerapolturev and 
the anti-PD-1 therapy can be administered independently of each other where 
appropriate. Should the investigator determine an AE is related to anti-PD-1 therapy and 
not lerapolturev, continuation of lerapolturev injections is allowed (or vice versa). 
However, if the AE is determined to be related to the combination, this should be noted 
and treatment with both therapies should be held until resolution, as described above.  
 
Permanent Discontinuation: 
Lerapolturev should be permanently discontinued if any lerapolturev-related Grade 3 or 
greater hematologic or non-hematologic toxicity fails to resolve to Grade 1 or baseline 
OR occurs more than twice (ie, three episodes = permanent discontinuation). 
 
5.5.2 
Anti-PD-1 Therapy 
For suspected irAEs related to anti-PD-1 therapy, the anti-PD-1 therapy may be withheld 
or permanently discontinued based on the severity of the adverse reaction, in accordance 
with FDA-approved package labeling and physician discretion.   
 
Withholding anti-PD-1 Therapy:  
The anti-PD-1 must be withheld for any of the following: 
• Grade 2 pneumonitis 
• Grade 2 or 3 colitis 
• Grade 3 or 4 endocrinopathies 
• Grade 2 nephritis 
• Grade 3 severe skin reactions or suspected Stevens-Johnson syndrome (SJS) or 
toxic epidermal necrolysis (TEN) 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater 
than 3 and up to 5 times upper limit of normal (ULN) or total bilirubin greater than 
1.5 and up to 3 times ULN 
• Any other severe or Grade 3 treatment-related AE  
 
Lerapolturev is not required to be withheld for participants enrolled in Arm 2, provided the 
investigator determines the AE requiring holding of the anti-PD-1 dose is not related to or 

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worsened by lerapolturev. The anti-PD-1 therapy can resume in participants whose 
adverse reactions recover to Grade ≤1 or baseline. 
Permanent Discontinuation: 
Anti-PD-1 therapy should be permanently discontinued for any of the following AEs  
• Any life-threatening adverse reaction (excluding endocrinopathies controlled with 
hormone replacement therapy) 
• Grade 3 or 4 pneumonitis or recurrent pneumonitis of Grade 2 severity 
• Grade 3 or 4 nephritis 
• Grade 4 severe skin reactions or confirmed SJS or TEN  
• AST or ALT greater than 5 times ULN  
o For participants with liver metastasis who begin treatment with Grade 2 
AST or ALT, discontinue if AST or ALT increases by greater than or equal 
to 50% relative to baseline and lasts for at least 1 week  
• Total bilirubin greater than 3 times ULN. 
• Grade 3 or 4 infusion-related reactions 
• Inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks 
• Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled 
with hormone replacement therapy) that do not recover to Grade 0-1 within 12 
weeks after last dose of the anti-PD-1 
• Any severe or Grade 3 treatment-related adverse reaction that recurs 
 
Management of anti-PD-1-related irAE:  
Always refer to the manufacturer’s prescribing information for the most current 
recommendations for management of irAE. Additional information can also be found in 
the NCCN Guidelines for Management of Immunotherapy-Related Toxicities40.  
• Suspected pneumonitis: Participants should be evaluated with radiographic 
imaging. They will receive corticosteroids (initial dose of 1 to 2 mg/kg/day 
prednisone or equivalent followed by a taper) for Grade 2 or greater pneumonitis. 
The anti-PD-1 must be withheld for moderate (Grade 2) pneumonitis, and 
permanently discontinued for severe (Grade 3), life-threatening (Grade 4), or 
recurrent moderate (Grade 2) pneumonitis. 
• Colitis: Participants must be monitored for signs and symptoms of colitis and 
administered corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or 
equivalent followed by a taper) for Grade 2 or greater colitis. The anti-PD-1 must 
be withheld for moderate (Grade 2) or severe (Grade 3) colitis, and permanently 
discontinued for life-threatening (Grade 4) colitis.  
• Hepatitis: Participants must be monitored for changes in liver function tests. They 
must receive corticosteroids (initial dose of 0.5 to 1 mg/kg/day [for Grade 2 
hepatitis] and 1 to 2 mg/kg/day [for Grade 3 or greater hepatitis] prednisone or 

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equivalent followed by a taper) and, based on severity of liver enzyme elevations, 
the anti-PD-1 must be discontinued.  
• Hypophysitis (including hypopituitarism and adrenal insufficiency): Participants 
must be monitored for signs and symptoms of endocrine origin. They will receive 
corticosteroids and hormone replacement as clinically indicated. The anti-PD-1 
must be withheld for moderate (Grade 2) and severe (Grade 3) hypophysitis and 
must be discontinued for severe (Grade 3) hypophysitis that does not recover or 
life-threatening (Grade 4) hypophysitis.  
• Thyroid disorders: Anti-PD-1 products can cause thyroid disorders, including 
hyperthyroidism, hypothyroidism, and thyroiditis. Participants must be followed 
for changes in thyroid function (at the start of treatment, periodically every 4 to 6 
weeks during treatment, and as indicated based on clinical evaluation) and for 
clinical signs and symptoms of thyroid disorders per the SOA (Table 1 or Table 2 
[Arm 2 lerapolturev + nivolumab]). Hypothyroidism will be treated by replacement 
hormones. Hyperthyroidism will be managed with thionamides and beta-blockers 
as appropriate. The anti-PD-1 must be withheld or discontinued for severe 
(Grade 3) or life-threatening (Grade 4) hyperthyroidism.  
• Hyperglycemia: Participants must be regularly monitored for blood glucose or 
other parameters of Type 1 diabetes. They must be treated with insulin and the 
anti-PD-1 withheld. In case of severe (Grade 3) hyperglycemia, they will receive 
anti-hyperglycemics.  
• Nephritis: Participants must be evaluated for renal function. They will be given 
corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed 
by a taper) for Grade 2 or greater nephritis. The anti-PD-1 must be withheld for 
moderate (Grade 2) nephritis and must be permanently discontinuation for 
severe (Grade 3) or life-threatening (Grade 4) nephritis.  
• Skin disorders: Immune-mediated rashes, including Stevens-Johnson Syndrome 
(SJS) and Toxic Epidermal Necrolysis (TEN) (some cases with fatal outcome), 
exfoliative dermatitis, and bullous pemphigoid, can occur. Participants must be 
monitored for suspected severe skin reactions and exclude other causes. Based 
on the severity of the adverse reaction, the anti-PD-1 must be withheld or 
permanently discontinued. Participants with Grade 2 or higher dermatologic 
toxicity will receive topical corticosteroids and/or systemic corticosteroids (initial 
dose 0.5 – 1.0 mg/kg/d prednisone or equivalent). For signs or symptoms of SJS 
or TEN, the anti-PD-1 must be withheld, and the participant must be referred to 
specialized care for assessment and treatment. In case SJS or TEN is confirmed, 
the anti-PD-1 must be permanently discontinued. 
• Infusion related reactions: During infusion, monitor patients for signs and 
symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, 
flushing, rash, hypotension, hypoxemia, and fever. For severe (Grade 3) or life-
threatening (Grade 4) infusion-related reactions, stop infusion and permanently 
discontinue pembrolizumab. Follow the recommend management practices noted 

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in the current package insert or in keeping with current medical practices when 
managing reactions noted during or after anti-PD-1 agent infusion. For severe or 
life-threatening 
infusion 
related 
reactions, 
this 
may 
include IV 
dexamethasone followed by oral steroids. Other immunosuppressive treatment 
should 
also 
be 
initiated 
if 
the 
reaction 
cannot 
be 
controlled 
by corticosteroids alone.  
Management of AEs related to CRS or ICANS:  
Administration of lerapolturev has not been associated with CRS or ICANS in the limited 
number of melanoma patients treated to date, or in the 190 patients treated with 
lerapolturev in other indications (Istari data on file). However, the current study is 
investigating lerapolturev in conjunction with concurrent anti-PD-1 therapy, which given 
the immune-mediated mechanism of action, could potentially affect the safety profile of 
lerapolturev. Therefore, monitoring of CRS or ICANS as AEs of special interest (AESI) 
will occur in this trial, which are each defined in Section 9.2. This includes reporting any 
AESI of CRS or ICANS within 24 hours of awareness of the event, regardless of severity 
or seriousness.   
NOTE: Per the American Society for Transplantation and Cellular Therapy (ASTCT) 
consensus guidelines41, symptoms of CRS or ICANS are primarily experienced in the first 
two weeks of therapy. 
Participants with suspected CRS should have lerapolturev and/or anti-PD1 therapy held, 
and a blood sample should be obtained and sent to the central laboratory for cytokine 
profiling. Therapy may resume upon resolution of CRS-related AEs to Grade 1 or 
baseline, per investigator discretion. ASTCT41 and/or institutional guidelines for treatment 
should be applied for management of CRS, including the use of corticosteroids and 
tocilizumab for Grade 3 or higher CRS, including whether or not to resume study therapy 
upon AESI resolution. 
Participants with neurological symptoms of suspected ICANS should have lerapolturev 
and/or anti-PD-1 therapy held until resolution of the ICANS-related AEs to Grade 1 or 
baseline. In addition, each participant should have a neurological exam that includes the 
Immune Effector Cell-Associated Encephalopathy (ICE) screening tool (Appendix I) per 
ASTCT guidelines, as well as a blood sample obtained for cytokine profiling as above.  
ASTCT41 and/or institutional treatment guidelines should be followed for ICANS-related 
AE management, including the administration of corticosteroids, or whether or not to 
resume study therapy upon AESI resolution.   

