A Phase 2, Open-label, Single-arm Study Evaluating the Efficacy, Safety and Tolerability of Lerapolturev (PVSRIPO) and the Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of Patients With Recurrent Glioblastoma
Phase: PHASE2
Conditions: Glioblastoma, Recurrent Glioblastoma, Supratentorial Glioblastoma, Brain Tumor
Sponsor: Istari Oncology, Inc.

Confidential 
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CLINICAL STUDY PROTOCOL 
Study Title: A Phase 2, Open-label, Single-arm Study Evaluating the Efficacy, Safety and 
Tolerability of Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) and the Immune 
Checkpoint Inhibitor Pembrolizumab in the Treatment of Patients with Recurrent Glioblastoma 
 
 
Protocol Number: 
LUMINOS-101 (previously PVSRIPO ICI rGBM 201) 
Clinical Phase 
Phase 2 Therapeutic Protocol 
US IND Number 
IND 014735 
Protocol Date: 
Version 4.0, 26May2021 
Sponsor: 
Istari Oncology, Inc. 
430 Davis Drive 
Morrisville, NC 27560 
 
 
Confidentiality Statement 
This study will be performed in compliance with Good Clinical Practice (GCP) and applicable regulatory 
requirements, including the archiving of essential documents.  Information contained in this protocol is 
confidential in nature, and may not be used, divulged, published, or otherwise disclosed to others except to the 
extent necessary to obtain approval of the institutional review board or independent ethics committee, or as 
required by law.  Persons to whom this information is disclosed should be informed that this information is 
confidential and may not be further disclosed without the express written consent of Istari Oncology, Inc. (Istari) 
 
 

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Protocol Approval Signature Page 
Sponsor Representative(s) 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge 
it accurately describes the planned conduct of the study. 
 
 
 
 
W. Garrett Nichols, MD, MS 
CMO, Istari Oncology, Inc. 
 
Date 
 
 

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Investigator Protocol Agreement 
I have read and understand this protocol and agree: 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
To conduct the study in compliance with this protocol, any future amendments, and with any 
other study conduct procedures provided by the Sponsor, Istari. 
• 
To conduct the study as outlined herein, in accordance with 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. 
• 
Not to implement any deviations from or changes to the protocol without prior agreement from 
the Sponsor and prior review and written approval from the Institutional Review Board 
(IRB)/Institutional Ethics Committee (IEC), except as necessary to eliminate an immediate 
hazard to study patient(s), or for administrative aspects of the study (where permitted by all 
applicable regulatory requirements). 
• 
To ensure that all persons assisting me with the study are adequately informed about the 
investigational product(s) and of their study-related duties and functions as described in the 
protocol. 
• 
To completely inform all participants in this study concerning the pertinent details and purpose of 
the study prior to their agreement to participate in the study in accordance with GCP and 
regulatory authority requirements. 
• 
To be responsible for maintaining each patient’s consent form in the study file and providing each 
patient with a signed copy of the consent form. 
• 
To periodic on-site and/or remote monitoring of the source documents and case report forms by 
Istari or designee.  
• 
To allow access to files for audit or inspection purposes by the Sponsor or by competent 
regulatory authorities. 
• 
That I am thoroughly familiar with the appropriate use of the investigational product(s), as 
described in the protocol and any additional information provided by the Sponsor including but 
not limited to the following: the current Investigator’s Brochure and approved product label, if 
applicable. 
Hence, I: 
• 
Agree to supply Istari with any information regarding financial arrangements and interests.  
• 
Agree to promptly update any information if any relevant changes occur during the study and for 
1 year following completion of the study; and, 
• 
Agree that Istari may disclose this information about such financial arrangements and interests to 
regulatory authorities. 
Investigator Name (Print): 
 
Date Signed: 
 
Investigator Signature: 
 
 
 

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NOTICE REGARDING IMMUNOPROGRESSION 
DUE TO KNOWN PVSRIPO-MEDIATED TREATMENT EFFECTS, INCREASED 
TUMOR SIZE ON RADIOGRAPHIC IMAGING FOLLOWING PVSRIPO 
ADMINISTRATION MAY OCCUR. EXCEPT IN CASES OF IMMINENT LIFE-
THREATENING EMERGENCY, CONSULT WITH SPONSOR OR THEIR DESIGNEE 
PRIOR TO INITIATING NON-PROTOCOL-SPECIFIED TUMOR TREATMENTS OR 
PERFORMING SURGICAL RESECTION.  
• PVSRIPO’s immune-mediated mechanism of action (MOA) is known to result in atypical 
tumor imaging responses that can manifest as polycystic or pseudoprogressive appearance, 
including areas of new enhancement and tumor enlargement (termed immunoprogression) that 
can persist for up to 6 or more months after infusion. Thus, reliance on radiographic imaging 
standard criteria (eg, Immunotherapy Response Assessment for Neuro-oncology (iRANO)[1]) 
for determining disease progression is not optimal for PVSRIPO-based therapy; see Table 3 
for modified response criteria. 
• The time to objective radiographic anti-tumor response ranged from approximately 5 to 29 
months post-infusion in the Recurrent Glioblastoma (rGBM) PVSRIPO Phase 1 study 
(Pro00031169; median time to response 15 months). 
• For patients to have the best opportunity for an immune-mediated anti-tumor response, 
experience suggests that patients should be managed as noted below and as outlined in the 
protocol. 
Treatment emergent adverse events should be managed at the discretion of the principal 
investigator, with patient safety being the primary consideration. Based on prior 
experience, the best recommended management of treatment-induced peritumoral edema 
or of a pseudoprogressive, polycystic, expansive-type of tumor appearance (ie, 
immunoprogression) within 6 months of any PVSRIPO infusion is as follows: 
• Radiographic findings but patient asymptomatic/stable: 
o Observe and continue to follow per protocol 
• Radiographic findings with new onset/worsening clinical symptoms: 
o Preferred: Low dose bevacizumab (7.5mg/kg every (q) 3 weeks; few cycles as possible 
to achieve symptom control) 
o Initiation of low dose steroids (dexamethasone ≤ 4mg/day) if rapid response is 
clinically indicated  
o Other supportive care treatments, as required (eg, antiepileptics)  
 
 

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Summary of Major Protocol Amendment Changes 
Protocol Version and 
Date (from, to) 
Summary of Major Changes by Section 
Version 3 (23April2021) 
to Version 4 
(21May2021) 
• 
Updated Table 1 to clarify timing of certain laboratory schedule of 
assessments and their description throughout the text. 
• 
Updated Sections 5.2.1 and 5.2.2 to include guidance regarding 
platelet support both pre-infusion and prior to catheter removal. 
 
 
 

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Protocol Synopsis 
Protocol Title 
A Phase 2, Open-Label, Single-Arm Study Evaluating the Efficacy, Safety and 
Tolerability of Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) and the 
Immune Checkpoint Inhibitor Pembrolizumab for the Treatment of Patients with 
Recurrent Glioblastoma 
Protocol Number 
PVSRIPO ICI rGBM 201 
Rationale and 
Background 
We hypothesize that PVSRIPO, a novel recombinant poliovirus (PV)/rhinovirus, 
oncolytic viral immunotherapeutic, when infused directly into non-immunogenic 
rGBM tumors, coupled with immune checkpoint inhibitors (ICI), may serve to 
generate a potent and specific anti-tumor response given their respective 
mechanisms of action. The ICI pembrolizumab is a programmed cell death 
receptor-1 (PD-1)-blocking antibody indicated in a number of malignancies and 
tumor types that has been reasonably well tolerated, with or without surgical 
resection, in patients with rGBM. In addition, pre-clinical data and limited 
clinical use outside of structured trials suggest that PVSRIPO followed by 
pembrolizumab may be associated with additive to synergistic anti-tumor 
responses [2-7]. 
Objectives 
To evaluate the following after intratumoral infusion of PVSRIPO and treatment 
with at least one dose of pembrolizumab in rGBM patients: 
Objectives 
Endpoints/Evaluation Criteria 
Primary (efficacy)  
Anti-tumor activity: 
 
• 
Objective response rate (ORR): Proportion 
of patients with confirmed CR or PR. 
• 
Duration of response (DOR): KM curves 
showing median DOR for all patients that 
have confirmed CR or PR.  
• 
Durable radiographic response (DRR): 
Proportion of patients with confirmed 
response (CR or PR) that lasts for ≥ 6 
months. Radiographic outcomes will be 
assessed via iRANO criteria [1] in this 
protocol.   
 

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Primary (safety)  
Safety/tolerability: 
• 
Frequency and severity of treatment-
emergent adverse events (TEAE) via 
Common Terminology Criteria for Adverse 
Events (CTCAE, v5.0) for patients receiving 
PVSRIPO and at least one dose of 
pembrolizumab.  
Secondary (efficacy)  
Anti-tumor activity:  
 
• 
Disease Control Rate (DCR): Comprised of 
patients achieving CR, PR or SD for ≥ 6 
months. 
• 
Duration of disease control (DDC): KM 
curves showing median DDC for patients 
with confirmed CR, confirmed PR or SD for 
≥ 6 months. 
Survival 
• 
Overall and landmark survival: Proportion of 
patients alive at ≥ 6, ≥ 12 and at 24 months 
post-PVSRIPO infusion as calculated by 
Kaplan-Meier methods.  
Progression free survival 
• 
If calculable, progression free survival (PFS) 
will be estimated based on the time from 
PVSRIPO infusion to death or confirmed 
progression, based on the definition of 
progression noted in Table 3. 
Secondary (safety) 
 
• 
Frequency and severity TEAE via CTCAE 
for patients receiving PVSRIPO alone 
without pembrolizumab (any reason). 
Exploratory 
Identification of 
biomarkers of anti-tumor 
response to PVSRIPO 
followed by 
pembrolizumab  
Assessment of tumor tissue and blood samples 
for identification of genetic, cytologic, histologic 
and/or other markers that demonstrate 
pharmacodynamic activity of PVSRIPO or 
correlate with anti-tumor response.  
Alternative assessment of 
radiographic 
response/progression/PFS 
Radiographic outcomes will also be analyzed as 
described in Table 3 for endpoint determination. 
All responses must be confirmed via two 
consecutive MRI assessments at least 4 weeks 
apart. If on bevacizumab therapy when response 
first noted, response will be confirmed 
≥ 8 weeks. 
Patient-reported 
outcomes 
Assessment of patient-reported quality of life and 
activities of daily living capabilities. 
Study Design 
This Phase 2 single-arm trial in patients with rGBM will characterize the 
efficacy, safety and tolerability of PVSRIPO intratumoral infusion followed by 
intravenous (IV) pembrolizumab 2 to 4 weeks later, and every 3 weeks, 
thereafter.  

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The study will begin with a safety lead-in for evaluation of dose-limiting toxicity 
(DLT) of the combination prior to full open enrollment. As such, the first 3 
patients will be sequentially enrolled with a mandatory waiting period of 21 to 
28 days after the immediate prior patient’s PVSRIPO infusion to allow for DLT 
assessment. The DLT evaluation period will begin once a patient receives 
PVSRIPO followed by the first dose of pembrolizumab and continue for 21 days 
after the first dose of pembrolizumab (± 3 days to account for weekends, patient 
visit scheduling issues, etc.). The initial DLT assessment will be based on the 
first 3 patients, which may be expanded up to 6 patients if any DLT are noted in 
the first 3 (see Sections 3 and 7.4 for additional detail regarding DLT 
assessment). 
The first planned dose of pembrolizumab at Week 2 will be delayed by up to 2 
additional weeks in patients with any ongoing ≥ Grade 3 peritumoral edema 
(PTE) or cerebral edema (CE) or ≥ Grade 2 AEs related to PTE or CE following 
PVSRIPO infusion or signs or symptoms related to these events that require 
active treatment (eg, treatment-emergent or worsening events such as 
hemiparesis requiring ≤ 4 mg/day dexamethasone or seizure requiring anti-
epileptics; see Section 5.7.2), until such events resolve to ≤ Grade 1. If such 
events have not resolved to ≤ Grade 1 by Week 4 post-PVSRIPO infusion, the 
patient will not receive pembrolizumab under this trial and will be replaced. 
Pembrolizumab may be administered any time between Weeks 2 and 4 once 
events resolve as outlined above, as applicable. The first planned 
pembrolizumab treatment may also be delayed for administrative or other 
reasons, including other TEAE that in the Investigator’s opinion warrants 
delayed pembrolizumab treatment, but the first pembrolizumab treatment must 
occur by Week 4 post-PVSRIPO infusion, as noted above. 
In addition, if a patient requires > 4 mg/day of dexamethasone or equivalent 
prior to the first dose of pembrolizumab, the patient will not receive 
pembrolizumab under this trial and will be replaced. These replaced patients will 
not be considered in the initial DLT assessment of the combination but will be 
eligible for additional follow-up in this study and will be summarized separately 
from those receiving the combination. Their information may be utilized in 
exploratory comparative summaries relative to patients treated with PVSRIPO 
and ≥ 1 dose of pembrolizumab in this study.  
If ≤ 33% of the initial participants in the safety lead in (≤ 1 of 3 or if > 1 patient 
of the first 3 experiences a DLT and 3 additional patients are included for DLT 
assessment, ≤ 2 of 6 patients) experience a DLT, the twenty-four remaining 
participants will be enrolled. If > 33% of participants (ie, ≥ 3 of 6) experience a 
DLT, the study will be halted, and the treatment plan modified, or the study may 
be closed. After the DLT evaluation period and the study is open to full 
enrollment, ongoing monitoring of TEAEs will occur on at least a monthly basis. 
Planned Number 
of Participants 
Approximately 30 participants receiving PVSRIPO followed by pembrolizumab. 
Patients receiving PVSRIPO only for any reason will be followed according to 
the schedule of assessments with MRI and required visits occurring 
approximately every 9 weeks after Week 11; these patients will be replaced to 
achieve the approximate total of n=30 receiving PVSRIPO and pembrolizumab. 
Study Entry 
Criteria 
Inclusion Criteria (IC): 
1. ≥ 18 years of age. 

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2. Actively growing recurrent supratentorial glioblastoma confirmed by biopsy 
by the site’s neuropathologist or designate. 
o Histologically confirmed recurrent glioblastoma within 6 weeks of 
PVSRIPO infusion will not require a biopsy to confirm active tumor 
prior to catheter placement. However, biopsy confirmation of 
glioblastoma must be provided if not completed within 6 weeks of 
catheter placement. 
o Progression of primary glioblastoma or transformation from a lower 
grade to a higher grade is acceptable for recurrence and as for primary 
glioblastoma, must be confirmed via prior histology by site pathologist. 
3. Enhancing lesion ≥1 cm shortest diameter to ≤ 5.5 cm longest diameter in all 
planes, but occurrence within the prior resection cavity should not contribute 
to the longest diameter measurement. 
4. Before catheter placement based on screening MRI and at the time of 
catheter placement via computed tomography (CT) prior to infusion, 
neurosurgical investigator must confirm both tumor location (> 1 cm from 
eloquent brain) as well as placement of infusion catheter within or through 
the progressive enhancing tumor is feasible and at a safe distance relative to 
eloquent brain function, with the tip of the catheter being placed: 
a. Within the enhancing portion or in the vicinity of enhancement of target 
lesion (ie, infiltrative disease)  
b. ≥ 0.5 cm from ventricles 
c. ≥ 1 cm deep into the brain 
d. ≥ 0.5 cm from the corpus callosum 
Patients with ongoing neurologic symptoms with enhancing disease 
within 1cm of eloquent brain are excluded. 
5. First or second relapse supported by MRI or CT scan; relapse is defined as 
progression following initial/prior therapy(ies). 
6. Failed previous first line therapy: maximum surgical resection and 
radiotherapy (RT) (plus concomitant chemotherapy followed by 
maintenance chemotherapy if unknown or methylated O6-methylguanine-
DNA methyltransferase (MGMT) promoter). Patients who begin but do not 
complete chemotherapy/RT may still be considered for eligibility at the 
discretion of Sponsor.  
7. Karnofsky performance status (KPS) ≥ 70 at screening and baseline. 
8. Undergone prior vaccination against PV and received a boost immunization 
with trivalent IPOL® (PV Vaccine Inactivated) (Sanofi-Pasteur SA) at least 
1 week, but less than 6 weeks, prior to administration of PVSRIPO (within 6 
months of PVSRIPO retreatment). Note: Patients who are unsure of their 
prior vaccination status or have not been vaccinated must provide proof of 
vaccination and/or evidence of anti-PV immunity prior to enrollment, as 
applicable. 
9. Ability to safely discontinue anti-coagulant therapy(ies) prior to 
biopsy/catheter placement, as required per site/surgical guidelines, in the 
opinion of the investigator.  
10. Hemoglobin ≥ 9 g/dl prior to biopsy/catheter placement. 
11. Platelet count ≥ 100,000/microliter (µL, unsupported); ≥ 125,000/µL (can be 
supported via platelet transfusion and/or with a Sponsor-approved bone 
marrow stimulant/colony stimulating factor, eg, romiplostim) at 
biopsy/catheter placement.  

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12. Absolute neutrophil count (ANC) ≥ 1000/µL prior to biopsy/catheter 
placement. 
13. Creatinine ≤ 1.2 x upper limit of normal (ULN) prior to biopsy/catheter 
placement. 
14. Total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase (ALP) ≤ 2.5 x ULN prior to biopsy/catheter 
placement. 
15. PT and aPTT ≤ 1.2 x ULN prior to biopsy/catheter placement. 
16. If undetectable anti-tetanus toxoid immunoglobulin G (ATT IgG) at screen, 
Tdap booster vaccine > 1 week prior to biopsy/catheter placement. 
17. Patients must be willing and able to understand and provide written 
informed consent. 
 
Exclusion Criteria (EC): 
1. Received prior therapy with an anti-PD-1, anti-programmed cell death-
ligand 1 (anti-PD-L1), anti-programmed cell death-ligand 2 (anti-PD-L2), 
anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen (CTLA)-4 
antibody (including ipilimumab or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways) ≤ 12 weeks prior to 
PVSRIPO infusion (note: does not apply for patients treated with 
pembrolizumab under this protocol who are eligible for PVSRIPO 
retreatment). Note: patients who had previously permanently discontinued 
any anti-PD-1 or PD-L1 therapy due to severe or life-threatening immune-
related AE are excluded.  
2. Excluded are: 
a. Neoplastic lesions in the brainstem, cerebellum, or spinal cord 
b. Radiological evidence of active/growing multifocal disease: no size 
increase > 0.5 cm in any direction of any other enhancing non-target 
lesions present at baseline confirmed via most recent, prior, consecutive 
MRIs at least 3 months apart. However, two lesions totaling ≤5.5cm of 
enhancing disease (total diameter) connected by T2 flair are not 
excluded 
c. Tumors with ≥ 1 cm of contrast-enhancing tumor component crossing 
the midline (crossing the corpus callosum) 
d. Extensive subependymal disease: multiple lesions or lesions covering 
> 50% of subependymal space. Tumor touching subependymal space 
allowed 
e. Extensive leptomeningeal disease: multiple lesions or lesions covering 
> 50% of leptomeninges. Tumor touching leptomeninges allowed 
3. Has received systemic immunosuppressive treatments other than systemic 
corticosteroids (eg, methotrexate, chloroquine, azathioprine) within six 
months of PVSRIPO infusion. 
4. Requires treatment with high dose systemic corticosteroids, defined as 
dexamethasone > 4 mg/day or equivalent, within 2 weeks of PVSRIPO 
infusion. 
5. Prior interstitial brachytherapy, implanted chemotherapy, stereotactic 
radiosurgery or therapeutics delivered by local injection or convection 
enhanced delivery (CED), including PVSRIPO (except for qualifying 
patients being retreated with PVSRIPO within this trial). 

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6. Pregnant and/or breast feeding female; patient/female partner of 
childbearing potential who is unwilling to utilize protocol-defined 
acceptable form of contraception for duration of study. 
7. Impending/life-threatening cerebral herniation syndrome, per 
neurosurgeon/designate. 
8. Severe, active co-morbidity, defined as follows: 
a. Infection requiring IV treatment/unexplained febrile illness (maximum 
temperature (Tmax) > 99.5°F/37.5°C)  
b. Known immunosuppressive disease/human immunodeficiency virus 
infection  
c. Known active hepatitis B (HBV) or C (HCV) infection via positive viral 
Deoxyribonucleic Acid (DNA) or Ribonucleic Acid (RNA), respectively  
d. Unstable or severe intercurrent medical conditions such as severe heart 
disease (New York Heart Association Class 3 or 4) 
e. Known lung disease with forced expiratory volume in 1st second of 
expiration < 50% 
f. Uncontrolled diabetes mellitus (eg, hemoglobin A1C level > 7.0% with 
treatment) 
g. History of other malignancy requiring active treatment within 2 years of 
biopsy/catheter placement 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 overall survival (OS) of > 90%) 
9. Known albumin allergy. 
10. Uncontrolled unexplained bleeding and/or hemoptysis within 4 weeks of 
biopsy/catheter placement. 
11. Inability to undergo brain MRI with and without contrast. History of 
severe/anaphylactic reaction to gadolinium contrast agent is excluded. Mild 
allergy (eg, rash) acceptable with prophylactic acetaminophen and 
diphenhydramine. 
12. History of neurological complications due to PV infection. 
13. Not recovered from toxic side effects (alopecia acceptable) and/or no current 
or prior tumor treatments within the following timeframe relative to 
biopsy/catheter placement:  
a. Chemotherapy or bevacizumab ≤ 4 weeks (except for nitrosourea [6 
weeks] or metronomic dosed chemotherapy such as daily temozolomide, 
etoposide or cyclophosphamide [1 week])  
b. Tumor treating fields ≤ 7 days  
c. RT of brain ≤ 12 weeks, except for progressive disease outside of the 
radiation field or 2 progressive scans at least 4 weeks apart or 
histopathologic confirmation 
14. History of agammaglobulinemia. 
15. Known hypersensitivity to pembrolizumab, or any components of 
pembrolizumab. 
16. Active autoimmune disease requiring systemic immunomodulatory 
treatment within the past 12 months; physiologic replacement therapy (eg, 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment. 
 

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Concomitant 
Treatment 
Pembrolizumab: 200 mg given via IV infusion every 3 weeks (q 3 weeks) up to 
a maximum of 24 months. 
As needed at Investigator discretion for the management of events noted 
below: 
Bevacizumab and/or dexamethasone: 
Based on previous studies, the recommended best standard of care (BSC) for 
control of PTE or CE-related sequalae after PVSRIPO infusion and/or 
combination of PVSRIPO and pembrolizumab, as needed, are: 
• 
Preferred ≥ 2 weeks post-PVSRIPO infusion: low dose bevacizumab 
(7.5 mg/kg q 3 weeks)  
o Treatment with bevacizumab for the shortest course possible is 
desired over dexamethasone use for control of PTE or CE, when 
deemed safe to use by the investigator  
o Treatment with higher doses of bevacizumab for > 2 cycles is 
not permitted per protocol  
• 
Within 2 weeks of PVSRIPO infusion or thereafter, at the treating 
clinician’s discretion if rapid results are required: low dose 
dexamethasone (≤ 4 mg/day)  
o As low a dose as possible, for the shortest duration possible is 
desirable for managing PTE or CE. However, participants 
should primarily be managed with bevacizumab, thereafter 
• 
Other supportive care treatments (eg, anti-epileptics for seizure) 
For the management of any immune-related AE (irAE) after the first dose of 
pembrolizumab, as low a dose as possible of dexamethasone (ideally 
≤ 4 mg/day), for the shortest duration possible, is desirable. Patients requiring 
> 4 mg/day of dexamethasone or equivalent prior to the first dose of 
pembrolizumab will be replaced.  
Any irAE should ultimately be managed at the investigator’s discretion with 
patient safety as the primary consideration.  
Investigational 
Product(s) 
PVSRIPO: Oncolytic Polio/Rhinovirus Recombinant; 5x107 tissue culture 
infectious dose (TCID)50 delivered via CED intratumorally 
Reference Product 
(comparator) 
No active comparator at study outset (may be adapted to include a randomized 
comparator in the future); comparisons may be made to external controls in 
similar rGBM populations treated with PVSRIPO alone, pembrolizumab (or 
other anti-PD-1/ICI) alone or other to treatments/combination of treatments. 
Planned Study 
Sites 
Approximately 10 
Criteria for 
Evaluation 
Laboratory and clinical evaluation including physical examination, KPS, 
neurological examination (including via the NANO scale) [8], assessment of AE 
and survival, as well as radiographic evaluations, will be assessed at regular 
intervals to evaluate safety and efficacy. 
Biological samples, including blood/blood cells and tumor biopsy tissue (when 
available) will be collected to evaluate exploratory assessments of 
immune/genetic markers and other factors that may impact response. 

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Statistical 
Methods 
This single-arm study is designed to evaluate the efficacy, safety and tolerability 
of PVSRIPO when followed by pembrolizumab treatment in patients with 
rGBM. Summary statistics (eg, n, %, confidence intervals [CI]) will be 
employed to describe the key findings (ORR, DOR, incidence and severity of 
DLT, Grade 3 or higher AE, etc.). 
Adverse events considered related to screening or other pre-infusion procedures 
that are not standard of care (eg, PV booster, biopsy prior to infusion, catheter 
placement without PVSRIPO infusion) will be summarized separately from 
TEAE (after PVSRIPO infusion), as will data from patients receiving only 
PVSRIPO and not at least one dose of pembrolizumab. The number of doses of 
pembrolizumab received and other baseline characteristics will also be explored 
as variables for safety and efficacy (eg, age, number of prior recurrences, KPS, 
NANO score, extent of prior resection, prior bevacizumab and chemotherapy 
use, tumor genetic profile).  
All patients enrolled and treated with PVSRIPO will be summarized in all 
analyses. In addition, a per-protocol analysis will also explore the impact of 
excluding patients meeting pre-defined criteria from radiographic and survival 
analyses as outlined in Section 8. For comparisons of efficacy or safety relative 
to PVSRIPO alone or pembrolizumab alone from other data sources, both the 
overall and per-protocol populations may be considered.  
The statistical analysis plan (SAP) will provide additional detail regarding 
planned statistical summary methods and analyses. 
Determination of 
Sample Size 
Based on an interim summary of the Phase 1 study data of PVSRIPO in rGBM 
(Pro00031169), an ORR of 11.5% was demonstrated (7/61 patients). With 30 
subjects treated in this study, there is >75% power to demonstrate a 20% or 
greater improvement in ORR with the addition of pembrolizumab (ORR > 31%, 
two-sided P<0.05). 
The planned evaluable sample size of 30 patients will allow initial assessment of 
the anti-tumor response via the criteria noted in Table 3 and survival over time, 
to inform future study adaptations and/or the sample size and study design of 
new trials. The design will also allow for assessment of the efficacy, safety and 
tolerability of PVSRIPO plus pembrolizumab, relative to accumulated 
experience with PVSRIPO alone (eg, [5], data on file, Istari) and published or 
other data available with pembrolizumab alone in patients with rGBM (eg, [3]). 
Study and 
Treatment 
Duration 
Maximum planned duration of follow-up: Up to 24 months (104 weeks). 
Participants achieving 24 months of follow-up may be offered participation in a 
roll-over protocol or other mechanism for longer-term follow-up. 
Planned treatment duration: 
• 
Single PVSRIPO infusion at baseline (retreatment allowed for 
qualifying patients (ie, no ongoing AE ≥ Grade 2 related to peritumoral 
edema, tolerated initial PVSRIPO infusion well) with enhancing disease 
≥ 6 months from initial PVSRIPO infusion (with or without post-
infusion resection ≥ 4 weeks after retreatment); see Section 3).  
• 
Pembrolizumab (200 mg IV infusion), q 3 weeks up to Week 104 
(maximum of approximately 102 weeks of treatment), or until irAE 
meeting criteria for discontinuation or confirmed progression via criteria 
noted in Table 3). 

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Treatment interruption/discontinuation with pembrolizumab: 
Adverse events of an immunologic etiology, including infusion related reactions, 
have been associated with pembrolizumab exposure. Depending on the severity 
of the irAE, pembrolizumab should be temporarily withheld or permanently 
discontinued as outlined in Section 7.5.3 and the most recent Keytruda® 
(pembrolizumab) package insert (PI) and “Guide for Keytruda®” provided in the 
study administration manual (SAM).   
In general, for an irAE requiring dose interruptions, low-dose dexamethasone 
(≤ 4 mg/day) should be initiated and tapered when the irAE is ≤ Grade 1. 
For patients with irAE meeting dose interruption criteria, the next dose of 
pembrolizumab will be withheld until the irAE has been reduced to ≤ Grade 1 
and dexamethasone (or equivalent) dose has been tapered to ≤ 4 mg/day and/or 
discontinued.  
Pembrolizumab should be permanently discontinued for severe infusion-related 
reactions and for irAE that do not resolve within 12 weeks of the last dose of 
pembrolizumab or dexamethasone (or equivalent) cannot be reduced to ≤ 4 
mg/day within 12 weeks.  
Subjects who discontinue pembrolizumab should continue to be followed until 
resolution of AEs and for clinical outcomes, as detailed in Sections 5.4 through 
5.6.  
Figure 1 Study Schema for Initial Safety/Efficacy Evaluation (n=30) 
 

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Table 1 
Schedule of Assessments 
Description 
Screening1 
Treatment and Follow-Up Periods18 
Screen. 
Period 1 
Screen. 
Period 2 
Catheter/ 
PVSRIPO2 
Post-PVSRIPO infusion, pembrolizumab treatment and 
Follow-Up (± 7 days)3 
 
 
Week 
Within 6 
wks. of 
catheter 
placement 
Within 1 
wk. 
relative to 
catheter 
placement 
 
1 
2 
U  
(3-4)5 
5 or +3 
wk.  
8 or +3 
wk.  
11; + every 
3 wks. to 
wk.104 
max. 
Follow-Up 
End of Study 
visit 
Day 
Day -42 to -
8 
Day -7 to -
1  
0 (+1 day)  
1 
14 
(28) 
35 or 
+21  
56 or 
+21  
+21d up to 
max. 730 
days 
From 
discontinuation 
of 
pembrolizumab 
Anytime for 
permanent 
discontinuation 
Visit 
1 
2 
3 
4 
5 
U 
6 
7 
≥ 8 
≥ 8 
General 
Evaluations 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
X 
 
 
 
 
 
 
 
 
Physical Exam6,7 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Neurologic Exam7 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
NANO 
assessment7 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
KPS7 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
PRO4 
 
X 
 
X 
 
 
X 
 
X 
 
 
Adverse Events 
 
Continuous (including AE due to non-SOC screening procedures) 
Concomitant 
Medications 
 
Continuous (throughout the duration of the study) 
Lab Evaluations 
 
 
PV booster 
vaccine 
X 
 
 
 
 
 
 
 
 
 
 
CBC w/diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
CMP 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Pancreatitis labs 
(amylase, lipase)  
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
PT, aPTT 
 
X 
 
 
 
 
X 
X 
 
 
 
Pregnancy Test8 
 
X 
 
 
 
 
 
 
 
 
Thyroid Panel9 
 
X 
 
 
X 
 
 
X 
X 
 
 
ATT IgG10 
X 
 
 
 