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6 
DISCONTINUATION OF STUDY TREATMENT, TREATMENT BEYOND 
PROGRESSION, PARTICIPANT COMPLETION AND WITHDRAWAL, AND 
STUDY TERMINATION 
6.1 
Discontinuation of Study Treatment 
Study drug(s) (defined as lerapolturev, nivolumab or pembrolizumab) will be discontinued 
if any of the following events occur during the study: 
• A participant suffers an AE that, in the judgment of the Investigator, Sponsor, or 
Medical Monitor, presents an unacceptable risk to the participant 
• General or specific changes in the participant’s condition (eg, a significant 
intercurrent illness or complication) that, in the judgment of the Investigator, are 
unacceptable for further administration of study drug 
• Occurrence of pregnancy during the study 
• Significant noncompliance with protocol requirements 
• The Sponsor or legal representative of the Sponsor requests the participant to 
withdraw 
• Withdrawal of consent 
 
• Lost to follow-up 
 
• Participant has radiologically documented disease progression and the physician 
determines the participant is not deriving clinical benefit as defined in Section 6.2 
• Where permanent discontinuation of all study drugs is indicated in the dose 
modifications guidelines (see Section 5.5) 
At the time of study drug discontinuation, an EOT visit should be completed with 
assessments performed as shown in appropriate General Schedule of Assessments 
(Table 1 or Table 2 depending on treatment group). The Investigator or Designee will 
document the reason for study drug discontinuation on the applicable electronic case 
report form (eCRF). When discontinuation is due to a SAE or a Grade 3 or 4 toxicity 
considered to be related to study drug(s), the Investigator should follow the event until 
resolution, return to baseline, or it is deemed that further recovery is unlikely. Data on 
these events should be collected in the eCRF. In the event a participant discontinues due 
to pregnancy, the Investigator or designee should notify the Medical Monitor by telephone 
within 24 hours of pregnancy confirmation (see Section 7.3.5). 

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6.2 
Treatment Beyond Progression  
Evidence indicates some patients treated with immunotherapy may derive clinical benefit 
after initial evidence of apparent disease progression42,43. Therefore, study drug 
administration may be continued until loss of clinical benefit, provided the participant 
appears to be deriving clinical benefit and the Investigator believes it is in the best interest 
of the participant to continue. Treatment past disease progression per RECIST 1.1 should 
only be considered if a participant is clinically stable and has the following:  
• Evidence of clinical benefit as assessed by the Investigator; assessment of clinical 
benefit should take into account whether the participant is clinically deteriorating 
and unlikely to receive further benefit from continued treatment 
• Absence of symptoms and signs (including worsening of laboratory values; eg, 
new or worsening hypercalcemia) indicating unequivocal progression of disease 
• No decline in ECOG performance status that can be attributed to disease 
progression 
• Absence of tumor growth at critical anatomical sites (eg, leptomeningeal disease) 
that cannot be managed by protocol-allowed medical interventions 
Decisions to continue treatment beyond initial progression per RECIST 1.1 may be 
discussed with the medical monitor and should be documented in the study records.  
Participants with radiographic disease progression confirmed at a subsequent tumor 
assessment (ie, iCPD) may be considered for continued study treatment at the discretion 
of the investigator if they continue to meet the criteria above and have evidence of clinical 
benefit. 
6.3 
Participant Withdrawal from the Trial 
Participants may be withdrawn from the study under any of the following circumstances: 
 
• Withdrawal of consent 
• Lost to follow-up 
• Administrative reasons (eg, Sponsor decision) 
• Major violation of the protocol 
• If in the opinion of the investigator, it is in the best interest of the participant 
• Non-compliance 
• Termination of the study 
Participant follow-up should continue as specified in the protocol until the scheduled date 
of study completion, or until recovery or stabilization of an AE, whichever comes last. All 

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participants that permanently discontinue study treatment should be followed for survival 
and disease progression outcomes; these assessments may be made via telephone 
contact if local follow-up is not possible.  At minimum, all participants should have an EOT 
visit that includes tumor measurements (imaging and cutaneous measurements) and a 
focused physical assessment prior to study withdrawal. Chemistry and hematology 
should be collected, if possible. Investigators should also provide a final and best overall 
anti-tumor response assessment with the eCRF.  
Lost to Follow-up 
A participant will be considered lost to follow-up if they fail to return for 2 scheduled visits 
and are unable to be contacted by the study site. The following actions must be taken if 
a participant fails to return to the clinic for a required study visit: 
• The site must attempt to contact the participant, reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, they will be considered to 
have withdrawn from the study. 
Participants who are lost to follow-up may be replaced at the Sponsor’s discretion.  
6.4 
Study Termination 
The entire study may be terminated by the Sponsor in the event of any of the following: 
• Upon discussion with the Data and Safety Monitoring Committee, the occurrence 
of AEs unknown to date with respect to their nature, severity, and duration, or an 
unexpected increase in the incidence of known AEs. 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of participants 
• Cancellation of the drug development program 
• Sponsor decision for other reasons 

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7 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SOAs (Table 1 and Table 2 
[Arm 2: lerapolturev + nivolumab]). Adherence to the study design requirements, including 
those specified in the SOA, is essential and required for study conduct. Immediate safety 
concerns should be discussed with the Sponsor immediately upon occurrence/awareness 
to determine if the participant should continue or discontinue the study drug treatments.  
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria prior to randomization. The investigator will maintain 
a screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure, as applicable.  
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count, scans) and obtained before signing of the ICF may be utilized for screening 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SOA.  
7.1 
Efficacy Evaluations 
Anti-tumor evaluations will be conducted as specified in the appropriate SOA (Table 1 
and Table 2 [Arm 2: lerapolturev + nivolumab]). Unscheduled assessments should be 
considered if clinically indicated, and results collected in the eCRF. The anti-tumor activity 
evaluations include the following: 
• Tumor measurements: All participants will undergo an extent of disease evaluation 
consisting of a chest, abdomen and pelvis CT, a brain MRI and skin caliper 
measurement (with photograph) of target lesions. Designation of which lesions are 
to be target lesions for assessment of anti-tumor response should be based on 
RECIST 1.1 guidelines. All participants will undergo repeat evaluations of their 
extent of disease per the SOA, or as clinically indicated. Imaging modalities should 
remain consistent throughout study. Evaluation of treatment response by imaging 
and/or caliper/ruler measurement will be performed according to RECIST 1.1 
criteria (NOTE: evaluation of tumor response per iRECIST is exploratory). Where 
possible, target lesions for assessment of tumor response should be separate from 
lesions chosen for biopsy (injected or non-injected). RECIST/iRECIST target 
lesions are not required to be lesions injected with lerapolturev. Participants 
without evidence of CNS disease at screening are not required to have brain MRI 
while on study, provided they remain without clinical evidence of progression in the 
CNS space. 
o NOTE: All MRIs should be performed with and without contrast, provided 
the participant can tolerate the contrast agent. A CT of the brain (with IV 
contrast if not contraindicated) may be performed in lieu of an MRI for those 
participants unable to receive an MRI.  

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• Long term follow-up: Study personnel will obtain survival information and 
radiographic scans (if the participant discontinued study for any reason other than 
radiographic progression or death) per SOC during the follow-up phase. Personnel 
should collect this information (including post-study anti-cancer therapies) during 
a participant’s routine clinic visit, review of the local medical records, by 
communicating with referring healthcare providers for participants who do not 
return to the study site for their subsequent care, or review of the Social Security 
Death Index. 
7.2 
Safety Assessments 
7.2.1 
Physical Examination and Vital Signs 
The screening physical examination will be a complete physical exam of major body 
systems and include, the general appearance of the participant, height and weight, vital 
signs (temperature, blood pressure (systolic and diastolic blood pressure [mmHg]), 
respiratory rate, and heart rate (bpm)), examination of the skin, ears, nose, throat, lungs, 
heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous 
system. During the Treatment Phase and at the EOT visit, focused and symptom-directed 
physical examination and weight assessment should be performed per the corresponding 
SOA (Table 1 and Table 2 [Arm 2: lerapolturev + nivolumab]) or as clinically indicated. In 
addition, an evaluation of all skin lesions, including those injected with lerapolturev at the 
previous treatment visit, should be performed prior to subsequent lerapolturev injection 
while on study. Only clinically relevant abnormalities found during the screening physical 
examination should be recorded and reported in the medical history eCRF. Clinically 
relevant abnormalities that present during study participation should be reported as AEs, 
where appropriate.  
7.2.2 
Clinical Safety Laboratory Assessments 
Laboratory assessments that will be conducted during the study are listed below: 
• Hematologic assessments include complete blood count with differential, which 
measures the following:  
• 
Hemoglobin 
• 
WBC count with differential  
• 
Platelet count 
• Chemistry assessments including the following analytes: 
• 
LDH 
• 
Glucose  
• 
Calcium 
• 
Sodium 
• 
Potassium  
• 
Bicarbonate 

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• 
Chloride 
• 
BUN 
• 
Creatinine  
• 
Total protein 
• 
Albumin 
• 
ALP 
• 
AST 
• 
ALT 
• 
Total bilirubin 
• 
Amylase 
• 
Lipase 
• INR, PT, PTT (or aPTT), as performed/reported per institutional standards 
• Beta-hCG, if applicable, within 2 days prior to Day 1 and approximately every 12 
weeks thereafter, while on study  
• TSH, free T4, and free T3  
All protocol-required laboratory assessments, as outlined above, must be conducted in 
accordance with the laboratory manual and the appropriate SOA (Table 1 and Table 2 
[Arm 2: lerapolturev + nivolumab]). The investigator must review the laboratory report, 
document this review, and record any clinically relevant changes occurring during the 
study as AEs in the eCRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which are not 
associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant's condition. 
All laboratory tests with values considered clinically significantly abnormal after the first 
lerapolturev injection through EOT visit should be repeated approximately weekly until 
the values return to Grade 1 or baseline, or are no longer considered clinically significant 
by the investigator or medical monitor. 
If such values do not return to ≤Grade 1 or baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and entered as an AE (as 
applicable), and the Sponsor notified. 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (eg, SAE, AE, or dose modification), 
then the results must be recorded in the eCRF.  
NOTE: Only report clinically significant laboratory abnormalities as AE when a diagnosis 
for the condition resulting in the laboratory abnormality is not available/not possible. 

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7.3 
Adverse Events, Immune-Related Adverse Events, Adverse Events of 
Interest and Serious Adverse Events 
Potential AEs will be spontaneously solicited from the participant (or, when appropriate, 
by a caregiver, surrogate, or the participant's legally acceptable representative) for the 
duration of the study. 
The definitions of an AE, irAE, AESI, or SAE can be found in Section 9.2.  
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE, irAE, AESI, or SAE and remain 
responsible for following up AEs that are serious, considered related to lerapolturev 
and/or lerapolturev in combination with anti-PD-1 therapy or study procedures that 
caused the participant to discontinue the study. 
7.3.1 
Time Period and Frequency for Collecting Information on Adverse 
Events, Immune-Related Adverse Events, Serious Adverse Events and 
Adverse Events of Special Interest  
Table 4 provides an overview of the time periods and frequency for AE, irAE, SAE, and 
AESI reporting. Any AEs and SAEs related to screening procedures that are not SOC 
(eg, PV vaccination booster) will be collected from signing of the ICF. All other 
AEs/AESI/SAEs will be collected upon commencement of lerapolturev administration (ie, 
events that are treatment emergent). Collection of AEs will continue until 30 days and 
SAEs and AESIs for 90 days after completion of the participant's last dose of study 
drug(s), including any contact for follow-up of safety (Note: treatment-related SAEs will 
be followed until resolution or stabilization). The investigator will immediately report to the 
Sponsor any SAE (whether or not considered study drug-related, including those listed in 
the protocol or IB) and must include an assessment of whether there is a reasonable 
possibility that lerapolturev caused the event.  
Disease progression is not to be reported as an AE/SAE. 
 
 
 

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Table 8. 
Time Windows and Frequency for Reporting Based on AE Type 
 
Reporting 
 
Start 
End 
Timeframe 
SAE 
Signing of ICF 
≤90 days of last 
dose of 
lerapolturev or 
anti-PD-1:  all SAE 
 
Within 24 hours of awareness 
AE 
• 
During screening, 
only AE deemed 
related to PV 
booster or 
mandatory per 
protocol biopsy  
• 
All other AE after 
1st lerapolturev 
injection 
≤30 days of last 
dose of 
lerapolturev or 
anti-PD-1 
Per study agreement 
AESI & 
irAE 
• 
During screening, 
only if deemed 
related to PV 
booster 
• 
After 1st 
lerapolturev 
injection 
≤90 days of last 
dose of 
lerapolturev or 
anti-PD-1 
• 
For irAE: Per study agreement 
• 
For CRS or ICANS ONLY:  
o Within 24 hours of 
awareness  
• 
For ISR: 
o Grade 3/4: Within 24 
hours of awareness 
o Grade1/2 ISR: Per 
study agreement 
 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Section 9.2. The investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. In addition, any AESI of CRS, ICANS, or Grade 3 or 
4 injection site reaction (ISR), should also be reported to the Sponsor within 24 hours, 
regardless of seriousness per the study’s safety reporting guidelines. An AESI of Grade 
1 or 2 ISR should be reported in accordance with the site’s study agreement.  
Investigators are not obligated to actively seek AEs, irAEs, AESIs or SAEs after 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a condition resulting in death, at any time after a participant has been discharged 
from the study, and he/she considers the event to be reasonably related to lerapolturev, 
lerapolturev in combination with anti-PD-1 or study participation, the investigator must 
promptly notify the Sponsor or designee. 
The method of recording, evaluating, and assessing causality of AEs, irAEs, AESIs and 
SAEs, and the procedures for completing and transmitting SAE reports, are provided in 
Section 9.2. 

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7.3.2 
Method of Detecting Adverse Events, Immune-Related Adverse Events, 
Adverse Events of Special Interest and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs, irAEs, AESIs and/or SAEs. 
Open-ended and non-leading verbal questioning of the participant is the preferred method 
to inquire about AE occurrences.  
7.3.3 
Follow-up of Adverse Events, Immune-Related Adverse Events, 
Adverse Events of Special Interest and Serious Adverse Events 
After the initial AE/irAE/AESI/SAE report, the investigator is required to proactively follow 
each participant at subsequent visits/contacts. All SAEs and non-serious irAEs and AESIs 
(see Section 9.2) will be followed until satisfactory resolution, the investigator deems the 
event to be chronic, the participant is stable, or the participant is lost to follow-up (as 
defined in Section 6.3). Supporting documentation of the event may be requested by the 
Sponsor and should be provided as soon as possible. Further information on follow-up 
procedures is provided in Section 9.2. 
7.3.4 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator is required to promptly (ie, within 24 hours) notify the Sponsor of the 
occurrence of an SAE, so that legal and ethical obligations towards the safety of 
participants and the safety of a study drug under clinical investigation are met.  
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study drug under clinical investigation. 
The Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent 
Ethics Committees (IEC), and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate, according to 
local requirements. 
  
7.3.5 
Notification of Pregnancy 
Because all participants are required to have a boost immunization of trivalent inactivated 
IPOL™, risk of lerapolturev transmission from mother to fetus after intratumoral injection 
is expected to be limited. Because risk is unknown, all participants will be required to 
utilize contraception during receipt of lerapolturev injections.  In addition, use of PD-1 
inhibitors may increase risk of fetal harm when administered to pregnant women. Women 
should be advised of the potential risk to a fetus and to use effective contraception during 
treatment with anti-PD1 therapy and for 150 days after the last dose received. 