 
 
 
 
 
 
 
LSQ11 
X 
X 
 
 
X 
 
X 
 
 
 
 
Whole blood, 
research 
analyses12 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Disease 
Evaluations 
 
 
MRI13 
X 
 
 
(X)  
X 
X 
X 
X 
X 
X 
CT Scan14 
 
 
X 
 
 
 
 
 
 
 
 

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Description 
Screening1 
Treatment and Follow-Up Periods18 
Screen. 
Period 1 
Screen. 
Period 2 
Catheter/ 
PVSRIPO2 
Post-PVSRIPO infusion, pembrolizumab treatment and 
Follow-Up (± 7 days)3 
 
 
Week 
Within 6 
wks. of 
catheter 
placement 
Within 1 
wk. 
relative to 
catheter 
placement 
 
1 
2 
U  
(3-4)5 
5 or +3 
wk.  
8 or +3 
wk.  
11; + every 
3 wks. to 
wk.104 
max. 
Follow-Up 
End of Study 
visit 
Day 
Day -42 to -
8 
Day -7 to -
1  
0 (+1 day)  
1 
14 
(28) 
35 or 
+21  
56 or 
+21  
+21d up to 
max. 730 
days 
From 
discontinuation 
of 
pembrolizumab 
Anytime for 
permanent 
discontinuation 
Visit 
1 
2 
3 
4 
5 
U 
6 
7 
≥ 8 
≥ 8 
Biopsy/Tumor 
research 
analyses15 
 
 
X 
 
 
 
 
 
 
 
 
Unscheduled 
biopsy/tumor 
tissue collection16 
 
 
Continuous 
 
ORR/DOR/OS/ 
PFS 
 
 
Continuous 
 
Treatment(s) 
 
 
PVSRIPO17 
 
 
X 
 
 
 
 
 
X 
 
 
Pembrolizumab18 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Abbreviations: AE: adverse event; aPTT: activated partial thromboplastin time; ATT IgG: anti-tetanus toxoid immunoglobulin G; CBC with diff: Complete Blood Count with 
differential; CMP: Comprehensive Metabolic Panel; KPSL: Karnofsky performance status score; LSQ: lymphocyte Subset quantitation; NANO: Neurologic Assessment in Neuro-
Oncology; PRO: patient-reported outcome; PT: prothrombin time; PV: poliovirus; SOC: standard of care; U: Unscheduled; Wk.: Week 
1 At Screening Period 1, lab evaluations will occur first, followed by patients receiving their single PV booster vaccine. 
2 Catheter placement and PVSRIPO infusion (+1 day window or extension as approved by Sponsor). PVSRIPO infusion occurs only following confirmation of GBM at time of 
catheter placement or within 6 weeks of visit 3. If diagnosis of GBM is not confirmed/patient not infused, patient is a screen failure. Platelet count should be confirmed prior to 
catheter placement as well as at time of catheter removal and should remain consistent with inclusion criteria 11. Should the platelet count be less than 125 x 109/L on the day of 
catheter removal, a platelet transfusion should be administered and platelet count confirmed to be greater than 125 x 109/L prior to catheter removal. 
3 Following Visit 4, all tests and procedures have a ±7-day window except for DLT assessment period for first 3 to 6 patients (21 days ± 3 days) post-first pembrolizumab 
infusion). 
4 Questionnaires in support of PROs to occur at visits 2, 4, 6, 8 and then every 9-12 weeks per scheduled imaging visit follow-up. 
5 Unscheduled (U): Visit occurs between visits 5 and 6 only if first dose of pembrolizumab is delayed from planned administration at visit 5. If first pembrolizumab infusion is 
delayed, the schedule of assessments shifts accordingly so the next visit occurs 3 weeks after the date of first pembrolizumab administration. 
6 Includes height, weight, body surface area, vital signs (blood pressure, heart rate, respiratory rate, temperature). 
7 Physical exam, neurologic exam with NANO and KPS daily after PVSRIPO infusion until day of discharge from hospital. 
8 Individuals of childbearing potential, pregnancy test (urine or serum) within 48 h of catheter placement. Repeat every 6 months or any time pregnancy suspected. 
9 Thyroid panel (at a minimum: TSH and free T4; may include free and total T3) should occur every 6 weeks while patient is receiving pembrolizumab. 
10 If undetectable anti-tetanus toxoid immunoglobulin G (ATT IgG) at screen, then Tdap booster vaccine > 1 week prior to biopsy/catheter placement. 
11 LSQ analysis should include the following (both %, and ABS): CD3 T, CD4 T, CD8 T, CD19 B, CD56 NK cells.   LSQ should be collected at visit 1 (pre-boost), visit 2 (post-
boost), and before pembrolizumab doses at visits 5 and 6. 
12 Collection of whole blood for biomarker analyses where indicated. Collected at visit 1 (pre-boost) and visit 2 (post-boost), before pembrolizumab doses at visits 5, 6, 8, and at 
End of Study visit for progression. 

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13 MRI with and without contrast. Screening MRI conducted within 14 days prior to catheter placement. If neurologic deficit presents at visit 5 and pembrolizumab dose is held to 
days 15 to 28, MRI should be conducted and precede pembrolizumab administration. After week 11, MRI to occur every 9-12 weeks or more frequently, at the discretion of the 
treating physician. 
14 CT occurs before infusion to confirm placement criteria and after catheter is removed, post-infusion, to confirm no bleeding. 
15 If possible, up to 3 additional core biopsies will be obtained for biomarker testing (if not available from archival tissue obtained within 6 weeks). 
16 Results from an unscheduled or unplanned biopsy and/or surgical resection should be recorded in the eCRF, and remaining tissue may be requested for analysis. 
17 PVSRIPO retreatment may be allowed for confirmed progression  ≥ 12 months post-initial PVSRIPO infusion with Sponsor/designee approval. 
18 All visit assessments should be conducted before pembrolizumab administration. Pembrolizumab should be administered every 3 weeks ± 1 week through week 104, with the 
first dose at day 14 but up to day 28, if required. If pembrolizumab is permanently discontinued, then safety laboratory evaluations that are not SOC are no longer required 30 days 
after the date of pembrolizumab discontinuation. 
 

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Table of Contents 
Protocol Approval Signature Page ...................................................................................................2 
Investigator Protocol Agreement .....................................................................................................3 
NOTICE REGARDING IMMUNOPROGRESSION .....................................................................4 
Summary of Major Protocol Amendment Changes .........................................................................5 
Protocol Synopsis.............................................................................................................................6 
Table of Contents ...........................................................................................................................18 
List of Tables .................................................................................................................................21 
List of Figures ................................................................................................................................21 
List of Abbreviations .....................................................................................................................22 
1 
Introduction ..................................................................................................................25 
1.1 
Indication .....................................................................................................................26 
 
Current Therapies.........................................................................................................26 
 
Investigational Therapies .............................................................................................26 
1.2 
Protocol Therapies .......................................................................................................26 
 
PVSRIPO Overview ....................................................................................................26 
 
Summary of Nonclinical Studies with PVSRIPO ........................................................27 
 
Summary of rGBM Clinical Studies with PVSRIPO ..................................................27 
1.3 
Pembrolizumab (Overview in GBM)...........................................................................28 
1.4 
Study Rationale ............................................................................................................29 
 
Rationale for Dose Selection .......................................................................................30 
2 
Study Objectives and Endpoints ..................................................................................31 
2.1 
Efficacy, Safety, and Exploratory Objectives and Endpoints ......................................31 
 
Primary Efficacy Endpoints .........................................................................................31 
 
Primary and Secondary Safety Endpoints ....................................................................31 
2.2 
Secondary Efficacy Endpoints .....................................................................................33 
2.3 
Exploratory Endpoints .................................................................................................33 
3 
Study Design ................................................................................................................33 
3.1 
Safety Run-in and DLT Assessment ............................................................................34 
3.2 
Delay in pembrolizumab administration for ongoing peritumoral or cerebral edema 
(or other TEAE/reasons) ..............................................................................................35 
4 
Study Population ..........................................................................................................36 
4.1 
Inclusion Criteria .........................................................................................................36 
4.2 
Exclusion Criteria ........................................................................................................37 
 
Additional Exclusion Criteria per Sponsor or Designee: Notification of Enrollment 
Goal Met ......................................................................................................................39 
4.3 
Patient Identification (ID) ............................................................................................40 
4.4 
Removal, Replacement, or Early Withdrawal of Patients from Therapy or Assessment
......................................................................................................................................40 
4.5 
Handling of Withdrawals .............................................................................................40 
4.6 
Sponsor's Termination of Study ...................................................................................41 
5 
Investigational Plan and Study Procedures ..................................................................41 
5.1 
Screening Period ..........................................................................................................41 
 
Screening Period 1 (within 6 weeks to 8 days of catheter placement) (Visit 1) ..........41 
 
Screening Period 2 (as close to infusion as possible but within 7 days prior to catheter 
placement, unless otherwise noted) (Visit 2) ...............................................................42 

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5.2 
PVSRIPO Treatment Period ........................................................................................43 
 
Day 0 (Visit 3; catheter placement) .............................................................................43 
 
PVSRIPO Infusion (Day 0 or Day 1 [Visit 4]) ............................................................46 
5.3 
Post-PVSRIPO Treatment, Pembrolizumab Treatment and Follow-up Periods .........46 
 
Delayed 1st Pembrolizumab Treatment: Week 3 to 4 visit (if needed) and Shift in 
Schedule of Assessments (Unscheduled Visit) ............................................................48 
 
Week 5 or + 3 weeks from 1st pembrolizumab treatment visit (± 1 week; assessments 
occur before pembrolizumab treatment; Visit 6) .........................................................50 
 
Week 8 or + 3 weeks from last visit (± 1 week; Visit 7) .............................................50 
 
Week 11 (or + 3 weeks from last visit; Visit 8) to Week 104 post-infusion ...............51 
5.4 
Early Discontinuation/End of Study Visit ...................................................................52 
5.5 
Follow-Up Period of Off Study Participants/Patients Permanently Discontinuing 
Pembrolizumab ............................................................................................................53 
5.6 
Follow-up for Patients Temporarily Interrupting Pembrolizumab ..............................53 
5.7 
Study Assessments .......................................................................................................54 
 
Physical Examination...................................................................................................54 
 
Radiographic Imaging ..................................................................................................54 
 
Laboratory Assessments ..............................................................................................55 
 
Patient-Reported Outcomes .........................................................................................55 
 
Other Assessments .......................................................................................................56 
6 
Therapies Under Investigation .....................................................................................56 
6.1 
Method of Assigning Patients to Treatment ................................................................57 
6.2 
Investigational Product: PVSRIPO ..............................................................................57 
 
Name, Classification and Mechanism of Action .........................................................57 
 
Packaging, Labeling and how Supplied .......................................................................57 
6.2.2.1 
Potential Risks with Use ..............................................................................................57 
 
Shipment, Receipt and Storage ....................................................................................58 
 
Preparation, Dispensing and Administration ...............................................................58 
6.3 
Accountability and Compliance of Investigational Products .......................................59 
 
Disposal and Destruction .............................................................................................59 
6.4 
Additional Study Therapy: Pembrolizumab ................................................................59 
 
Pembrolizumab Classification and Mechanism of Action ...........................................59 
 
Packaging, Labeling and how Supplied .......................................................................60 
6.4.2.1 
Potential Risks with Use ..............................................................................................60 
 
Shipment, Receipt and Storage ....................................................................................60 
 
Preparation, Dispensing and Administration ...............................................................60 
6.4.4.1 
Disposal and Destruction .............................................................................................61 
6.5 
Prior and Concomitant Therapy ...................................................................................61 
 
Prior Therapy ...............................................................................................................61 
 
Other Concomitant Therapy ........................................................................................62 
 
Prohibited Medications/Therapies ...............................................................................62 
 
Permitted Medications/Medications for Management of Cerebral Edema and irAE ..62 
6.5.4.1 
Steroids ........................................................................................................................63 
6.5.4.2 
Bevacizumab ................................................................................................................63 
6.5.4.3 
Concomitant Medications for Immune-related Adverse Events ..................................64 
7 
Safety and Pharmacovigilance .....................................................................................65 

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7.1 
Adverse Events ............................................................................................................65 
 
Laboratory Based Abnormalities .................................................................................66 
 
Non-Treatment Emergent Adverse Events ..................................................................67 
 
Treatment Emergent Adverse Events ..........................................................................67 
7.2 
Serious Adverse Events ...............................................................................................67 
7.3 
Definition of an Unexpected Adverse Event ...............................................................69 
7.4 
Assessment and Definition of Dose Limiting Toxicity ...............................................69 
7.5 
Adverse Events of Special Interest ..............................................................................71 
 
Cerebral Spinal Fluid Leakage or Aseptic Meningitis .................................................71 
 
Cerebral or Peritumoral Edema ...................................................................................71 
 
Adverse Events of Immunologic Etiology Associated with Pembrolizumab ..............72 
7.6 
Notification for Serious or Unexpected Adverse Events .............................................74 
8 
Statistical Analyses ......................................................................................................75 
8.1 
Sample Size Considerations .........................................................................................75 
8.2 
Analyzed Population Sets ............................................................................................76 
8.3 
Handling of Missing Data ............................................................................................76 
8.4 
Statistical Analysis Plan ...............................................................................................76 
 
Disposition of Patients .................................................................................................76 
 
Protocol Deviations ......................................................................................................76 
 
Demographics, Disease Characteristics and Medical History .....................................77 
 
Demographics ..............................................................................................................77 
8.4.4.1 
Disease Characteristics ................................................................................................77 
8.4.4.2 
Medical History ...........................................................................................................77 
8.4.4.3 
Prior and Concomitant Medications or Therapies .......................................................78 
8.4.4.4 
Unscheduled Visits ......................................................................................................78 
 
Safety Analysis ............................................................................................................78 
 
Efficacy Analysis .........................................................................................................79 
8.4.6.1 
Objective Response Rate and Disease Control Rate ....................................................81 
8.4.6.2 
Duration of Response and Durable Radiographic Response .......................................85 
8.4.6.3 
Progression Free Survival ............................................................................................85 
8.4.6.4 
Landmark Survival.......................................................................................................85 
8.4.6.5 
Overall Survival ...........................................................................................................85 
9 
Ethical Considerations .................................................................................................85 
9.1 
Institutional Review Board or Independent Ethics Committee ...................................85 
9.2 
Ethical Conduct of the Study .......................................................................................86 
9.3 
Data and Safety Monitoring Board (DSMB) ...............................................................87 
9.4 
Protocol Revisions and/or Deviations ..........................................................................87 
9.5 
Patient Information and Consent .................................................................................87 
9.6 
Personal Data Protection and Confidentiality ..............................................................89 
10 
Quality Control and Quality Assurance .......................................................................89 
10.1 
Audits and Inspections .................................................................................................89 
10.2 
Study Monitoring .........................................................................................................90 
 
Source Document .........................................................................................................90 
 
Case Report Form ........................................................................................................90 
10.3 
Quality Laboratory Standards ......................................................................................91 
10.4 
Data Management ........................................................................................................91 

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11 
Study Administration ...................................................................................................91 
11.1 
Participating Sites/Study Centers .................................................................................91 
11.2 
Required Documents Prior to Study Initiation.............................................................91 
11.3 
Clinical Trial Supplies .................................................................................................92 
11.4 
Investigator Site File ....................................................................................................92 
11.5 
Study Completion ........................................................................................................93 
11.6 
Final Report .................................................................................................................93 
11.7 
Retention of Study Records .........................................................................................94 
11.8 
Confidentiality and Publication ...................................................................................94 
12 
References ....................................................................................................................95 
 
List of Tables 
Table 1 
Schedule of Assessments .............................................................................................15 
Table 2 
Summary of Study Objectives and Endpoints .............................................................32 
Table 3 
Criteria for Determination of Response/Progression with PVSRIPO Followed by 
Pembrolizumab ............................................................................................................82 
 
List of Figures 
Figure 1 
Study Schema for Initial Safety/Efficacy Evaluation (n=30) ......................................14 
Figure 2 
Genetic Structure of PVSRIPO ....................................................................................27 
Figure 3 
Mouse Glioma Model Shows Greater Reduction in Tumor Volume with a Murine 
PVSRIPO in Combination with PD-1 Inhibition than Either Agent Alone.................30 
Figure 4 
Example of Initial Increase in Lesion Size with PVSRIPO Treatment Followed by 
Retraction .....................................................................................................................83 
Figure 5 
Example of New Enhancement/Disease Tracking after PVSRIPO Treatment, Which 
Resolves over Time......................................................................................................84 
 

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List of Abbreviations 
Abbreviation 
Stands For 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
APC 
Antigen Presenting Cell 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
ATT 
Anti-tetanus toxoid  
BSC 
Best Standard of Care 
C 
Celsius 
CBC 
Complete Blood Count 
CE 
Cerebral Edema 
CED 
Convection-Enhanced Delivery 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
cm 
Centimeter 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central Nervous System 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA 
Cytotoxic T-lymphocyte-associated antigen 
DCR 
Disease Control Rate 
DDC 
Duration of Disease Control 
dL 
Deciliter 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration of Response 
DRR 
Durable Radiographic Response 
DSMB 
Data and Safety Monitoring Board 
EC 
Exclusion Criteria 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor 
EGFRvIII 
Epidermal Growth Factor Receptor (variant III) 
EMA 
European Medicines Agency 
EOS 
End of Study 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FLAIR 
Fluid-Attenuated Inversion Recovery 
g 
Gram 
GBM 
Glioblastoma 
GCP 
Good Clinical Practice 
GTR 
Gross Total Resection 
h 
hour 

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Abbreviation 
Stands For 
HBV 
Hepatitis B Virus 
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HRV2 
Human Rhinovirus Type 2 
HSA 
Human Serum Albumin 
IB 
Investigator’s Brochure  
IC 
Inclusion Criteria 
ICF 
Informed Consent Form 
ICH 
International Council of Harmonization 
ICI 
Immune Checkpoint Inhibitor 
ICU 
Intensive Care Unit 
ID 
Identification  
IDH 
Isocitrate Dehydrogenase 
IEC 
Institutional Ethics Committee 
IFN 
Interferon 
IgG 
Immunoglobulin G 
IND 
Investigational New Drug 
IPOL 
Poliovirus Vaccine Inactivated 
IPHP 
Investigational Product Handling Plan 
irAE 
Immune-related Adverse Event 
iRANO 
Immunotherapy Response Assessment for Neuro-oncology  
IRB 
Institutional Review Board 
IRES 
Internal Ribosomal Entry Site 
IV 
Intravenous 
kg 
Kilogram 
KPS 
Karnofsky Performance Status 
LS 
Landmark Survival  
LSQ 
Lymphocyte Subset Quantitation 
MDSC 
Myeloid-Derived Suppressor Cell 
mg 
Milligram 
MGMT 
O6-methylguanine-DNA methyltransferase 
mL 
Milliliter 
mM 
Millimolar 
MOA 
Mechanism of action  
MRI 
Magnetic Resonance Imaging 
NANO 
The Neurologic Assessment in Neuro-Oncology scale 
NK 
Natural Killer 
ORR 
Objective Radiographic Response/Objective Response Rate  
OS 
Overall Survival 
PBS 
Phosphate Buffered Saline 
PD 
Progressive Disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed cell death-ligand 1 
PD-L2 
Programmed cell death-ligand 2 
PFS 
Progression Free Survival 
PHI 
Protected Health Information 

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Abbreviation 
Stands For 
PI 
Package Insert 
PR 
Partial Response 
PT 
Prothrombin Time 
PRO 
Patient-Reported Outcome 
PTE 
Peritumoral Edema 
PV 
Poliovirus 
PV1S 
Serotype 1 Live-Attenuated (Sabin™) PV Vaccine 
PVSRIPO 
Poliovirus/Rhinovirus Recombinant 
q 
Quaque (each or every) 
rGBM 
Recurrent Glioblastoma 
RNA 
Ribonucleic Acid 
RT 
Radiotherapy 
SAE 
Serious Adverse Event 
SAM 
Study Administration Manual 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SJS 
Stevens-Johnson syndrome 
SOA 
Schedule of Assessments 
SOC 
Standard of Care 
SOP 
Standard Operating Procedures 
STR 
Subtotal Resection 
SUSAR 
Suspected Unexpected Adverse Reaction 
TAM 
Tumor-Associated Macrophage 
TBK1 
TANK-binding kinase 1 
TCID50 
Median Tissue Culture Infectious Dose 
Tdap 
Diphtheria, tetanus, and whooping cough (pertussis) booster vaccine 
TEAE 
Treatment Emergent Adverse Event 
TEN 
Toxic Epidermal Necrolysis 
TERT 
Telomerase Reverse Transcriptase 
Tmax 
Maximum Temperature 
Treg 
Regulatory T Cell 
TSH 
Thyroid stimulating hormone 
U 
Unscheduled 
µg 
Microgram 
ULN 
Upper Limit of Normal 
US 
United States 
USP 
United States Pharmacopeia 
VEGF 
Vascular Endothelial Growth Factor 
WHO 
World Health Organization 
Wk. 
Week 
 
 

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1 
Introduction 
Glioblastoma (GBM) is the most common primary central nervous system malignancy and has a 
poor prognosis. Standard first-line treatment includes maximal surgical resection followed by 
adjuvant radio-chemotherapy, which produces only modest survival benefit and tumors 
inevitably recur. Therapeutic options at the time of relapse are extremely limited; in recent years, 
only bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal 
antibody and tumor treating fields have been approved for recurrent (r) GBM [9]. Despite these 
therapies and others, the median OS in rGBM patients failing earlier lines of therapy is still only 
6 to 10 months, and there are very few long-term survivors [10]. Treatment failure is due in part 
to the presence of the blood-brain barrier and poor penetration of cytotoxic drugs into the tumor, 
coupled by the notorious heterogeneity and immunosuppressive nature of rGBM, limiting the 
therapeutic value of agents that target a single aspect of the disease [9, 11]. Clearly, new 
approaches are needed to improve outcomes. 
Oncolytic virus-based immunotherapy for brain tumors is a unique approach with several 
advantages over more conventional drugs. For example, certain oncolytic viruses are capable of 
selective tumor cell killing with a range of inflammatory and immune-stimulatory effects on the 
tumor itself, the tumor stromal component and the host immune system at large. The objective of 
oncolytic immunotherapy is to recruit effective immune responses against tumor-associated 
antigens that can produce lasting immunologic control of cancers. This tumor-specific targeting 
may be enhanced by immune checkpoint blockade, unleashing the full power of the immune 
system to recognize and attack the malignancy. 
PVSRIPO is a genetically recombinant, non-pathogenic PV/rhinovirus chimera with a tumor-
specific and conditional replication phenotype. PVSRIPO is administered by CED directly into 
the growing tumor; there is no resection performed at baseline. Delivery via CED circumvents 
the blood-brain barrier, a process by which large molecules (> 400 daltons) are directly infused 
under pressure into a tumor through a catheter. This delivery method results in adequate 
distribution of such molecules into the tumor over large areas via inherent interstitial fluid 
pathways [12, 13].  
Immunologically, tumor cells evade immunosurveillance and progress through different 
mechanisms, including activation of immune checkpoint pathways that suppress antitumor 
immune responses. The PD-1 signaling pathway is one such pathway that negatively regulates T-
cell-mediated, anti-tumor immune responses. Clinical data shows that blockade of PD-1 
significantly enhances antitumor immunity, leading to durable clinical response and long-term 
survival in some patients in a number of cancers (for a review, see [14]). 

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Therefore, the aim of this study in patients with rGBM is to examine the efficacy and 
safety/tolerability of PVSRIPO treatment followed by the ICI, anti-PD-1 antibody, 
pembrolizumab. 
1.1 
Indication 
The disease under study is rGBM: a fast-growing and aggressive primary brain tumor that 
develops from star-shaped glial cells (astrocytes and oligodendrocytes). The OS is around 6 to 
10 months depending on the therapeutic agents, number of recurrences, prior treatment failures, 
tumor mutations, KPS, etc. [10].  
 
Current Therapies 
Approved agents for the treatment of rGBM may include repeat surgical debulking, RT along 
with chemotherapeutics and targeted therapies. Examples from these classes include lomustine, 
temozolomide, bevacizumab, etoposide and procarbazine. Drug eluting wafers like polifeprosan 
20 with carmustine and devices such as tumor treating fields are also approved. Despite this, the 
National Comprehensive Cancer Network Guidelines recognizes that there is no globally 
accepted standard of care (SOC) nor effective treatment options for rGBM leading to long-term 
survival; given the poor prognosis, patients are encouraged to enroll in clinical trials for access to 
novel therapies [10, 15, 16]. 
 
Investigational Therapies 
There are several ongoing studies of experimental therapies alone or in combination with current 
therapies in recurrent glioblastoma (see: clinicaltrials.gov [17], under “condition or disease” 
search: recurrent glioblastoma).  
1.2 
Protocol Therapies 
 
PVSRIPO Overview 
PVSRIPO (investigational product) is a modified version of the serotype 1 live-attenuated 
(Sabin) PV vaccine (PV1S) with its cognate internal ribosome entry site (IRES) replaced with 
that of human rhinovirus type 2 (HRV2) (see Figure 2). Its immunogenic properties and low 
potential for long-term sequelae are expected to be similar to the vaccine. PV1S has been safely 
administered to > 10 billion individuals worldwide without untoward long-term sequelae. The 
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The foreign internal ribosome entry site of PVSRIPO causes neuronal incompetence: a failure to 
recruit host ribosomes, translate viral genomes, and propagate in neurons, which ablates 
neurovirulence (ie, ability to cause infectious polio) [18]. 
Figure 2 Genetic Structure of PVSRIPO 
 
Figure 2: PVSRIPO is PV1S containing a heterologous IRES of HRV2. The IRES is a cis-acting, non-
coding genetic element within the 5’ untranslated region of all enteroviruses and is essential for 
translation of the viral genome. PVSRIPO is a non-enveloped, positive-sense single stranded RNA virus 
with a genome of ~7300 nucleotides in length. PVSRIPO particles consist of a proteinaceous capsid 
composed of 60 copies of each of 4 capsid proteins (VP1-VP4) arranged in icosahedral geometry. Since 
the coding regions for the viral polyprotein (giving rise to all viral polypeptides) of PVSRIPO and PV1S 
are the same, the physical structure of the viral capsid and all non-structural viral polypeptides of 
PVSRIPO and PV1S are identical. 
 
Summary of Nonclinical Studies with PVSRIPO 
In animal tumor models, oncolytic PVs elicit efficient anti-neoplastic effects resulting in tumor 
regression and, eventually, destruction [19]. There is histologic evidence for direct, virus-
mediated tumor cell killing and indirect, host-mediated inflammatory responses directed against 
tumor. PVSRIPO has undergone extensive dose-range finding, toxicology, biodistribution, 
shedding and neutralizing antibody tests with intrathalamic inoculation of up to 5 x 109 TCID50 
in Cynomolgus monkeys (M. Fascicularis) [18]. These investigations 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 in saliva, urine or stool; 
(vi) presence of a neutralizing antibody response. 
 
Summary of rGBM Clinical Studies with PVSRIPO  
The first-in-human PVSRIPO study (Pro00031169) investigated PVSRIPO delivered via CED in 
61 adult patients with rGBM who failed prior SOC therapies (any recurrence; 1 to 5.5 cm 
contrast-enhancing supratentorial tumor). Dose levels ranging from 107 up to 1010 TCID50 were 
examined in a dose escalation phase followed by a dose expansion phase, which established the 

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recommended Phase 2 dose of 5x107 TCID50 [5]. In the dose-expansion phase (n=31), 19% of 
patients had a PVSRIPO-related AE of grade 3 or higher. Events most often attributed to 
PVSRIPO included those related to PTE or CE (eg, headache, pyramidal tract syndrome, seizure, 
dysphasia) and PVSRIPO was well tolerated systemically.  
In the ongoing multicenter Phase 2 study (Pro00077024), as of August 2020, 120 adult rGBM 
patients with similar inclusion criteria as the Phase 1 study (Pro00031169; limited to 2nd 
recurrence), have been treated with PVSRIPO at 5x107 TCID50. Based on a recent safety 
summary of the ongoing Phase 1 and 2 studies conducted in February of 2020, TEAE with some 
degree of attribution to PVSRIPO treatment occurring in ≥ 20% of patients included localized 
inflammation with nervous system disorders related to PTE (eg, headache, pyramidal tract 
syndrome, seizure, dysphasia) and fatigue. 
Based on an earlier published summary of the 61 patients in the Phase 1 study, the estimated 
percentage of rGBM patients surviving long-term (ie, landmark survival [LS]) in patients treated 
with PVSRIPO was 21% at 24 through 60 months [5]. This was favorable when compared to 
criteria matched external controls and a literature summary. The estimated percentage of patients 
surviving in the external control group was only 4% at 36 months and 2% at 60 months. In the 
summary of interventional studies of marketed and investigational agents in rGBM patients 
reported in the recent literature, the weighted mean estimate of patients surviving at 36 months 
was 2.71% (9 treatment arms) and 0.56% at 60 months (6 treatment arms) (data on file, Istari). 
In addition, 4 patients have been successfully treated with PVSRIPO via compassionate use 
(single patient protocol/Investigator Investigational New Drug [IND]), which was followed by at 
least one dose of pembrolizumab at the treating investigator’s discretion. These limited 
experiences demonstrate initial feasibility of the approach. To date, no serious adverse events 
(SAE) or events of increased severity beyond those expected for each agent were noted with the 
combination (data on file, Istari). Indicators of potential and early onset anti-tumor activity (eg, 
“soap-bubble” degeneration of PVSRIPO infused enhancing lesion) in these limited experiences 
also support expansion of this approach in a formal protocol powered to demonstrate an 
appreciable improvement in response relative to single agent therapy, while rigorously 
evaluating safety.  
1.3 
Pembrolizumab (Overview in GBM) 
Immune checkpoint inhibitors have been studied extensively in GBM (for reviews, see [6, 7]). 
Clinical studies with pembrolizumab and other PD-1 inhibitors have shown that these agents 
have been relatively well tolerated in rGBM patients, with low rates of discontinuation due to 
AEs related to cerebral edema [3, 4, 20, 21]. However, efficacy results with PD-1 inhibitors have 