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Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study drugs and until 150 days after the last dose. If a 
pregnancy is reported, the investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
7.4 
Tissue and Blood-Based Biomarker and Cytokine Analyses  
Tissue Biopsy Collection: Participants are required to submit a baseline tumor biopsy to 
enroll in the study. Submission of archival tissue is allowed if collected within 4 months 
prior to Cycle 1, Day 1, and the participant received no intervening systemic/intratumoral 
anti-cancer therapy between biopsy collection and Cycle 1, Day 1 (eg, focal RT of non-
biopsied lesions is allowed). If no archival tissue meeting these requirements is available, 
a baseline tumor biopsy should be collected during the Screening Period. During study 
participation, mandatory biopsies should be collected from injected lesions, non-injected 
lesions, and draining lymph nodes per the corresponding SOA (Table 1 and Table 2 [Arm 
2: lerapolturev + nivolumab]). For participants in Arm 1 that crossover to Arm 2, additional 
mandatory biopsies of an injected lesion, non-injected lesion, and draining lymph node 
should be performed at the time of crossover and on treatment as described in the 
treatment group’s SOA (Table 1 and Table 2 [Arm 2: lerapolturev + nivolumab]).  
At all timepoints, biopsies from all three sites (injected lesion, noninjected lesions and 
draining lymph nodes) should be collected if the biopsy is technically feasible and does 
not put the participant at significant risk. Examples of biopsy sites considered to be of 
significant risk include, but are not limited to the following: biopsies of the brain, lung, 
mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, 
stomach, or bowel wall. For those situations where the investigator determines biopsy of 
a lesion would (1) lead to a significant decrease in the size of the lesion such that 
response assessment by RECIST 1.1 would be confounded, or (2) increase the risk of 
lerapolturev leakage from the lesion, the mandatory biopsy for that timepoint can be 
waived. In addition, complete resection of target lesions is prohibited unless necessary 
for participant’s safety as determined by the investigator.    
Tissue samples may be analyzed by immunohistochemical staining, RNA and/or DNA 
sequencing, and other molecular techniques to confirm the presence of lerapolturev, and 
to determine the presence or absence of biomarkers that may (1) predict response to 
lerapolturev, (2) measure the associated immune response and/or changes in immune 
cell function over time, or (3) to further characterize lerapolturev’s mechanism of action. 
Samples (blood and tissue) may be stored and used for future research for up to 10 years. 
Blood Biopsy Collection: Mandatory blood samples should be drawn during the screening 
period and while on study, as described in the appropriate SOA (Table 1 and Table 2 

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[Arm 2: lerapolturev + nivolumab]), to facilitate evaluation of immune cell function and 
cytokine profiles before and after study treatment administration. Participants in Arm 
1 who crossover to Arm 2 should also have blood samples collected at the time of 
crossover and on treatment as described in the requisite SOA (Table 1 and Table 2 
[Arm 2: lerapolturev + nivolumab]). In addition, an additional sample is to be drawn in 
the event any participant (regardless of treatment arm) experiences an AESI of CRS 
or ICANS. This sample should be drawn as soon as possible after learning of the 
event, to facilitate the interrogation of potentially relevant changes in circulating 
cytokine levels.  
Blood samples may be interrogated by cytokine and flow cytometric analyses, RNA 
and/or DNA sequencing, and other molecular techniques to evaluate signatures of anti-
tumor immune response to lerapolturev in circulation. In addition, various immune cell 
types, including peripheral blood mononuclear cells, may be isolated and assayed via 
genetic and proteomic techniques to evaluate any changes in cell function following 
treatment with lerapolturev with or without concurrent anti-PD-1. These samples will be 
stored under the appropriate conditions as described in the laboratory manual and 
analyzed as a group by the Sponsor or designee at designated intervals.  Samples (blood 
and tissue) may be stored and used for future research for up to 10 years. 
8 
STATISTICAL CONSIDERATIONS 
8.1 
Stratification Factors 
Participants receiving lerapolturev injections using the Q3/4W schedule ± anti-PD-1 
therapy will be stratified based on time since prior anti PD-1/L1 exposure (≤6 weeks 
versus >6 weeks) and baseline LDH (normal versus >ULN). 
Participants receiving lerapolturev injections using the QW schedule ± anti-PD-1 therapy 
will be stratified based on type of anti-PD-1/L1 resistance (primary versus secondary as 
defined in Kluger et al7) and baseline LDH (normal versus >ULN). 
8.2 
Statistical Hypotheses 
Lerapolturev administered in combination with anti-PD-1 therapy on the QW injection 
schedule to participants with anti-PD-1 refractory melanoma will result in an ORR of 
≥ 33%.   
8.3 
Sample Size Determination  
The determination of sample size in this two-arm, randomized open-label Phase 2 trial 
was based on feasibility and logistical considerations. As discussed in Section 1.1, the 
Sponsor estimates that the true activity of anti-PD-1 re-challenge in the anti-PD-1 
refractory population eligible for this study is less than 10%. Therefore, lerapolturev 
administered in combination with anti-PD-1 therapy using the QW injection schedule, will 
be considered to have anti-tumor activity in the anti-PD-1 refractory melanoma population 

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if the lower bound of the 95% CI is above 10%. We estimate the sample size for 
participants receiving lerapolturev (QW schedule) ± anti-PD-1 therapy to be 
approximately 30 participants (n=15 per arm). Therefore, 5 of 15 participants (ie, 33%) in 
Arm 2 treated with the lerapolturev/anti-PD-1 combination (QW schedule) must have an 
objective response for the 95% CI to be greater than 10% (95% CI: 11.8% to 61.6%).  
Additional comparisons (eg, Arm 1 versus Arm 2; Q3/4W schedule vs QW schedule for 
each Arm etc.) are planned. However, no formal hypothesis will be tested. Additional 
detail will be provided in the statistical analysis plan (SAP). 
8.4 
Populations for Analyses 
For participants receiving the QW schedule of lerapolturev injections, enrollment will be 
stratified based on baseline LDH levels (normal versus >ULN) and type of anti-PD-1/L1 
resistance (primary versus secondary), primarily for the purpose of balancing key 
participant descriptors between the treatment arms. For purposes of analysis, the 
following key populations are defined; additional populations may be defined in the SAP: 
Population 
Description 
Intent-to-treat  
All participants who sign the ICF and are randomized 
Efficacy--QW 
Schedule 
Participants receiving at least one lerapolturev injection on the 
QW schedule and at least 1 post-baseline evaluation  
Efficacy—Q3/4W 
Schedule 
Participants receiving at least one lerapolturev injection on the 
Q3/4W schedule and at least 1 post-baseline evaluation 
Crossover 
Participants from Arm 1 receiving at least one lerapolturev 
injection with concurrent anti-PD-1 and at least 1 post-crossover 
evaluation 
Safety—QW 
Schedule 
Participants receiving at least one lerapolturev injection on the 
QW schedule 
Safety—Q3/4W 
Schedule 
Participants receiving at least one lerapolturev injection on the 
Q3/4W schedule 
8.5 
Statistical Analyses 
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for 
missing data. The statistical approach described in the SAP will supersede the statistical 
approach described here, in the event of discrepancy. This section is a summary of the 
planned statistical analyses for key endpoints of interest. 
8.5.1 
Efficacy Analyses 
The primary endpoint for measuring anti-tumor activity will be ORR, which will be 
evaluated once participants have reached at least Week 26, based on RECIST 1.1. ORR 
will be described as the overall number (%) of participants in each treatment arm with CR 

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or PR and will be presented along with the respective 95% confidence intervals (CI) for 
each arm. For Arm 1, the primary analysis will include participant response prior to anti-
PD-1 re-challenge (eg, before crossover to Arm 2).  ORR by treatment stratum and 
lerapolturev dosing schedule will be conducted, as will other pre-determined subgroups 
defined in the SAP. 
Additional secondary endpoints, including DOR, DRR, DCR, PFS and OS will also be 
summarized. DRR will be presented as the number (%) of participants with CR or PR 
lasting ≥6 months, along with 95% CI. DCR will be shown as the number (%) of 
participants with SD, PR, or CR together with the 95% CI. DOR, PFS and OS will be 
described using the Kaplan-Meier method. Additional details will be included in the SAP. 
8.5.2 
Translational Analyses 
As a primary objective, markers of immune activation in response to lerapolturev 
treatment (with or without anti-PD-1) will be evaluated in both injected and non-injected 
lesions. Participants with a baseline and at least 1 post-treatment biopsy will be analyzed 
for changes in the number of CD8+ TILs located within the TME, as well as for changes 
in PD-L1 expression. Additional exploratory analyses will be performed to characterize 
changes in other important markers of immune function following treatment with single-
agent lerapolturev or with the lerapolturev/ anti-PD-1 combination. In general, pre- and 
post-treatment tissue biopsies will be assayed for changes in immune cell density by 
histology or other molecular techniques (eg, flow cytometry). Changes in T cell receptor 
repertoire, and chemokine and/or cytokine profiles in blood samples and/or tissue will also 
be assayed at the gene and/or protein expression level, as appropriate. All results will be 
described by summary statistics as outlined in the SAP.  
 
8.5.3 
Safety Analyses 
Participants receiving at least one lerapolturev injection will be analyzed for safety. Any 
AEs reported after the initiation of study treatment and ≤30 days after the last dose of 
study treatment are defined as treatment emergent. For each treatment-emergent AE, 
the maximum grade experienced by each participant will be summarized with frequency 
distributions. Adverse event tabulations will include all treatment emergent events 
(regardless of attribution), and a tabulation for all study-related interventions that are at 
least possibly related to lerapolturev. Adverse events occurring during screening due to 
lerapolturev-related procedures that are not standard of care (eg, PV booster) will be 
considered related to lerapolturev and summarized separately.  
8.5.4 
Exploratory Analyses  
Exploratory objectives evaluating subgroup analyses, such as outcomes for participants 
based on BRAF status, primary versus secondary resistance, time since prior anti-PD-1 
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baseline LDH levels or others (as described in Section 2.1) will be summarized by 
endpoints, including DOR, DRR, DCR, PFS and OS. DRR will be presented as the 
number (%) of participants with CR or PR lasting ≥6 months, along with 95% CI. DCR will 
be shown as the number (%) of participants with SD, PR, or CR together with the 95% 
CI. DOR, PFS and OS will be described using the Kaplan-Meier method. For the analysis 
of response following crossover from Arm 1 to Arm 2, the baseline for anti-tumor response 
in this subgroup will based on the size of the tumor at the time of crossover and will be 
summarized separately. Anti-tumor response (ie, ORR, DOR, and DRR) based on 
iRECIST will also be summarized with descriptive statistics, as appropriate. 
In addition, a per-protocol population (no major protocol deviations, etc.) and predictors 
of lerapolturev response and/or changes in markers of immune function will be 
summarized by summary statistics, as appropriate. Additional details regarding these and 
other analyses will be described in the SAP.  
8.6 
Interim Analysis (IA) 
No interim analysis will be conducted for this study. Rather, efficacy results for 
participants receiving the Q3/4W schedule and QW schedule will be summarized 
separately for participants receiving either lerapolturev monotherapy or lerapolturev in 
combination with anti-PD-1 therapy, as described in the SAP.  

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9 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
9.1 
Regulatory, Ethical, and Trial Oversight Considerations 
9.1.1 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the 
following: 
o Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and applicable ICH Good Clinical Practice (GCP) 
Guidelines 
o Applicable federal, state, and local regulations  
• 
The protocol, ICF, IB, and other relevant documents (eg, advertisements) must 
be submitted to an IRB/IEC by the investigator and reviewed and approved by 
the IRB/IEC before the study is initiated.  
• 
Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The investigator will be responsible for the following: 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, and all other 
applicable local regulations. 
o Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC. 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures. 
9.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
study and for 1 year after completion of the study. 
9.1.3 
Informed Consent Process 
Participants must be informed that their participation is voluntary. The investigator or 
his/her representative will provide full and adequate written and oral explanation of the 
nature of the study to the participant or his/her legally authorized representative (LAR) 
and answer all questions regarding the study.  

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Participants or their LAR will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or trial center.  
The medical record must include a statement that written informed consent was obtained 
before the participant was screened for the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study, when required.  
A copy of the ICF(s) must be provided to the participant or the LAR.  
9.1.4 
Data Protection 
All personal information for participants in the study will be kept strictly confidential and 
will be protected by the investigators, investigational site staff, the Sponsor, and any third 
parties working on behalf of the Sponsor. Every effort will be made to maintain the 
confidentiality of any personal information that identify the participant by name (eg, signed 
ICF, laboratory reports, clinic charts), except to the extent necessary to allow monitoring 
or auditing by the Sponsor or designee, and auditing by the FDA, or other regulatory 
authorities.   
To protect participant privacy, coded information will be labeled in a way that will not 
identify the participant to the Sponsor and others who may see the information at the 
Sponsor location. The participant must be informed that his/her medical records may be 
examined by study monitors, Clinical Quality Assurance auditors, other authorized 
personnel appointed by the Sponsor, by appropriate IRB/IEC members, and by inspectors 
from regulatory authorities. The participant must also be informed that his/her personal 
study-related data will be used by the Sponsor in accordance with local data protection 
law. The level of disclosure must also be explained to the participant.  
This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participants.  
9.1.5 
Data and Safety Monitoring Committee 
An external DSMC has been engaged to closely monitor the safety of the interventions 
under investigation during this study.  The DSMC was tasked to review the data during 
(1) the safety run-in, (2) once 12 participants treated with the Q3/4W schedule were 
randomized and completed the DLT period (eg, after approximately six participants have 
been treated with lerapolturev plus anti-PD1 therapy), (3) at the previously planned 
interim analysis (IA) and (4) approximately every 4 months after the IA.  

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As mentioned in Section 3.1, the DSMC met on 20 December 2021 to review all available 
safety data collected following clearance of the DLT monitoring period of the 12th 
participant randomized (all receiving Q3/4W schedule) (18 participants total: n=6 from the 
safety run-in and n=12 randomized [n=6 per arm]), as well as to discuss the feasibility of 
increasing the lerapolturev dose and changing the dosing schedule (ie, max dose of 
1.6 x 109 TCID50 administered using the QW schedule). Given the favorable tolerability 
profile of lerapolturev, when given alone or in combination with anti-PD-1, the DSMC 
supported the Sponsor’s recommendation to change the lerapolturev dose and schedule, 
with the agreement that the next DSMC meeting should occur once 12 participants (n=6 
per arm) have received the QW lerapolturev dosing schedule and have cleared the DLT 
period. As before, the DSMC will make recommendations regarding whether adjustments 
to lerapolturev dose are warranted, as well as whether to continue the study as planned. 
Based on this agreement with the DSMC and other logistical considerations, the DSMC 
will no longer meet to review data at the previously planned IA. Once the planned QW 
schedule safety evaluation is complete, the DSMC will continue to meet approximately 
every 4 months thereafter, as previously described.   
The DSMC will also review any DLTs that are deemed at least possibly related to 
lerapolturev and any SUSARs on an ongoing basis during the conduct of the trial; and 
may provide additional recommendations with regard to lerapolturev dose and/or other 
modifications to study conduct. For example, dosing of current participants may be held 
to evaluate SUSARs that have not been described to date with respect to their nature, 
severity, and duration, or if there is an unexpected increase in the incidence of known 
AEs in excess of expectations (with lerapolturev and/or anti-PD-1 therapy). The DSMC 
may also formulate recommendations relating to the selection, recruitment, and retention 
of participants and their management. Additional details regarding the responsibility of 
the DSMC/its chair will be provided in a DSMC charter document, as applicable. 
9.1.6 
Data Quality Assurance 
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, imaging data). The investigator is responsible 
for verifying that all data entries are correct and must maintain accurate documentation 
(source data) that supports the information entered in the eCRF. The investigator must 
also permit study-related monitoring, audits, IRB/IEC review, and regulatory agency 
inspections and provide direct access to source data documents. Investigators will keep 
personal medical records and a list that links each participant’s name to his or her code 
number as part of the study requirements according to local regulatory and legal 
requirements.  

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The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. Study monitors will perform ongoing source data verification 
to confirm that data entered into the eCRF by authorized site personnel are accurate, 
complete, and verifiable from source documents. Ultimately, the study monitors will help 
ensure that the safety and rights of participants are being protected, that the study is 
being conducted in accordance with the currently approved protocol, as well as any other 
study agreements, ICH GCP, and all applicable regulatory requirements.  
All essential records and documents pertaining to the conduct of this study must be 
retained by the investigator for the following time periods:  
• At least 2 years after the last marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region; or 
• At least 2 years have elapsed since the formal discontinuation of clinical development 
of the study drug 
These documents should be retained for a longer period, if required by applicable 
regulatory requirements or by the executed clinical trial agreement with the Sponsor. It is 
the responsibility of the Sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. The executed clinical trial agreement will 
govern if language differs from that contained herein. No records may be transferred to 
another location or party without written notification to the Sponsor.  
9.1.7 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or ICH GCP. The 
noncompliance may be either on the part of the participant, the investigator, or the study 
site staff. As a result of deviations, corrective actions may be developed by the site and 
implemented promptly.  
It is the responsibility of the site investigator to use continuous vigilance to identify and 
report deviations according to ICH and/or Sponsor requirements. All deviations must be 
addressed in study source documents and reported to the Sponsor. Protocol deviations 
must be sent to the reviewing IRB/IEC, per their policies. The site investigator is 
responsible for knowing and adhering to the reviewing IRB/IEC requirements. 
9.1.8 
Source Documents 
Source documents are necessary to provide evidence for the existence of the participant 
and to substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. Source data includes (but is not limited to): in-patient hospital charts, 
clinic notes, out-patient records, original tests results, pathology reports, laboratory data, 
worksheets, investigational product accountability records, consent forms, etc. 