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generally showed disappointing results when administered as a single agent in rGBM patients 
and even in combination with approved agents. For example, in a Phase 2 study in rGBM 
patients, pembrolizumab alone or in combination with bevacizumab had limited activity [21].   
Encouraging improvements in OS were noted in small single agent trials of pembrolizumab in 
rGBM patients eligible for surgical resection, when administered in the neoadjuvant setting 
(given both prior to and after resection); n=15 (median OS of 13.57 months [3]) and in another 
15 patient trial investigating the same (median OS of 20 months) [4], but not when administered 
only after resection (median OS of 7.5 months [3]). These findings suggest that other stimuli 
may be required to recruit immune cells to the tumor even with checkpoint blockade. 
Preliminary evidence supportive of this concept has been noted via an ongoing investigation with 
another oncolytic virus (oncolytic adenovirus, DNX-2401) in combination with pembrolizumab. 
A recent interim analysis reported that 47% of patients receiving the combination (n=48) 
experienced clinical benefit, noted as stable disease or better [22]. 
1.4 
Study Rationale 
At this time, there are no immune therapies indicated for GBM, a highly immunosuppressive 
tumor [11]. Learning from previous studies, the future of immune therapy for GBM appears most 
hopeful for combinations that seek to increase expression of tumor-specific neo-antigens, 
coupled with checkpoint inhibition, to overcome the profound immune blockade associated with 
this disease.  
The mechanistic rationale for following PVSRIPO therapy with the PD-1 inhibitor 
pembrolizumab, in patients with rGBM, is supported by the following: 
1. Tumor infection with PVSRIPO causes direct tumor cell killing, which is known to 
induce the release of tumor-specific antigens that facilitate antitumor immunity [2].  
2. PVSRIPO also sub-lethally infects antigen presenting cells (APCs), such as tumor-
associated macrophages and dendritic cells. This causes chronic, sub-lethal viral 
propagation, provoking a persistent type I interferon (IFN)-dominant inflammatory 
response [2].  
3. TANK-binding kinase 1 (TBK1) plays a pivotal role in antiviral innate immunity and the 
oncolytic virus PVSRIPO works by engaging a TBK1-IFN regulatory factor 3-driven 
type-I/III IFN response [2]. This powerful signal to T-cell activation is naturally 
restricted by PD-1. Therefore, combining PVSRIPO with an anti-PD-1 agent is 
mechanistically logical to provoke a maximal, antitumor, T-cell response in 
immunologically “cold” tumors, such as rGBM.  
4. This direct lytic tumor cell killing, coupled with infection and pro-inflammatory 
stimulation of APCs, produces tumor antigen-specific, anti-tumor immunity. Thus, 

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PVSRIPO facilitates recognition and targeting of tumors by the immune system, which 
should act synergistically with pembrolizumab.  
5. Mouse models of GBM support this paradigm; the combination of PVSRIPO with a ICI 
leads to a greater anti-tumor response than either agent alone (see Figure 3). 
6. The clinical experience, to date: 4 patients have been treated with PVSRIPO followed by 
at least one dose of pembrolizumab under expanded access/compassionate use, 
demonstrating initial feasibility and tolerability of the approach. Indicators of potential 
and early onset anti-tumor activity in these limited experiences support expansion of this 
approach in a formal protocol.   
Given this supportive information, we hypothesize that mechanistically, use of PVSRIPO and 
pembrolizumab together may act synergistically to yield superior response and survival rates 
relative to either agent used alone, in a tolerable manner. 
Figure 3 Mouse Glioma Model Shows Greater Reduction in Tumor Volume with a 
Murine PVSRIPO in Combination with PD-1 Inhibition than Either Agent Alone 
 
Figure 3: CT2A-CD155 tumors were implanted subcutaneously and treated with mock (DMEM)/mRIPO (mouse 
equivalent of PVSRIPO; denoted as OncPV above; 5 x 106 TCID) on day 0. Anti-PD1/control immunoglobulin G 
(IgG)2A was administered intraperitoneally on days 0, 3, 6 and 9 (250μg at each interval). Four experimental groups 
were treated as follows (n=12 each group): (i) Mock/Mock: DMEM (mRIPO control) + IgG2A (250μg; anti-PD1 
control); (ii) Mock/anti-PD1: DMEM (mRIPO control) + anti-PD1 (250μg); (iii) mRIPO/Mock: PVSRIPO (5 x 106 
TCID) + IgG2A (250μg; anti-PD1 control); (iv) mRIPO/anti-PD1: PVSRIPO (5 x 106 TCID) + anti-PD1 (250μg) 
(data on file, Istari). 
 
Rationale for Dose Selection 
PVSRIPO: As noted, the dose for PVSRIPO treatment and retreatment (if applicable) was 
selected based on IND-directed toxicity studies and the Phase 1 study (Pro00031169; 

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ClinicalTrials.gov Identifier: NCT01491893) in adults with rGBM (n=61) and is supported by 
the data in over 100 patients in the ongoing multicenter Phase 2 study (Pro00077024; 
ClinicalTrials.gov Identifier: NCT02986178). The PVSRIPO dose identified in the Phase 1 
study, being used in the Phase 2 study and to be utilized in this study is 5x107 TCID50.  
Pembrolizumab: The recommended dose of pembrolizumab is keeping with prior investigations 
in rGBM [3, 4, 20, 21] that were well tolerated: 200 mg administered as an IV infusion over 30 
minutes every 3 weeks. Treatment is planned to continue up to a maximum of Week 104 
(approximately 23.5 months), until confirmed disease progression or unacceptable toxicity 
leading to discontinuation. 
2 
Study Objectives and Endpoints 
2.1 
Efficacy, Safety, and Exploratory Objectives and Endpoints 
The study objectives and corresponding endpoints are described in greater detail below and are 
summarized in Table 2. Endpoints evaluated by iRANO criteria will focus on patients treated 
with PVSRIPO followed by at least one dose of pembrolizumab. 
 
Primary Efficacy Endpoints 
• ORR: Proportion of patients with confirmed CR or PR.  
• DOR: KM curves showing median DOR for all patients that have confirmed CR or PR.  
• DRR: Proportion of patients with confirmed response (CR or PR) that lasts for ≥ 6 
months. 
Objective response (CR or PR), stable disease and confirmed progression will be determined via 
criteria noted in Table 3. 
 
Primary and Secondary Safety Endpoints 
Primary: Safety and tolerability, including assessment of DLT, will be assessed by evaluating 
the frequency and severity of TEAE via CTCAE (v5.0) when PVSRIPO is followed by at least 
one dose of pembrolizumab.  
Secondary: Patients receiving PVSRIPO alone will also be summarized for frequency and 
severity of TEAE but separately and as a secondary endpoint. 

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Table 2 
Summary of Study Objectives and Endpoints 
Objectives 
Endpoints/Evaluation Criteria 
Primary (efficacy)  
Anti-tumor activity: 
 
• 
ORR: Proportion of patients with confirmed CR or PR.  
• 
DOR: KM curves showing median DOR for all patients that 
have confirmed CR or PR.  
• 
DRR: Proportion of patients with confirmed response (CR or 
PR) that lasts for ≥ 6 months. Radiographic outcomes will 
be assessed via iRANO criteria [1] in this protocol.   
Primary (safety)  
Safety/tolerability: 
• 
Frequency and severity of TEAE via CTCAE (v5.0) for 
patients receiving PVSRIPO and at least one dose of 
pembrolizumab.  
Secondary (efficacy)  
Anti-tumor activity:  
 
• 
DCR: Comprised of patients achieving CR, PR or SD for ≥ 6 
months. 
• 
DDC: KM curves showing median DDC for patients with 
confirmed CR, confirmed PR or SD for ≥ 6 months. 
Survival 
• 
Overall and landmark survival: Proportion of patients alive at 
≥ 6, ≥ 12 and at 24 months post-PVSRIPO infusion as 
calculated by Kaplan-Meier methods.  
Progression free survival 
• 
If calculable, PFS will be estimated based on the time from 
PVSRIPO infusion to death or confirmed progression, based 
on the definition of progression noted in Table 3. 
Secondary (safety) 
 
• 
Frequency and severity TEAE via CTCAE for patients 
receiving PVSRIPO alone without pembrolizumab (any 
reason). 
Exploratory 
Identification of biomarkers 
of anti-tumor response to 
PVSRIPO followed by 
pembrolizumab  
Assessment of tumor tissue and blood samples for identification 
of genetic, cytologic, histologic and/or other markers that 
demonstrate pharmacodynamic activity of PVSRIPO or correlate 
with anti-tumor response.  
Alternative assessment of 
radiographic 
response/progression/PFS 
Radiographic outcomes will also be analyzed as described in 
Table 3 for endpoint determination. 
All response must be confirmed via two consecutive MRI 
assessments at least 4 weeks apart. If on bevacizumab therapy 
when response first noted, response will be confirmed ≥ 8 weeks 
off bevacizumab, via MRI. 
Patient-reported outcomes 
Assessment of patient-reported quality of life and activities 
of daily living capabilities 

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2.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will include the following and will be assessed through a 
maximum of 24 months post-PVSRIPO infusion: 
• DCR: Comprised of patients achieving CR, PR or SD for ≥ 6 months. 
• DDC: KM curves showing median DDC for patients with confirmed CR, confirmed PR 
or SD for ≥ 6 months. 
• Overall and landmark survival: Proportion of patients alive at ≥ 6, ≥ 12 and 24 months 
post-PVSRIPO infusion as calculated by Kaplan-Meier methods. 
• Progression free survival: Calculated from the time of PVSRIPO infusion to death or 
confirmed progression via the definition outlined in Table 3.  
2.3 
Exploratory Endpoints 
Exploratory endpoints include assessment of changes in markers of immune function from 
baseline and identification of genetic, cytologic, histologic and/or other markers (ie, biomarkers) 
that may correlate with response via analysis of biologic samples (includes blood, serum, cells, 
tumor biopsy).  
In addition, radiographic response and PFS as determined via iRANO criteria will also be 
explored, and patient-reported outcomes will be assessed over the course of treatment. 
3 
Study Design 
To establish therapeutic intent and adequately assess the risk/benefit profile, in the first protocol 
amendment, the study sample size was adjusted to allow for sufficient statistical power to 
demonstrate a meaningful difference in response, relative to monotherapy, and efficacy was 
elevated to a primary endpoint. 
This is an open-label, single-arm, non-randomized study characterizing the efficacy, safety and 
tolerability of PVSRIPO delivered via intratumoral infusion followed by pembrolizumab in 
patients with rGBM. 
Approximately 30 eligible participants, 18 years of age or older, will be enrolled and treated with 
PVSRIPO and at least a single dose of pembrolizumab in this study. The maximum planned 
duration of follow-up in this study is up to 24 months (104 weeks), and consists of the following 
treatments: 

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• Single PVSRIPO infusion at baseline. 
o Note: retreatment with PVSRIPO is allowed for qualifying patients with 
enhancing disease ≥ 12 months from initial PVSRIPO infusion 
• Pembrolizumab (200 mg IV infusion) initiated 14 days after PVSRIPO infusion (up to 28 
days, if necessary), given q 3 weeks, through Week 104 (23.5 months of treatment) or 
until irAE meeting criteria for dose interruption/discontinuation or confirmed progression 
(must consider clinical and radiographic assessments as outlined in Section 8.4.6.1 and 
Table 3) 
Patients reaching 24 months on this study may be offered participation in a longer-term follow-
up/PVSRIPO retreatment protocol or other mechanisms. 
The study will occur in the following periods as outlined in Table 1 and Figure 1. 
• Screening Period 1: Between 1 and 6 weeks prior to catheter placement  
• Screening Period 2: Within 7 days of catheter placement 
• PVSRIPO Catheter Placement and Biopsy (if required) Period: Day 0 
• PVSRIPO Infusion Period/Baseline: Single PVSRIPO infusion at Day 0 or Day 1 (unless 
extension granted by Sponsor) 
• Post-PVSRIPO infusion, pembrolizumab treatment and follow-up Period: 
pembrolizumab starting at Week 2 (up to Week 4, max) and every 3 weeks thereafter, to 
a maximum of Week 104 (approximately 23.5 months maximum pembrolizumab 
treatment duration) 
Participants with enhancing disease ≥ 12 months from a prior PVSRIPO infusion and meet the 
key IC/EC for retreatment will be eligible for additional PVSRIPO infusion(s). 
The study may be adapted or expanded in one or more larger cohorts of participants, in 
consultation with the DSMB, based on interim review and considering the totality of the study 
data. 
3.1 
Safety Run-in and DLT Assessment 
This study will start with a safety run-in period. The first 3 participants will be sequentially 
enrolled, with a mandatory waiting period of 21 to 28 days after the immediate prior patient’s 
PVSRIPO treatment before the next patient receives PVSRIPO. The 21- to 28-day waiting period 
also applies after the third patient receives PVSRIPO, prior to PVSRIPO treatment of the fourth 
patient.  
The DLT evaluation period for the first 3 patients will begin once a patient who received 
PVSRIPO receives the first dose of pembrolizumab and continue for 21 days (± 3 days to 

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account for variations in patient visit scheduling, weekends, etc.) after this first dose of 
pembrolizumab. This wait period allows sufficient time for safety review prior to the next patient 
receiving their first dose of pembrolizumab. If ≥ 2 of the first 3 patients treated with PVSRIPO 
followed by 1 dose of pembrolizumab experience a DLT, accrual will be halted, and the 
treatment plan may be modified, or the study may be closed. 
If no DLT occurs in the first 3 participants, the dosing regimen will continue as planned and an 
additional 27 participants will be enrolled to further characterize safety and anti-tumor activity of 
treatment with PVSRIPO plus pembrolizumab.   
However, if only 1 patient experiences a DLT of the first 3 participants treated, an additional 
3 participants will be enrolled (without a waiting period between participants) to undergo DLT 
evaluation. If ≤ 33% of participants (ie, ≤ 2 of 6 total) experience a DLT, the 24 remaining 
participants will be enrolled. If > 33% of participants (ie, ≥ 3 of 6) experience a DLT, the study 
will be halted, and the treatment plan modified, or the study may be closed.  After the DLT 
evaluation period, ongoing monitoring of TEAEs will occur on at least a monthly basis by the 
Sponsor safety review team and by the DSMB, as specified in the safety plan and applicable 
charter, respectively. 
If one of the first 3 (or 6) participants accrued withdraws from the study during the DLT 
evaluation period for reasons unrelated to the occurrence of a DLT, the participant will be 
replaced for the purpose of the initial DLT assessment. For details regarding events and criteria 
for meeting the definition of a DLT, see Section 7.4. 
3.2 
Delay in pembrolizumab administration for ongoing peritumoral or cerebral 
edema (or other TEAE/reasons) 
Peritumoral edema may be associated with PVSRIPO treatment and there is potential for the 
same after immune checkpoint inhibition. As such, the first planned dose of pembrolizumab 
(scheduled 2 weeks after PVSRIPO infusion) will be delayed by up to two additional weeks in 
participants with any ongoing ≥ Grade 3 PTE or CE or ≥ Grade 2 AEs related to PTE or CE 
following PVSRIPO infusion requiring active treatment, such as new or worsening neurologic 
signs and symptoms (eg, hemiparesis requiring ≤ 4 mg/day dexamethasone or seizure requiring 
anti-epileptics), until such events resolve to ≤ Grade 1.  
If such events have not resolved to ≤ Grade 1 by 4 weeks post-PVSRIPO infusion, or the patient 
has not received pembrolizumab for any reason by 4 weeks post-PVSRIPO infusion, the 
participant will not receive pembrolizumab under this trial and will be replaced. If a participant 
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participant will not receive pembrolizumab under this trial and will also be replaced. These 
replaced participants will not be considered in the initial DLT assessment of the treatment with 
PVSRIPO and pembrolizumab. 
4 
Study Population 
4.1 
Inclusion Criteria 
All tumor size and location-related eligibility criteria listed below will be independently verified 
by the Sponsor or their designee prior to patient enrollment. 
A patient will be eligible for inclusion in the study if he/she meets all the following criteria prior 
to Day 0 (ie, catheter placement for PVSRIPO infusion) and after catheter placement, where 
specified: 
1. ≥ 18 years of age. 
2. Actively growing recurrent supratentorial glioblastoma confirmed by biopsy by the site’s 
neuropathologist or designee. 
o Recurrent glioblastoma histologically confirmed within 6 weeks prior to PVSRIPO 
infusion will not require a biopsy to confirm active tumor prior to catheter placement. 
However, biopsy confirmation of glioblastoma must be provided prior to PVSRIPO 
infusion if histological confirmation is not completed within 6 weeks prior to catheter 
placement. 
o For the purpose of this protocol, “recurrence” is defined by either progression of 
primary glioblastoma or transformation from a lower grade to a higher grade. Note 
that in the case of transformation, this change must be confirmed via histology by site 
pathologist.  
3. Enhancing lesion ≥1 cm shortest diameter to ≤ 5.5 cm longest diameter in all planes; 
occurrence within the prior resection cavity should not contribute to the longest diameter 
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4. Before catheter placement based on screening MRI and at the time of catheter placement via 
CT prior to infusion, neurosurgical investigator must confirm both tumor location (> 1 cm 
from eloquent brain) as well as placement of infusion catheter within or through the 
progressive enhancing tumor is feasible and at a safe distance relative to eloquent brain 
function, with the tip of the catheter being placed: 
a. Within the enhancing portion or in the vicinity of enhancement of target lesion (ie, 
infiltrative disease)  
b. ≥ 0.5 cm from ventricles 
c. ≥ 1 cm deep into the brain 
d. ≥ 0.5 cm from the corpus callosum 
5. First or second relapse supported by MRI or CT scan; relapse is defined as progression 
following initial/prior therapy(ies). 
6. Failed previous first line therapy: maximum surgical resection and RT (plus concomitant 
chemotherapy followed by maintenance chemotherapy if unknown or MGMT promoter). 
Patients who begin but do not complete chemotherapy/RT may still be considered for 
eligibility at the discretion of Sponsor.  
7. KPS ≥ 70 at screening and baseline. 
8. Undergone prior vaccination against PV and received a boost immunization with trivalent 
IPOL® (Sanofi-Pasteur SA) at least 1 week, but less than 6 weeks, prior to administration of 
PVSRIPO (within 6 months of PVSRIPO retreatment). Note: Patients who are unsure of their 
prior vaccination status/who have not been vaccinated must provide proof of vaccination 
and/or evidence of anti-PV immunity prior to enrollment, as applicable.  
9. Ability to safely discontinue anti-coagulant therapy(ies) prior to biopsy/catheter placement, 
as required per site/surgical guidelines, in the opinion of the investigator.  
10. Hemoglobin ≥ 9 g/dL prior to biopsy/catheter placement. 
11. Platelet count ≥ 100,000/µL (unsupported); ≥ 125,000/ µL (can be supported via platelet 
transfusion) at biopsy/catheter placement and/or with a Sponsor-approved bone marrow 
stimulant/colony stimulating factor, eg, romiplostim). 
12. ANC ≥ 1000/µL prior to biopsy/catheter placement. 
13. Creatinine ≤ 1.2 x ULN prior to biopsy/catheter placement. 
14. Total bilirubin, ALT, AST, ALP ≤ 2.5 x ULN prior to biopsy/catheter placement. 
15. PT and aPTT ≤ 1.2 x ULN prior to biopsy/catheter placement. 
16. If undetectable ATT IgG at screen, Tdap booster vaccine > 1 week prior to biopsy/catheter 
placement. 
17. Patients must be willing and able to understand and provide written informed consent. 
4.2 
Exclusion Criteria 
A patient will not be eligible for inclusion in this study if he/she meets any of the following 
criteria prior to Day 0 (PVSRIPO catheter placement): 