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Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
Remote methods to access source documents may be used throughout the conduct of 
the study.  For example, remote access to study charts and regulatory files may be 
required throughout the conduct of the study.  In addition, remote monitoring visits may 
also be performed, as needed. 
9.1.9 
Study and Site Closure 
The Sponsor or designee reserves the right to temporarily suspend or close the study, 
either at a single site or all sites, at any time for any reason. If such action is taken, the 
Sponsor will discuss this with the investigator (including the reasons for taking such 
action) at that time. The Sponsor will promptly inform all other investigators and 
institutions conducting the study if the study is suspended or terminated for safety 
reasons. The Sponsor will also inform necessary regulatory authorities of the suspension 
or termination of the study and the reason(s) for the action. If required by applicable 
regulations, the investigator must inform the IRB/IEC promptly and provide the reason for 
the suspension or termination. 
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents/records are complete, study supplies (including study drug) have 
been collected and/or are accounted for, remaining data issues are clarified or resolved, 
and study-site closure visit has been performed. 
Reasons for the early closure of a study site by the Sponsor or investigator 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/SOPs, or GCP 
guidelines. 
• 
Inadequate recruitment of participants by the investigator. 
• 
Discontinuation of further lerapolturev development. 
9.1.10 
Confidentiality and Publication Policy 
The investigator and other study site personnel will keep confidential any information 
provided by the Sponsor related to this study (including this protocol) and all data and 
records generated while conducting the study. The investigational site will not use the 
information, data, or records for any purpose other than conducting the study, in keeping 
with all provisions related to such in the executed clinical trial agreement. 

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• The results of this study may be published or presented at scientific meetings, only 
with documented Sponsor approval. The investigator is required to submit all 
manuscripts or abstracts to the Sponsor for review or approval before submission.  
• In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 

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9.2 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study drug(s), whether or not considered 
related to the study drug(s). 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study drug(s). 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (ie, not related 
to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study drug(s) administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
drug(s) or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfil the definition of an 
AE or SAE. 
 

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Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital, including elective/planned medical 
procedures). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
Definition of SAE: 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing 
hospitalization 
 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 

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• Results in persistent disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This includes abnormal birth outcomes (spontaneous abortion, 
fetal death, stillbirth, congenital anomalies, etc.) from pregnancies of participants who 
became pregnant (either female participants or female partners of male study 
participants).This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect 
Other situations: 
 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
Examples of such events include intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
Definition of Immune-Related Adverse Events (irAEs):  
An irAE is defined as: 
• 
Any adverse event affecting an organ system through an autoimmune or 
inflammatory mechanism, whereby the immune system is acting against normal 
tissue. Examples of irAEs, as well as recommendations for study drug management 
in the event of an irAE are described in Section 5.5.  
Definition of Adverse Events of Interest (AESI):  
An AESI is defined as:  
• Any AE (serious or non-serious) of scientific and medical concern for which 
ongoing monitoring and communication by the investigator to the Sponsor or 
designee may be appropriate. Such events may require further investigation to 
characterize and understand them. Any AESI should be entered in the eCRF.  

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Because lerapolturev is an immunotherapeutic administered by intratumoral injection, 
AESIs fall into 2 categories: 1.) AEs related to lerapolturev administration (ie, ISR), and 
2.) AEs related to CRS and ICANS, which can occur when the body’s immune cells 
release a bolus of inflammatory cytokines in response to an immunotherapeutic44. AESI 
related to CRS and ICANS should be reported to the Sponsor within 24 hours, 
regardless of severity or seriousness. AESI related to ISR does not require expedited 
reporting (ie, within 24 hours), unless considered an SAE. A brief overview of each 
AESI is outlined below.   
AEs associated with ISR: 
To more completely describe the signs and symptoms associated with ISR, additional 
information related to the parameters outline below should be collected, which have 
been adapted from FDA guidance for evaluating ISR in vaccine trials45 (see 
Appendix I), as well as past clinical experience with lerapolturev in melanoma.    
• Erythema  
• Induration 
• Pruritus  
• Ecchymosis/bruising/skin discoloration 
• Pain  
Each symptom will be graded on a scale of 1 to 4, as described in Appendix I, which 
may represent a measure of intensity, not seriousness. Thus, a Grade 3 or Grade 4 
sign or symptom may be severe, but not necessarily serious. Therefore, although all 
Grade 3/4 AEs of ISR should be reported within 24 hours, only AEs of ISR meeting the 
criteria for seriousness (see SAE definition above for a definition of seriousness) should 
be reported as an SAE. Where appropriate, reporting of symptoms may also require a 
measurement recorded as a continuous variable (ie, diameter of erythema).  
AEs associated with CRS and ICANS:  
The management of signs and symptoms of CRS and ICANS are described in 
Section 5.5 (Management of CRS and ICANS). CRS has been associated with 
administration of other immunotherapeutics, including oncolytic viruses, such as T-
VEC19 and CAR T cell therapies, but has not been detected in any participants treated 
with lerapolturev to data (Istari data on file). The ASTCT consensus guidelines describe 
that the onset of symptoms of CRS typically occur within 2 weeks of treatment41, and 
may include (but are not limited to):  
• Fever (required; ≥ 38°C) not attributable to any other cause or underlying 
condition 
• Hypoxia  
• Tachycardia  

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• Hypotension 
• Dyspnea 
 
Per the ASTCT consensus guidelines41, symptoms of ICANS are defined as AEs that 
result in “a pathologic process involving the CNS following any immune therapy that 
results in activation or engagement of endogenous or infused T cells and/or other 
immune effector cells.” AEs related to ICANS can include (but may not be limited to) 
the following:  
• Cerebral edema 
• Seizure 
• Motor weakness 
• Aphasia 
• Altered level of consciousness  
• Impaired cognition  
As stated, administration of lerapolturev has not been associated with CRS or ICANS 
in any participant treated with lerapolturev to date, regardless of indication (Istari data 
on file). Because the current study is investigating lerapolturev in conjunction with 
concurrent anti-PD-1 therapy, additional steps are being taken to characterize the 
occurrence of, duration of, and response to interventions for signs and symptoms of 
CRS and/or ICANS, should they occur. This includes reporting any AESI of CRS or 
ICANS within 24 hours of awareness of the event, regardless of severity or seriousness, 
as well as acute testing of plasma for cytokine profile, as outlined in Section 5.5. 
Suspected ICANS also requires a neurological exam which should include the ICE 
screening assessment, per Appendix I. All AESI of CRS and ICANS will be graded on 
a scale of 1 to 5 according the ASTCT consensus guidelines (see Appendix I).  
If any individual sign or symptom meets the criteria for seriousness (ie, results in new 
hospitalization, 
prolonged 
hospitalization, 
death, 
persistent 
or 
significant 
disability/incapacity, a life-threatening condition, or an event of medical significance), it 
should be reported as an SAE, as described in Section 7.3.4. 
 
 
 

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Recording and Follow-Up of AE, AESI and/or SAE 
AE, irAE, AESI and SAE Recording 
• 
When an AE/irAE/AESI/SAE occurs, it is the responsibility of the investigator to 
review all documentation (eg, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event and report the event within the appropriate 
timeframe. 
• 
The investigator will then record all relevant AE/irAE/AESI/SAE information in the 
eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor/designee in lieu of completion of the necessary 
eCRF page and/or any other safety event reporting form (if applicable) noted in the 
study’s safety reporting guidelines. 
NOTE: AESI of CRS or ICANS should be recorded in eCRF with the verbatim term 
of CRS or ICANS, rather than the individual signs and symptoms related to the 
AESI. The underlying signs and symptoms associated with the AESI should be 
reported per the study’s safety reporting guidelines and/or as part of the descriptive 
narrative, rather than as individual AEs.    
• 
There may be instances when copies of medical records for certain cases are 
requested the Sponsor/designee. In this case, all participant identifiers, except for 
the participant number, will be redacted on the copies of the medical records before 
submission. 
• 
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/AESI/SAE. 
Assessment of Intensity 
With the exception of AESIs related to CRS or ICANS, the investigator will assess 
severity grade for each AE, irAE, AESI (ISR only) and SAE reported during the study 
using the National Cancer Institute – Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) version 5 or later. AESI related to CRS or ICANS should be 
graded according to the ASTCT guidelines41 (see Appendix I). Any AE not listed in the 
NCI-CTCAE will be graded according to the investigator’s clinical judgment using the 
standard grades as follows: 
• 
Grade 1 (Mild): Awareness of symptoms that are easily tolerated, causing 
minimal discomfort and not interfering with everyday activities. 
• 
Grade 2 (Moderate): Sufficient discomfort is present to cause interference with 
normal activity. 
• 
Grade 3 (Severe): Extreme distress, causing significant impairment of 
functioning or incapacitation. Prevents normal everyday activities. 