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1. Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti- 
CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways) ≤ 12 weeks prior to PVSRIPO infusion (Note: 
does not apply for patients treated with pembrolizumab under this protocol who are eligible 
for PVSRIPO retreatment). Patients who had previously permanently discontinued any anti-
PD-1 or PD-L1 therapy due to severe or life-threatening immune-related AE are excluded. 
2. Excluded are: 
a. Neoplastic lesions in the brainstem, cerebellum, or spinal cord 
b. Radiological evidence of active/growing multifocal disease: no size increase > 0.5 cm in 
any direction of any other enhancing non-target lesions present at baseline confirmed via 
most recent, prior, consecutive MRIs at least 3 months apart. However, two lesions 
connected by T2 flair are not excluded. 
c. Tumors with ≥ 1cm of contrast-enhancing tumor component crossing the midline 
(crossing the corpus callosum) 
d. Extensive subependymal disease: multiple lesions or lesions covering > 50% of 
subependymal space. Tumor touching subependymal space allowed. 
e. Extensive leptomeningeal disease: multiple lesions or lesions covering > 50% of 
leptomeninges. Tumor touching leptomeninges allowed. 
3. Has received systemic immunosuppressive treatments other than systemic corticosteroids 
(eg, methotrexate, chloroquine, azathioprine) within six months of PVSRIPO infusion. 
4. Requires treatment with high dose systemic corticosteroids, defined as dexamethasone 
> 4 mg/day or equivalent, within 2 weeks of PVSRIPO infusion. 
5. Prior interstitial brachytherapy, implanted chemotherapy, stereotactic radiosurgery or 
therapeutics delivered by local injection or CED, including PVSRIPO (except for qualifying 
patients being retreated with PVSRIPO within this trial). 
6. Pregnant and/or breast feeding female; patient/female partner of childbearing potential who 
is unwilling to utilize protocol-defined acceptable form of contraception for duration of 
study. 
7. Impending/life-threatening cerebral herniation syndrome, per neurosurgeon/designate. 
8. Severe, active co-morbidity, defined as follows: 
a. Infection requiring IV treatment/unexplained febrile illness (Tmax > 99.5°F/37.5°C)  
b. Known immunosuppressive disease/human immunodeficiency virus infection 
c. Known active hepatitis B or C infection via positive viral DNA or RNA, respectively   
d. Unstable or severe intercurrent medical conditions such as severe heart disease (New 
York Heart Association Class 3 or 4) 
e. Known lung disease with forced expiratory volume in 1st second of expiration < 50% 
f. Uncontrolled diabetes mellitus (eg, hemoglobin A1C level > 7.0% with treatment) 
g. History of other malignancy requiring active treatment within 2 years of 
biopsy/catheter placement with the exception of those with a negligible risk of 

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metastasis or death (eg, resected cutaneous basal cell carcinoma, or other cancers with 
5-year OS of > 90%) 
9. Known albumin allergy. 
10. Uncontrolled unexplained bleeding and/or hemoptysis within 4 weeks of planned PVSRIPO 
infusion. 
11. Inability to undergo brain MRI with and without contrast. History of severe/anaphylactic 
reaction to gadolinium contrast agent is excluded. Mild allergy (eg, rash) acceptable with 
prophylactic acetaminophen and diphenhydramine. 
12. History of neurological complications due to PV infection. 
13. Not recovered from toxic side effects (alopecia acceptable) and/or no current or prior tumor 
treatments within the following timeframe relative to biopsy/catheter placement:  
a. Chemotherapy or bevacizumab ≤ 4 weeks (except for nitrosourea [6 weeks] or 
metronomic dosed chemotherapy such as daily temozolomide, etoposide or 
cyclophosphamide [1 week])  
b. Tumor treating fields ≤ 7 days  
c. RT of brain ≤ 12 weeks, except for progressive disease outside of the radiation field or 
2 progressive scans at least 4 weeks apart or histopathologic confirmation 
14. History of agammaglobulinemia. 
15. Known hypersensitivity to pembrolizumab, or any components of pembrolizumab. 
16. Active autoimmune disease requiring systemic immunomodulatory treatment within the past 
12 months; physiologic replacement therapy (eg, thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a 
form of systemic treatment. 
 
Additional Exclusion Criteria per Sponsor or Designee: Notification of 
Enrollment Goal Met 
1. The study is targeting balanced enrollment of patients with and without any prior anti-
angiogenic or anti-VEGF-targeted agent uses (eg, bevacizumab, cediranib, aflibercept, 
vandetanib, cabozantinib, sunitinib). As such, once 50% of planned patients (ie, 15 patients) 
are enrolled into either group, enrollment into the other group may end and future patients 
with that criterion may not be eligible. For example, after 15 patients who received prior anti-
VEGF therapy are enrolled and treated with PVSRIPO and ≥ 1 dose of pembrolizumab, 
enrollment may be limited to only patients without prior anti-VEGF therapy use. 
2. The study is targeting enrollment of ≥ 50% of patients who failed a prior chemotherapy 
regimen. If the study enrolls 40% of subjects who did not fail a prior chemotherapy regimen 
(ie, 12 of the first 30 subjects had no prior chemotherapy, which is not required if MGMT 
promotor unmethylated), enrollment into this group may be halted and future patients who 
did not have any prior chemotherapy may not be enrolled.  

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4.3 
Patient Identification (ID) 
Patients will be identified by a unique numeric patient ID assigned at time of screening. 
4.4 
Removal, Replacement, or Early Withdrawal of Patients from Therapy or 
Assessment 
Participants may voluntarily withdraw from the study at any time.  
The Investigator may also withdraw a participant from the study at any time based on his/her 
discretion. Reasons for Investigator-initiated withdrawal may include, but are not limited to the 
following: 
• Progressive disease as documented by MRI, physical examination, or tissue sample at 
any time after the completion of therapy requiring treatment with non-protocol therapy 
(in keeping with the criteria outlined in Table 3) 
• Pregnancy 
• Upon request of the participant 
• If, in the Investigator’s medical judgment, further participation would be injurious to the 
participant’s health or wellbeing 
• Development of intolerable symptoms 
• Protocol deviation 
• Non-compliance of the participant 
• Administrative issues 
4.5 
Handling of Withdrawals 
Participants withdrawing from the study prior to receiving PVSRIPO infusion, either voluntarily 
or due to ineligibility, will be considered non-evaluable in all but the screening analysis set (see 
Section 8); these patients will be replaced. Minimal information will be retained in the study 
database for screen failures. 
Patients who are treated with > 4 mg/day dexamethasone (or equivalent) prior to receiving the 
first dose of pembrolizumab and patients who do not receive ≥ 1 dose of pembrolizumab after 
PVSRIPO will also be replaced and will not contribute to the PVSRIPO plus pembrolizumab (ie, 
combination) datasets. These subjects will continue to be followed for safety and efficacy and 
will be summarized separately.  

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If patients do not enter the voluntary follow up period, all information as described at the next 
scheduled study visit if <11 weeks after PVSRIPO treatment or at the End of Study (EOS) visit, 
should be obtained, if possible and as applicable. 
Handling of early withdrawals for analyses are outlined in Section 8. 
4.6 
Sponsor's Termination of Study 
This study can be terminated at any time for any reason by the Sponsor. If this occurs, all 
participants should be notified as soon as possible to schedule their last study visit.  
5 
Investigational Plan and Study Procedures 
5.1 
Screening Period 
The patient’s most recent MRI, diagnosis and all other recent and relevant information should be 
considered against the study eligibility criteria prior to formally considering a patient for signing 
of informed consent and commencement of subsequent screening assessments and procedures. 
For example, subjects with tumor diameters > 5.5 cm (and which are not part of a prior resection 
cavity) noted on their most recent MRI should not be screened for inclusion on this study. 
 
Screening Period 1 (within 6 weeks to 8 days of catheter placement) (Visit 1) 
For potentially qualifying patients, the first screening examination period will take place within 6 
weeks, to at least 1 week, prior to catheter placement for PVSRIPO infusion and the patient will 
have the assessments below completed (see Table 1). 
Administrative: 
• An informed consent form (ICF) must be signed by the patient before any screening 
procedures are completed. 
• Medical History (includes details of tumor diagnosis, characteristics including molecular 
genetic testing, tumor treatment and surgical history, and evaluation of pre-existing 
conditions) 
Clinical: 
• AE assessment of any non-SOC screening procedures 

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Laboratory Assessments: 
• A blood test for lymphocyte subset quantitation (LSQ) and anti-tetanus toxoid (ATT) IgG 
(local lab) 
o Note: if ATT IgG is negative, must have a tetanus (Tdap) booster vaccine 
administered > 1 week from planned catheter placement for PVSRIPO infusion.  
• Complete blood count (CBC) with differential (SOC/local lab) 
• Comprehensive metabolic panel (CMP; SOC/local lab) 
• A blood draw for immunologic, genetic or other analyses will occur (whole blood).  
• These samples will be transferred to the designated laboratory in keeping with the SAM 
• After completion of blood draws for immune analysis, a single booster immunization of 
trivalent inactivated IPOL® (Sanofi-Pasteur SA; obtained via site) 
o ≥ 1 week but ≤ 6 weeks of the initial PVSRIPO infusion 
o ≥ 1 week but ≤ 6 months for any PVSRIPO retreatment 
 
Screening Period 2 (as close to infusion as possible but within 7 days prior to 
catheter placement, unless otherwise noted) (Visit 2) 
Whenever possible, when confirming eligibility based on the study IC/EC, the least invasive 
screening procedures (eg, KPS) noted below and in Table 1 should be performed first and the 
most invasive, performed last.  
As close to the planned PVSRIPO infusion as possible but at least within 7 days before catheter 
placement, the following will be conducted: 
Clinical assessments: 
• Medical history (since Screening 1) 
• Physical examination 
• Neurologic and NANO assessment  
• KPS  
• Patient-Reported Outcome (PRO) Assessment 
• AE Assessment 
• Concomitant Medications 

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Radiographic assessments: 
• Baseline MRI (or imaging with volumetric quantitation ability) of the brain with and without 
gadolinium contrast (within 14 days of biopsy/catheter placement)  
Laboratory assessments: 
• CBC with differential 
• CMP  
• Pancreatitis labs (amylase, lipase) 
• Prothrombin time (PT; SOC/local lab) and activated partial thromboplastin time (aPTT; 
SOC/local lab) 
• Thyroid panel (to include at a minimum: TSH, free T4 (thyroxine); may include free and 
total T3 (triiodothyronine); SOC/local lab) 
• LSQ 
• Whole blood collected for research analyses  
Within 48 hours of but prior to planned catheter placement: 
• Urine or serum-based pregnancy test for women of childbearing potential (urine or serum 
acceptable; a serum-based pregnancy test should be conducted in the event of equivocal 
results noted with urine test) 
5.2 
PVSRIPO Treatment Period 
See Table 1 for the complete study schedule of assessments during the PVSRIPO treatment 
period and pembrolizumab treatment and follow-up period.  
 
Day 0 (Visit 3; catheter placement) 
The following will occur on the day of PVSRIPO infusion: 
Clinical assessments (prior to PVSRIPO infusion): 
• Medical history, including any changes noted since Screening Period 2 
Laboratory assessments: 

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• CBC with differential (Platelet count should be confirmed prior to catheter placement as well 
as at time of catheter removal and should remain consistent with inclusion criteria 11. Should 
the platelet count be less than 125 x 109/L on the day of catheter removal, a platelet 
transfusion should be administered and platelet count confirmed to be greater than 125 x 
109/L prior to catheter removal) 
 
• Pregnancy test for individuals of childbearing potential prior to infusion if no results on file 
within 48 h of but before planned infusion 
Biopsy(ies): 
If there is no confirmation of diagnosis via histology based on a tissue sample obtained within 6 
weeks prior to planned infusion, a biopsy will be conducted prior to catheter placement and 
PVSRIPO infusion to confirm active tumor/high-grade glioma. After the biopsy is performed, 
the catheter is placed but PVSRIPO may not be infused until the qualifying diagnosis is made.  
If the biopsy at catheter placement does not confirm active tumor/high-grade glioma by the site 
pathologist, the patient will not receive PVSRIPO and will be withdrawn from the study as a 
screen failure. The catheter should be removed and followed by a CT scan to confirm no 
bleeding. 
Note: for all patients, including patients with tumor transformed from a lower grade to a higher 
grade, glioblastoma must be confirmed via prior histology by the site pathologist prior to 
biopsy/catheter placement. 
Stereotactic biopsy(ies) and catheter placement will be performed via the site’s standard of care 
prior to PVSRIPO administration, unless specified below. 
• After biopsy for confirmation of diagnosis (if required), if there is sufficient tissue 
available, up to three additional core biopsies will be obtained to undergo planned future 
molecular genetic testing as described in Section 5.7.4. If no additional biopsies are 
obtained but archival tissue is available within 6 weeks prior to infusion, that tissue will 
be requested/utilized for future testing. 
o For patients retreated with PVSRIPO, tissue for tumor typing and clinical 
pathologic testing per SOC should be obtained prior to the infusion and results 
reported on the electronic case report form (eCRF) when available  
o Note: results from any analyses conducted on tissue from other biopsies or 
unplanned surgical resections for the duration of a patient’s follow-up should be 
recorded in eCRF and remaining tissue may be requested for analysis 

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• The biopsy needle and catheter will be placed by the trained operating surgeon with 
stereotactic guidance using a MRI-compatible stereotactic head frame or a similar 
frameless device, and an Food and Drug Administration (FDA) cleared stereotaxic 
guidance system guided by a pre-operative MRI.  
• Site neurosurgeon(s) must be approved by the Sponsor or their designee prior to 
performing these procedures in study. This may require reviewing documentation of 
PVSRIPO-related administration experience or training, documentation of CED 
experience with study specific training, or related qualifications.  
• After biopsy(ies), a Sponsor-approved catheter (per the PVSRIPO Investigational Product 
Handling Plan [IPHP] or similar FDA cleared device with Sponsor approval) will be 
implanted in the operating room using sterile techniques, which may occur under general 
anesthesia at the discretion of the treating neurosurgeon, at the same site or a different 
site from that used for the biopsy.  
• The catheter will be tunneled beneath the scalp for a distance of at least 5 cm to aid in the 
prevention of infection. 
• The catheter will be placed within or through the progressive enhancing tumor, at a safe 
distance relative to eloquent brain function, with the tip of the catheter being placed: 
o Within the enhancing portion or in the vicinity of enhancement of target lesion 
(ie, infiltrative disease)  
o ≥ 0.5 cm from ventricles 
o ≥ 1 cm deep into the brain 
o ≥ 0.5 cm from the corpus callosum 
• A CT scan will be used to confirm catheter placement criteria post-operatively.  
• If anesthesia is utilized in the catheter placement procedure, use should be discontinued 
once there is CT scan confirmation of appropriate catheter placement.   
Patients will be treated with a prophylactic antibiotic prior to biopsy and catheter insertion 
per the site’s neurosurgical standard practice. 

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PVSRIPO Infusion (Day 0 or Day 1 [Visit 4]) 
Note: At the time of PVSRIPO infusion, emergency drugs, including epinephrine and 
diphenhydramine will be available and the neurologic status, oxygen saturation, and cardiac 
rhythm of the patient will be monitored. Drug infusion will occur in the neuro-intensive care unit 
(ICU) or neuro step down unit so that all other emergency facilities will be available. 
• CBC with differential (Platelet count should be confirmed prior to PVSRIPO infusion as well 
as at time of catheter removal and should remain consistent with inclusion criteria 11. Should 
the platelet count be less than 125 x 109/L on the day of catheter removal, a platelet 
transfusion should be administered and platelet count confirmed to be greater than 125 x 
109/L prior to catheter removal) 
 
• PVSRIPO infusion should occur on the same day (Day 0) or the day after catheter placement 
(Day 1) to allow flexibility due to the longer infusion (6.5 hr) and complexity of scheduling 
the necessary components for the infusion (eg, operating room time, surgeon, support team, 
pharmacy time, radiology appointments). However, under extenuating circumstances (eg, 
unavoidable scheduling issues, delayed diagnosis from biopsy, issues with investigational 
product or other critical supplies), so long as the patient remains in the neuro-ICU or neuro 
step-down unit, the time from catheter placement to PVSRIPO infusion may be extended up 
to 72 h post-placement with Sponsor approval. This timeframe is in keeping with other 
agents delivered safely via CED via similar procedures for even longer periods of time, 
which was not associated with increased risk of infection [23, 24]. If infusion is delayed, it 
will be recorded in the eCRF and patient’s source documents along with the rationale and the 
Sponsor’s approval.  
• See Section 6.2.4 for additional details pertaining to infusion of PVSRIPO 
Post-infusion assessments (Immediately following infusion): 
• After catheter removal, a CT scan of the brain (without contrast) will occur to confirm 
there is no bleed 
• AE assessment 
5.3 
Post-PVSRIPO Treatment, Pembrolizumab Treatment and Follow-up Periods 
During the post-PVSRIPO infusion treatment period and pembrolizumab treatment and follow-
up periods, the following will occur. 

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Day 1 post-PVSRIPO infusion (continuation of Visit 4): 
Clinical Assessment: 
• Conducted daily until discharge and documented within 18 h of discharge: 
o Physical examination 
o Neurologic and NANO assessment 
o KPS 
o PRO assessment 
o AE assessment 
o Concomitant Medications  
Laboratory Evaluation: 
• CBC with differential  
• CMP 
• Pancreatitis labs (amylase, lipase) 
Discharge: 
• Patients may be discharged after the above assessments are conducted and when 
patient is clinically stable post-PVSRIPO infusion 
Week 2 (± 1 week; assessments conducted before pembrolizumab treatment; Visit 5): 
Clinical Assessment: 
• Physical examination 
• Neurologic and NANO assessment 
• KPS 
• AE assessment 
• Concomitant Medications 
Radiographic Assessment: 
• MRI with and without contrast agent prior to planned pembrolizumab treatment only if 
patient presents with neurologic deficit or other symptoms that warrant withholding of 
pembrolizumab treatment and MRI would be considered informative at discretion of 
Investigator  
Laboratory Assessment: 

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• CBC with differential 
• CMP 
• Pancreatitis labs (amylase, lipase) 
• Thyroid panel 
• LSQ 
• Whole blood for research analyses  
Planned Treatment: 
• Pembrolizumab (200 mg IV infusion) 
 
Delayed 1st Pembrolizumab Treatment: Week 3 to 4 visit (if needed) and Shift in 
Schedule of Assessments (Unscheduled Visit) 
Note: If the 1st pembrolizumab infusion is delayed from Week 2 (Visit 5) due to ongoing AE, 
etc., the schedule of assessments (days, weeks) shifts accordingly so the next planned visit would 
occur 3 weeks after the date of 1st pembrolizumab infusion. For example, if a patient’s 1st 
treatment with pembrolizumab occurs at Week 3 (Study Day 21), their next scheduled clinic visit 
would be Week 6 (Study Day 42). 
The Week 3 to Week 4 visit is only required if the first planned dose of pembrolizumab is 
delayed from Week 2. 
The first pembrolizumab treatment is planned for Day 14 (2 weeks after PVSRIPO infusion); 
however, pembrolizumab treatment will be delayed by up to two additional weeks post-
PVSRIPO infusion in patients with any ongoing ≥ Grade 3 PTE or CE or ≥ Grade 2 AEs related 
to PTE or CE following PVSRIPO infusion or for any related events requiring active treatment 
(eg, TEAE such as new or worsening neurologic signs and symptoms like hemiparesis requiring 
≤ 4 mg/day dexamethasone or seizure requiring anti-epileptics), until such events resolve to 
≤ Grade 1. If such events have not resolved to ≤ Grade 1 within 28 days (4 weeks) post-
PVSRIPO infusion, the patient will not receive pembrolizumab under this trial and will be 
replaced.  
The first pembrolizumab treatment may also be delayed by up to two additional weeks post-
PVSRIPO infusion for administrative or other reasons, including other TEAE that in the 
Investigator’s opinion warrants delayed pembrolizumab treatment, but the 1st planned treatment 
should occur as close to Day 14 as possible.  
If the first pembrolizumab treatment is delayed for any reason, it may be given anytime between 
Weeks 2 through 4 so long as the event(s) leading to the delay have resolved as noted above. 

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There is a ± 7-day visit window for study visits after the first week of the study to account for 
these adjustments and to align future doses of pembrolizumab with the study visits and 
assessments.  
Patients requiring > 4 mg/day of dexamethasone or equivalent prior to the first dose of 
pembrolizumab will not receive pembrolizumab under this trial. 
Patients receiving PVSRIPO only will be followed according to the schedule of assessments with 
MRI and required visits occurring approximately every 9 weeks after Week 11. 
After the first pembrolizumab treatment, subsequent pembrolizumab treatments will occur every 
3 weeks (± 1 week) thereafter, up to Week 104 (24 months). Treatment with pembrolizumab may 
be interrupted and/or discontinued for irAE, as specified in Section 7.5.3 and discontinued for 
confirmed PD. NOTE: If pembrolizumab is permanently discontinued, then safety laboratory 
evaluations that are not SOC are no longer required after 30 days from the date of 
pembrolizumab discontinuation. 
If this visit is required due to delayed pembrolizumab treatment at Week 2, the following 
assessments at Week 3 to Week 4 should occur (prior to the first dose of pembrolizumab, as 
applicable): 
Clinical Assessment: 
• Physical examination 
• Neurologic and NANO assessment 
• KPS 
• AE assessment 
Radiographic Assessment: 
• MRI of the brain with and without gadolinium contrast per SOC 
Laboratory Assessment: 
• CBC with differential 
• CMP 
• Pancreatitis labs (amylase, lipase) 
 

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Week 5 or + 3 weeks from 1st pembrolizumab treatment visit (± 1 week; 
assessments occur before pembrolizumab treatment; Visit 6) 
All assessments should occur before the planned pembrolizumab administration. 
Clinical assessment: 
• Physical examination 
• Neurologic and NANO assessment 
• KPS 
• PRO Assessment 
• AE assessment 
• Final DLT assessment (Day 21 (± 3 days) post- 1st pembrolizumab treatment) for the first 
3 to 6 patients, as applicable, if received 1st dose at Week 2, as scheduled 
Radiographic Assessment: 
• MRI of the brain with and without gadolinium contrast per SOC  
Laboratory Assessment (before pembrolizumab treatment): 
• CBC with differential 
• CMP 
• Pancreatitis labs (amylase, lipase) 
• PT and aPTT 
• LSQ 
• Whole blood for research analyses 
Planned Treatment: 
• Pembrolizumab (200 mg IV infusion) 
 
Week 8 or + 3 weeks from last visit (± 1 week; Visit 7) 
The following will be conducted: 
Clinical Assessment: 
• Physical examination 
• Neurologic and NANO assessment 
• KPS 
• AE assessment 

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• MRI of the brain with and without gadolinium contrast per SOC 
Laboratory Assessments: 
• CBC with differential 
• CMP 
• Pancreatitis labs (amylase, lipase) 
• PT and aPTT 
• Thyroid panel  
Planned Treatment: 
• Pembrolizumab (200 mg IV infusion) 
 
Week 11 (or + 3 weeks from last visit; Visit 8) to Week 104 post-infusion 
After PVSRIPO infusion and while on pembrolizumab treatment, study visits occur 3 weeks (± 1 
week) through a maximum of 104 weeks that include the following: 
Clinical Assessment:  
• Physical examination 
• Neurologic and NANO assessment 
• KPS 
• PRO Assessment 
• AE assessment 
Radiographic Assessment: 
• MRI of the brain with and without gadolinium contrast. MRI should occur approximately 
every 9-12 weeks per SOC until through a maximum of 104 weeks 
Laboratory Assessments: 
• CBC with differential 
• CMP 
• Pancreatitis labs (amylase, lipase) 
• Pregnancy test (every 6 months or any time pregnancy suspected) 
• Thyroid Panel 
• Whole blood for research analyses 

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Planned Treatment: 
• Pembrolizumab (200 mg IV) treatment is planned to occur every 3 weeks up to a 
maximum of Week 104 (24 months).  
o Patients who remain on pembrolizumab will report for infusions every 3 weeks. If 
pembrolizumab is permanently discontinued, then safety laboratory evaluations 
that are not SOC are no longer required after 30 days from the date of 
pembrolizumab discontinuation. See Sections 5.5 and 5.6 for patients who 
permanently discontinue or interrupt pembrolizumab treatment before and after 
study Week 11. 
• In general, patients who discontinue pembrolizumab treatment and/or are no longer in the 
per protocol population (ie, have initiated non-study tumor treatments; see Section 8) 
should be followed per SOC, as possible/feasible.  
• If approved by Sponsor or designee, patients with confirmed progression meeting the key 
safety and infusion related eligibility criteria may be eligible for retreatment with 
PVSRIPO, ≥ 3 weeks after their last pembrolizumab treatment under this protocol.  
o Treatment with pembrolizumab or other treatments after PVSRIPO retreatment 
will be at the discretion of the investigator and will be recorded in the eCRF. 
 
5.4 
Early Discontinuation/End of Study Visit 
It is expected that all participants treated in the study, regardless of completion or 
discontinuation of study intervention or addition of non-protocol interventions, will remain in the 
study for long-term follow-up, per SOC.  
Before withdrawing a participant from the study, investigators should clarify and document the 
specific reason for the withdrawal. For example, the following scenarios may apply: 
• Discontinuation of study intervention(s), but completes remaining study assessments and 
agrees to collection of relevant follow-up information (ie, remains in study for long-term 
follow-up – this is the default scenario) 
• Discontinuation of study intervention and refuses study specific assessments, but agrees 
to collection of relevant follow-up information (remains in study for vital status and SOC 
MRI reporting) 
• Patient withdrew consent for any further study communication or follow-up from study 
site (ie, completely withdraws from study) 
If patient will not remain in follow-up and is permanently discontinuing the study, all 
assessments at the next scheduled study visit should be conducted (or as noted in the 
termination/end of study visit if after Week 11) or the information obtained, if possible.  

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5.5 
Follow-Up Period of Off Study Participants/Patients Permanently Discontinuing 
Pembrolizumab 
If a patient permanently discontinues pembrolizumab prior to or at Week 11, they should report 
to the clinic as scheduled for follow-up as noted in Table 1. 
Patients who no longer meet the criteria for the per protocol population (see Section 8) or 
patients who permanently discontinue pembrolizumab for confirmed progression or irAE 
requiring permanent discontinuation after Week 11 will remain in follow-up, where assessments 
will occur as outlined in the SOA noted in Table 1. However, the frequency should occur per 
SOC (ie, approximately every 9 weeks), as feasible.   
Entry of all applicable data and uploading of scans should occur no later than every 3 months. If 
SOC follow-up occurs less frequently (ie, greater than 3 months between visits/phone call), data 
should be transmitted within 2 weeks (± 1 week) of acquisition.   
Data to be entered in the eCRF during this period may include, but is not limited to the 
following: 
• Patient status: deceased or alive 
• Use of additional anti-cancer therapies and/or concomitant medications used to manage 
PVSRIPO-related inflammation (ie, corticosteroids, bevacizumab) and/or adjustments to 
such therapies since the last entry. 
o Entries should include start/stop date, dose, route, and frequency.   
• MRIs conducted per SOC  
o Any SOC MRIs (deidentified) may be requested by the Sponsor or Sponsor 
designee. For all SOC MRI, the assessment of tumor size, volume, and other 
characteristics should be recorded on the eCRF no less than every 6 months as 
well as in the event of disease progression. 
• Neurosurgical procedures required for reasons other than tumor progression (ie, for 
managing hydrocephalus) since last visit and details of these procedure(s).  
Results of any molecular, genetic, or histologic testing from all biopsies/tissue obtained since last 
recorded entry. 
5.6 
Follow-up for Patients Temporarily Interrupting Pembrolizumab 
Patients temporarily interrupting pembrolizumab for qualifying irAE as noted in Section 7.5.3 
should report to the clinic as scheduled for follow-up as noted in Table 1. 

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5.7 
Study Assessments 
The results of all study assessments outlined in Table 1 will be recorded on the eCRF and study 
source documents, as applicable. 
 