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AE, irAE, AESI and SAE Recording 
• 
Grade 4, (Life-threatening): Urgent intervention indicated. 
• 
Grade 5: Death. 
The investigator should use clinical judgment in assessing the severity of events not 
directly experienced by the participant (eg, laboratory abnormalities). 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study drug(s) and 
each occurrence of each AE/irAE/AESI/SAE and to record this determination in the 
eCRF. The AE must be characterized as unrelated, unlikely to be related, possibly 
related, probably related, or definitely related.  
o "Definitely related" conveys the adverse event has a timely relationship to 
administration of study treatment and there is no apparent, potential alternate 
etiology.  
o “Probably related” conveys that there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out.  
o “Possibly related” suggests that the association of the AE with the study 
treatment is unknown; however, the AE is not reasonably supported by other 
conditions.  
o “Unlikely to be related” suggests that only a remote connection exists between 
the study treatment and the AE. Other conditions, including chronic illness, 
progression or expression of the disease state or reaction to concomitant 
therapy, appear to explain the reported AE.  
o “Unrelated” is used if there is not a reasonable possibility that the study treatment 
caused the AE 
• 
The investigator should use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study drug(s) 
administration will be considered and investigated. 
• 
The investigator should consult the IB during his/her assessment. 
• 
For each AE/irAE/AESI/SAE, the investigator must document in the medical notes 
that he/she has reviewed the AE/irAE/AESI/SAE and has provided an assessment 
of causality, along with indication of the key pieces of evidence that factored into 
that determination. 
• 
There may be situations in which an AESI or SAE occurs, and the investigator has 
minimal information to include in the initial report to the Sponsor/designee. 
However, it is very important that the investigator always make an 
assessment of causality for every SAE before the initial transmission of the 
AESI or SAE to the Sponsor. 

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Assessment of Causality 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and may submit the relevant follow-up information with the updated 
causality assessment for the AESI or SAE. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs, irAEs, AESIs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE, irAEs, AESI or SAE as 
fully as possible. This may include additional laboratory tests or investigations, 
histopathological 
examinations, 
or 
consultation 
with 
other 
health 
care 
professionals. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The investigator will submit any updated AESI (for AESI related to CRS, ICANS, or 
Grade 3/4 ISR ONLY) or SAE data to the Sponsor within 24 hours of receipt of the 
information. 
 
 

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10 
ABBREVIATIONS 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ASTCT 
American Society for Transplantation and Cellular Therapy 
BPM 
Beats per minute 
CBC 
Complete blood count 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
case report form(s) (paper or electronic as appropriate for this study) 
CRS 
Cytokine release syndrome 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T lymphocytes 
CTLA-4 
Cytotoxic T-lymphocyte-associated protein 4 
DC 
Dendritic cell 
DCR 
Disease control rate 
DILI 
Drug-induced liver injury 
DLT 
Dose limiting toxicity 
DOR 
Duration of response 
DSMC 
Data safety monitoring committee 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
eCRF 
Electronic case report form 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
GBM 
Glioblastoma multiforme 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitic C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HSA 
Human serum albumin 
IA 
Interim analysis 
IB 
Investigator’s brochure 
ICANS 
Immune effector cell-associated neurotoxicity syndrome 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
INR 
International normalized ratio 

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IPHP 
Investigational product handling plan 
IPOL 
Immunization with PV Inactivated 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
iRECIST 
Immune response evaluation criteria in solid tumors 
IRES 
Internal ribosome entry site 
ISR 
Injection site reaction 
LAR 
Legally authorize representative 
LDH 
Lactose dehydrogenase 
MDRD 
Modification of diet in renal disease 
MRI 
Magnetic resonance imaging 
ORR 
Overall response rate 
OS 
Overall survival 
PBS 
Phosphate buffered saline 
pCR 
Pathologic complete response  
PD 
Progressive disease 
PD-1 
Program death receptor - 1 
PD-L1 
Programmed death-ligand 1 
PK 
pharmacokinetic(s) 
PQC 
Product Quality Complaint 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PV 
Poliovirus 
PV1S 
Poliovirus serotype 1 
PVR 
Polio virus receptor 
rGBM 
Recurrent glioblastoma multiforme 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SITC 
Society for Immunotherapy of Cancer 
SJS 
Stephen Johnson Syndrome 
SOA 
Schedule of assessments 
SUSAR 
suspected unexpected serious adverse reaction 
TBP 
Treatment beyond progression 
TCID 
Tissue culture infectious dose 
TEN 
Toxic epidermal necrolysis 
TME 
Tumor microenvironment 
T-VEC 
Talimogene laherparepvec 
ULN 
Upper limit of normal 
WBC 
White blood cell 

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11 
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12 
APPENDIX I 
ASTCT Consensus Grading for CRS adapted from Lee et al., 201941 
CRS 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Fever1 
Temperature 
≥38°C 
Temperature 
≥38°C 
Temperature ≥38°C 
Temperature ≥38°C 
Death due to 
CRS, where 
another factor is 
not the principle 
cause 
With 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring a 
vasopressor with or 
without vasopressin 
Requiring multiple 
vasopressors 
(excluding 
vasopressin) 
And/or2 
Hypoxia 
None 
Requiring low-flow 
nasal cannula3 or 
blow-by 
Requiring high-flow 
nasal cannula3, 
facemask, 
nonrebreather mask, or 
Venturi mask 
Requiring positive 
pressure (eg, CPAP, 
BiPAP, intubation and 
mechanical ventilation)  
Organ toxicities associated with CRS may be graded according to CTCAE v5.0, but do not influence CRS grading.  
1. 
Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic 
or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this 
case, CRS grading is driven by hypotension and/or hypoxia. 
2. 
CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, 
a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is 
classified as grade 3 CRS. 
3. 
Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, 
sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
 
ASTCT Consensus Grading for ICANS adapted from Lee et al., 201941 
ICANS grade is determined by the most severe event (ICE score [see below], level of consciousness, seizure, motor findings, raised 
ICP/cerebral edema) not attributable to any other cause; for example, a patient with an ICE score of 3 who has a generalized 
seizure is classified as grade 3 ICANS. N/A indicates not applicable. 
1. 
A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a patient with an ICE 
score of 0 may be classified as grade 4 ICANS if unarousable. 
2. 
Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication). 
3. 
Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, but they do 
not influence ICANS grading. 
4. 
Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from 
ICANS grading. It may be graded according to CTCAE v5.0. 
 
 
Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5  
ICE score1 
7 to 9 
3 to 6 
0 to 2 
0 (patient is unarousable and 
unable to perform ICE) 
Death due 
to 
ICANS 
where 
another 
cause is not 
the 
principle 
factor 
leading 
to this 
outcome 
Depressed level 
of consciousness2 
Awakens 
spontaneously 
Awakens 
to voice 
Awakens only to tactile 
stimulus 
Patient is unarousable or 
requires vigorous or reptitive 
tactile stimuli to arouse. Stupor 
or coma 
Seizure 
N/A 
N/A 
Any clinical seizure focal or 
generalized that resolves 
rapidly or nonconvulsive 
seizures on EEG that 
resolve with intervention 
Life-threatening prolonged 
seizure (>5min); or repetitive 
clinical or electrical seizures 
without return to baseline in 
between  
Motor findings3 
N/A 
N/A 
N/A 
Deep focal motor weakness 
such as hemiparesis or 
paraparesis  
Elevated 
ICP/cerebral 
edema  
N/A 
N/A 
Focal/local edema on 
neuroimaging4 
Diffuse cerebral edema on 
neuroimaging; decerebrate or 
decorticate posturing; or 
cranial nerve VI palsy; or 
papilledema; or Cushing’s triad 

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ASTCT ICE Screening Tool and Scoring adapted from Lee et al., 201941 
 
 
 
 
 
ISR Grading adapted from FDA Guidance for Vaccine Clinical Trials45 
 
Local Reaction to 
Injectable Product 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3)  
Potentially Life-
Threatening (Grade 4) 
Pain 
Does not interfere with 
activity 
Repeated use of non-
narcotic pain reliever 
>24 hours or interferes 
with activity  
Any use of narcotic 
pain reliever or 
prevents daily activity 
Emergency room (ER) 
visit or hospitalization  
Tenderness 
Mild discomfort to touch 
Discomfort with 
movement 
Significant discomfort 
at rest 
ER visit or 
hospitalization  
Erythema/Redness1 
2.5 to 5cm 
5.1 to 10cm 
>10cm 
Necrosis or exfoliative 
dermatitis 
Induration/Swelling2 
2.5 to 5cm and does not 
interfere with activity 
5.1 to 10cm or 
interferes with activity  
>10cm or prevents 
daily activity 
Necrosis  
 
1. 
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. 
2. 
Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement 
 
 
Category 
Task 
Score 
Orientation 
Orientation to year, month, city, hospital 
4 points 
Naming 
Ability to name 3 objects (eg, point to clock, pen, button) 
3 points 
Following 
Commands 
Ability to follow simple commands (eg, “show me 2 fingers” or “Close your 
eyes and stick out your tongue”) 
1 point 
Writing 
Ability to write a standard sentence (eg, “Our national bird is the bald eagle”) 
1 point 
Attention 
Ability to count backwards from 100 by 10 
1 point 

Istari Oncology, Inc 
 
 
LUMINOS-102 (PVSRIPO ICI M201) 
 
Protocol Amendment 4.0 14JAN2022 
Confidential  
 
Page 107 of 109 
 
13 
APPENDIX II 
Amendment Summary of Changes 
 
Amendment 4.0, 14January2022 
Protocol Amendment 4 includes the below major changes: 
- 
Updated PVSRIPO to lerapolturev throughout 
- 
Modified lerapolturev dose and dosing schedule 
o Modified other study assessment timepoints impacted by new dosing 
schedule 
o Added DSMC review once 12 participants have been treated on new dose 
and schedule (6 to each arm) and clear the DLT period 
- 
Modified the stratification factor of time since prior anti-PD-1/L1 exposure 
(≤6 weeks versus >6 weeks) to type of anti-PD-1/L1 resistance (primary versus 
secondary)  
- 
Modified crossover criteria 
- 
Modified study participant inclusion and exclusion criteria as per the below: 
o Patients with ocular, acral or mucosal melanoma are now excluded 
o Patients with M1c or M1d disease are now excluded 
o Inclusion criterion 5 was modified to clarify definition of resistance to anti-
PD-1/L1-based therapy 
o Patients must have not failed more than one prior anti-PD-1/L1-based 
regimen 
- 
Removed study interim analysis after 20 participants randomized 
 
Amendment 3.0, 23April2021 
Protocol Amendment 3 includes the below major changes: 
- 
Added a new primary objective: To evaluate the effect of PVSRIPO on the TME 
of injected and non-injected lesions when administered with and without 
anti-PD-1 therapy. 
- 
The primary safety endpoint of “anti-PD-1 AESI” was changed to “anti-PD-1 
irAEs” and an irAE definition was added to Section 9.2.   
- 
Modified study participant inclusion and exclusion criteria in Section 4 and the 
synopsis as per the below: 
o Inclusion criterion 3 was modified to clarify the melanoma subtypes 
eligible for study participation, requirements for qualifying biopsy and/or 
archival tissue, and to add the requirement that at least one melanoma 
lesion is amenable to biopsy while on study.  
o Inclusion criterion 8 no longer includes a minimum serum albumin 
requirement. 
o Exclusion criterion 1 was added to state exclusion of ocular melanoma 
o Exclusion criteria related to uncontrolled/symptomatic hypercalcemia and 
worsening steroid myopathy were removed. 
o Added exclusion criterion 20 to clarify that participants unable to interrupt 
anticoagulant use the day prior, the day of, and the day after each 
PVSRIPO injection are ineligible for the study. 

Istari Oncology, Inc 
 
 
LUMINOS-102 (PVSRIPO ICI M201) 
 
Protocol Amendment 4.0 14JAN2022 
Confidential  
 
Page 108 of 109 
 
- 
Modified pregnancy testing for women of childbearing potential from 
approximately every 6 months to approximately every 12 weeks during study 
participation. 
- 
Clarified the timing of thyroid function monitoring (along with allowable time 
windows) around were clarified. 
- 
Added mandatory on-study tissue biopsies of injected and non-injected lesions, 
as well as draining lymph nodes, at multiple timepoints. The types of lesions and 
conditions under which lesions should be biopsied was clarified throughout. 
- 
Added mandatory blood samples at multiple timepoints on-study. The Day 31 
blood sample was removed.  
- 
Updated the Cycle 2 lesion swabbing timepoint from Study Day 24 to Study Day 
22 to align with tissue biopsy and blood collection timepoints.  
- 
Clarified tumor imaging requirements throughout the document 
- 
Clarified crossover requirements for participants enrolled in the safety run-in. 
- 
Added clarification to Sections 5.2 and 5.3 to reflect the updated IPHP and 
device compatibility standards.  
- 
Added clarification in Section 5.4 that COVID vaccination with mRNA-based 
vaccines is allowed on study, provided the vaccine is administered as far away 
as possible from injected or injectable melanoma lesions and is given at least 2 
weeks before or after PVSRIPO injection. 
- 
Updated Section 5.4 to reflect prohibition of use of steroids with occlusive 
dressings, warfarin use at any time on study, as well as the use of other 
anticoagulants the day prior, the day of, or the day after PVSRIPO injection. 
- 
Updated Sections 7.3 and 9.2, along with other areas of the protocol to reflect the 
requirement to report Grade 3 or 4 ISR within 24 hours of awareness of the 
event.  
- 
Added Section 8.4.3 to outline the statistical approach to analysis of primary and 
exploratory translational medicine objectives. 
 
Amendment 2.0, 08November2020 
Protocol Amendment 2 includes the below major changes: 
- 
Added additional supporting information regarding the PV booster timing in 
Section 1.3.1. 
- 
Clarified or modified study participant inclusion and exclusion criteria in Section 4 
as per the below: 
o Inclusion criterion 4 modified to require that one melanoma lesion must be 
injectable and minimal lesion size is 5mm. Clarified that visceral lesions 
(eg liver, lung, retroperitoneal, subpleural lesions) are not considered 
injectable for the purposes of this trial. 
o Inclusion criterion 5 modified to require disease progression per iRECIST 
and added allowance of failure on anti-PD-L1 therapy.   
o Exclusion criterion 13 clarified permissible timeframe for receiving 
received prior systemic anti-cancer therapy to within 4 weeks or 5 
elimination half-lives, whichever is shorter- prior to treatment. 

Istari Oncology, Inc 
 
 
LUMINOS-102 (PVSRIPO ICI M201) 
 
Protocol Amendment 4.0 14JAN2022 
Confidential  
 
Page 109 of 109 
 
- 
For participants crossing over from Arm 1 to Arm 2, added requirement for 
complete tumor burden assessment (ie, scans or measurements) within 28 days 
of first treatment in Arm 2 (PVSRIPO/anti-PD-1 combination)  
- 
Clarified that qualifying scans prior to and during screening should be submitted 
to central imaging vendor, where possible 
- 
Expanded Section 6 to include information on discontinuation of study treatment, 
treatment beyond progression, and study termination. 
- 
Modified Section 7.2 Safety Assessments timeframe for reporting events to 
extend reporting periods through 30 days after the last dose of study therapy for 
AEs and 90 days after the last dose of study therapy or upon 
resolution/stabilization for AESI and SAEs. 
- 
Added amylase testing to biochemistry laboratory assessments in Section 7.2.2. 
- 
Modified DSMC meeting frequency in Section 9.1.5 to clarify IA meeting and 
allow for continued regular meetings approximately every 4 months following the 
IA. 
 
In addition, the study protocol number was modified from PVSRIPO ICI M201 to 
LUMINOS-102. 
 
Amendment 1.0, 09October2020 
The PVSRIPO ICI M201 study protocol Amendment 1 includes the below major 
changes: 
- 
Addition of a safety run-in of at least 6 subjects receiving single-agent PVSRIPO 
to characterize safety and tolerability of PVSRIPO when injected into multiple 
lesions per treatment visit. 
- 
Additional shedding samples to be collected from the PVSRIPO-injected lesions 
to assess for PVSRIPO poliovirus shedding, in addition to stool shedding testing 
for PVSRIPO poliovirus. 
- 
Modifying Inclusion Criterion 4 to require at least 2 measurable melanoma 
lesions according to RECIST 1.1 criteria. 
- 
Modified Inclusion Criterion 6 to specify radiographic confirmation of disease 
progression on prior anti-PD-1.  
- 
Additional safety monitoring for CRS and ICANS. 
- 
Mandatory blood biopsy samples at screening, prior to study treatment 
administration at Cycle 3, and upon crossover to Arm 2, where applicable. 
In addition, the nomenclature of study visits was updated from “Day” to “Cycle” for 
clarity and additional clarifications were added to various study visits and procedures to 
clarify requirements.