Physical Examination 
Standard physical examination per SOC, to include at least the following: 
• Height (carried over from baseline) 
• Weight 
• Body Surface Area 
• Vital Signs, including: 
o Blood pressure 
o Heart rate 
o Respiratory rate 
o Temperature 
In addition, a neurological examination, and assessment of NANO and KPS scores will be 
conducted and documented per institutional guidelines to contribute to assessment of clinical and 
neurologic status. 
 
Radiographic Imaging 
A baseline MRI of the brain with and without gadolinium contrast must be conducted within 14 
days of catheter placement for PVSRIPO infusion, but as close to biopsy/catheter placement as 
possible, and thereafter as scheduled in Table 1. Allowance will be made for the use of 
volumetric, contrast-enhancing imaging modalities as well, with Sponsor approval. Eligibility 
based on radiographic IC/EC will be based on the screening MRI obtained within 14 days of 
catheter placement; this MRI (and if required, recent prior MRIs) will be provided to the Sponsor 
or their designee for eligibility confirmation.   
In addition, a CT scan will occur immediately after catheter placement in an effort to ensure 
proper positioning, and immediately after catheter removal post-PVSRIPO infusion, to confirm 
there is no bleed. 
All MRI will be assessed by the investigator; tumor measurements and response will be recorded 
in the eCRF according to the response criteria outlined Section 8.4.6.1 summarized in Table 3. 
All de-identified images may be requested by the Sponsor for independent radiographic 
assessment and/or long-term storage. 

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Laboratory Assessments 
Laboratory assessments that will be conducted during the study are listed below: 
• CBC with differential 
• CMP (to include: Na, K, bicarbonate, Cl, BUN, Cr, AST, ALT, Alk phos, total bilirubin, 
amylase, lipase) 
• PT and aPTT 
• Thyroid Panel  
o TSH 
o Thyroxine (free T4) 
o May include free and total T3 (triiodothyronine) 
• Pregnancy test (beta- human chorionic gonadotropin (hCG); urine or serum) for women 
of childbearing potential within 14 days of catheter placement and 48 h of PVSRIPO 
infusion (and approximately every 6 months while on study treatments) 
• Whole blood for biomarker research analyses (may include but is not limited to immune 
and genetic analyses) 
Note: Whole blood for research analyses will not be collected prior to any retreatment 
with PVSRIPO, as applicable 
All required laboratory assessments must be conducted in accordance with this protocol.  The 
timing and frequency of laboratory assessments are specified in Table 1.   
• The laboratory tests (hematology, chemistry, coagulation, pregnancy testing) will be 
performed by the study center’s usual local laboratory (or similarly qualified laboratory 
under special circumstances with Sponsor approval) 
• Laboratory reports will be filed with the source documents, with the Investigator noting if 
any abnormalities are clinically significant and/or suggestive of an AE 
• Site personnel must enter results into the eCRF for the specified lab parameters (with 
units and reference ranges, which should be provided to the Sponsor or their designee at 
start-up) at the specified timepoint. 
Laboratory tests may be performed at additional times during the study as part of standard care 
and are not required to be reported. However, any laboratory test performed in association with 
an AE must be recorded in the participant’s eCRF and if not at a protocol-specified timepoint, as 
an unscheduled visit.   
 
Patient-Reported Outcomes 
To better understand the patient experience in this trial, two individual, standardized paper 
instruments, EORTC-QLQ-30 and EORTC QLQ-BN20 [25], will be administered during routine 

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clinic visits for the purposes of evaluating PROs at selected timepoints as defined in the 
Schedule of Assessments. Patients will be instructed on the use of the questionnaires upon 
enrollment into the trial and will be provided these questionnaires for completion upon 
designated clinic visits. A separate manual on the use of these questionnaires will be provided to 
each investigational site. 
 
Other Assessments 
Additional pathology/biomarker tests that may be performed on archival tissue and tissue 
obtained from any resections or biopsies post-baseline include but are not limited to the 
following:  
• PV receptor (CD155) expression 
• Epidermal Growth Factor Receptor (EGFR) vIII and wild-type EGFR status  
• MGMT promoter methylation/MGMT immunohistochemistry  
• Isocitrate Dehydrogenase (IDH) 1 and 2  
• Telomerase reverse transcriptase (TERT)  
• PD-1 and PD-L1  
• TP53 mutational status and p53 expression 
• Tumor mutational burden  
• Microsatellite instability-high status 
• IFN-γ 
• Granzyme B 
• Immune cells [including, natural killer (NK) cells, NK T-cells, Regulatory T cells 
(Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages 
(TAMs), and tumor antigen-specific T-cells] 
• T-cell receptor sequencing 
Research to identify signatures of potential PVSRIPO response will be conducted using patient 
blood samples and will occur as outlined in Table 1. These samples may be stored for future 
testing or analyzed by the Sponsor or their designee.  
6 
Therapies Under Investigation 
Information pertaining to the study-associated treatments are outlined below. Any required 
updates to Section 6 not impacting the safety of patients may be made via administrative 
memorandum until a protocol amendment can be issued. 

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6.1 
Method of Assigning Patients to Treatment 
All patients will be sequentially assigned to therapy via a unique numeric patient ID as they are 
enrolled. There is no randomization, as this is a single-arm trial. 
6.2 
Investigational Product: PVSRIPO 
 
Name, Classification and Mechanism of Action 
PVSRIPO is a modified version of the serotype 1 live-attenuated (Sabin™) PV vaccine and is 
classified as an oncolytic viral immunotherapeutic. 
 
Packaging, Labeling and how Supplied 
PVSRIPO 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). It is provided in sterile, 
single use glass vials with a green flip off top and each vial contains approximately 0.5 mL of 
stock PVSRIPO (2.24 x 109 TCID50). 
6.2.2.1 
Potential Risks with Use 
Detailed risks associated with PVSRIPO administration and use are outlined in greater detail in 
the Investigator’s Brochure (IB). Based on an expanded Phase 1 trial and an ongoing multicenter 
Phase 2 trial, PVSRIPO may result in neurologic changes/exacerbation of existing and new-onset 
neurologic signs and symptoms due to peritumoral inflammation/edema within 12 months of 
PVSRIPO infusion. These changes are best managed with low dose dexamethasone and/or 
bevacizumab as described in Section 6.5.4. 
Intracranial hemorrhage at infusion catheter removal has also been noted. This has been 
mitigated by inclusion criterion Number 11, requiring platelet counts ≥ 125,000/µl (supported 
via transfusion acceptable) at the time of catheter placement/biopsy. 
It is unknown if PVSRIPO can cause fetal harm; as such, female study participants and female 
partners of male study participants who are of childbearing potential should be advised to utilize 
effective forms of contraception for at least 30 days prior to and after any PVSRIPO infusion and 
for up to 4 months after the last dose of study drug received. Effective forms of birth control 
include using at least 2 methods, one of which should be a barrier method. Examples include: 
• 
Condom  
• 
Oral, injected, or implanted hormonal contraception 
• 
Placement of an intrauterine device or intrauterine system 

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• 
Occlusive cap (eg, diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository 
• 
Vasectomy or surgical castration ≥ 6 months prior to biopsy 
Surgical Complications: The stereotactic tumor biopsies and catheter implantation procedure 
carries a risk for cerebrospinal fluid leak, infection, hemorrhage, loss of neurologic function, 
non-neurologic complications, and death. These risks depend primarily on the preoperative 
condition of the patient, the size and location of the tumor and associated diseases. In addition, as 
is standard with surgical procedures, potential complications for stopping anti-coagulation 
therapy prior to surgery may include heart attack, stroke, or other life-threatening blood clots. 
The potential risk for the patient will be discussed in detail with the patient and family by the 
treating neurosurgeon or the neurosurgeon’s designee. 
It is recommended that adverse events related to potential PTE be managed as outlined in 
Section 6.5.4 (ie, low dose bevacizumab and/or dexamethasone as indicated). However, for 
unexpectedly severe cases of PTE or CE with associated clinical symptoms requiring treatment 
that are not managed successfully per the recommended practices or other measures, surgical 
resection of the lesion infused with PVSRIPO, approximately 4 weeks post PVSRIPO and 
approximately 2 weeks following the first dose of pembrolizumab, could occur at the discretion 
of the treating clinician and neurosurgeon. This resection is not planned as a part of the protocol 
and will be considered a DLT, as noted in Section 7.4. For more information on PVSRIPO, see 
the IB. 
 
Shipment, Receipt and Storage 
PVSRIPO and diluent will be supplied directly to the site by the Sponsor or their designee. 
PVSRIPO is shipped on dry ice at approximately -80°C with temperature monitoring and is 
stored long-term at ≤ -80 °C. Refer to the IPHP for additional handling, excursion and long-term 
storage conditions.   
The diluent for PVSRIPO is sterile 0.2% HSA in PBS. Each diluent vial contains approximately 
6.0 mL. The diluent is shipped and should be stored long-term under refrigerated conditions 
(between 2 to 8°C), with temperature monitoring. Refer to the IPHP for additional details. 
 
Preparation, Dispensing and Administration 
Details on the preparation, dispensing and transport of the prepared PVSRIPO infusate solution 
to deliver a final dose of 5 x 107 TCID50 to the patient are provided in greater detail in the GBM 
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(diluent), mixed via gentle inversion and presented in a 10 mL Infusion Syringe such that when 
3.0 mL is infused on study Day 0, a total dose of 5 x 107 TCID50 is administered to the patient.  
PVSRIPO infusate preparation will occur in each institution’s designated investigational 
pharmacy or equivalent. All handling of the investigational product will occur in a biosafety 
cabinet or a similarly contained environment.  
The infusion syringe specified in the IPHP is loaded into an FDA cleared infusion pump 
approved by the Sponsor (eg, Medfusion®3500 syringe infusion pump, Alaris™ Syringe Module 
Syringe Infusion Pump). Participants will receive PVSRIPO infusate by means of CED over a 
period of 6.5 h, at a rate of 0.5 mL/h through the tubing and catheter embedded into the patient’s 
tumor and affixed to the scalp (see Section 5.2.1 for details on catheter insertion). The infusion 
tubing and catheter are supplied by or must be approved by the Sponsor or their designee prior to 
use. Please refer to the PVSRIPO IPHP for additional details. 
6.3 
Accountability and Compliance of Investigational Products 
Drug accountability records will be maintained for all clinical study agents and supplies. All 
empty and partially used clinical study agents and supplies will be destroyed with appropriate 
documentation in accordance with institutional guidelines. All investigational product 
(PVSRIPO) will be administered in accordance with the conditions of this protocol. Only 
authorized site personnel may supply or administer investigational product. Each site’s 
designated investigational pharmacy will maintain detailed documentation of the receipt, 
dispensing and/or destruction of the investigational product, which will then be provided to the 
Sponsor or designee. Only participants enrolled in the study may receive investigational product, 
in accordance with all applicable regulatory requirements. Upon completion of the study, this 
material will undergo final inspection and reconciliation. 
 
Disposal and Destruction 
All materials coming into contact with PVSRIPO, including the infusion syringe/any overage 
after infusion, tubing, dressings, or coverings used to protect the infusion/priming site, will be 
disposed of as biological waste in the preparation and treatment rooms in accordance with 
institutional guidelines.  
6.4 
Additional Study Therapy: Pembrolizumab 
 
Pembrolizumab Classification and Mechanism of Action 
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Packaging, Labeling and how Supplied 
Pembrolizumab will be labeled according to the manufacturer’s specifications and is 
commercially supplied for injection as follows: 100 mg/4 mL (25 mg/mL) solution in a single-
dose vial; see the Keytruda® (pembrolizumab) PI for details. 
6.4.2.1 
Potential Risks with Use 
Based on its mechanism of action, pembrolizumab can cause severe, life-threatening irAE. Refer 
to Section 7.5.3 for dose interruption/stopping criteria for irAE as well as the Keytruda® 
(pembrolizumab) PI or “Guide for Keytruda®”.  
In addition, pembrolizumab may cause fetal harm when administered to a pregnant woman. 
Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through 
induction of maternal immune tolerance to fetal tissue. Women of childbearing potential should 
be advised of the potential risk to a fetus and to use effective contraception during treatment with 
pembrolizumab and for 4 months after the last dose received. 
 
Shipment, Receipt and Storage  
Pembrolizumab is planned to be obtained via prescription from a pharmacy and should be stored 
according to site pharmacy practices in keeping with the PI, with appropriate accountability. Any 
modifications to this plan will be outlined in the SAM and will not necessitate a protocol 
amendment. 
 
Preparation, Dispensing and Administration 
Pembrolizumab will be prepared, dispensed, and administered according to manufacturer’s 
specifications noted in the Preparation and Administration section of the product package insert 
and per pharmacy practices for this lawfully marketed agent. In brief, the required volume from 
the vial(s) will be withdrawn and transferred into an IV bag containing 0.9% Sodium Chloride 
Injection, United States Pharmacopeia (USP) or 5% Dextrose Injection, USP. Mix diluted 
solution by gentle inversion without shaking. The final concentration of the diluted solution 
should be between 1 mg/mL to 10 mg/mL.  
For additional information regarding procurement, distributors, and other resources for 
pembrolizumab, see the “Guide for Keytruda®”. In brief, regarding the diluted solution for 
infusion:  
• May be stored at room temperature for no more than 6 h from the time of dilution. This 
includes room temperature storage of the diluted solution, and the duration of infusion. 

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• May be stored under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 h 
from the time of dilution. If refrigerated, allow the diluted solution to come to room 
temperature prior to administration. 
• Discard after 6 h at room temperature or after 24 h under refrigeration. Do not freeze. 
• Diluted solution will be administered intravenously over 30 minutes through an 
intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 
micron in-line or add-on filter.   
• Do not co-administer other drugs through the same infusion line. 
The dose of pembrolizumab is keeping with prior investigations in rGBM that were well 
tolerated [3, 4, 20, 21]: 200 mg administered as an IV infusion over 30 minutes every 3 weeks up 
to Week 104 or until disease progression or unacceptable toxicity.  
6.4.4.1 
Disposal and Destruction  
Pembrolizumab will be disposed of per institutional guidelines and manufacturer’s 
specifications.  
6.5 
Prior and Concomitant Therapy 
At a minimum, the following will be captured for study as well as any prior and concomitant 
therapies as outlined below and specified in the eCRF Completion Guidelines:  
o When administered (start/stop dates) 
o Dose(s) 
o Route 
o Frequency  
o Reason for use (ie, indication)  
 
Prior Therapy 
All prior marketed and experimental tumor treatments along with pertinent information noted 
above, in addition to reason for failure (ie, progression, tolerability issues) will be recorded in the 
eCRF. This includes but is not limited to radiotherapy/radiosurgery, chemotherapy (eg, 
temozolomide, lomustine); carmustine implants/wafers; targeted therapies like bevacizumab or 
imatinib; devices (tumor treating fields), vaccines, etc. The extent of any prior resection (ie, 
gross total resection (GTR), subtotal resection (STR), biopsy) at diagnosis and later surgeries 
will also be noted. 
In addition, all medication taken within 30 days of baseline (PVSRIPO infusion) will be 
documented in the patient’s source documents and eCRF. Also refer to the IC/EC (see 

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Sections 4.1 and 4.2) for any therapies prohibited within the specified timeframe prior to 
treatment.  
 
Other Concomitant Therapy 
Concomitant therapies administered during the study must be recorded in the patient’s source 
documents and eCRF. Except for those utilized in management of peritumoral edema or AE, 
concomitant medications should be maintained at stable doses during the study, if appropriate. 
 
Prohibited Medications/Therapies 
Except for bevacizumab (7.5 mg/kg q 3 weeks), the following other therapies that are prohibited 
in patients while “on-study” include but are not limited to: 
• Anticancer systemic chemotherapy 
• Radiation therapy 
• Radiosurgery 
• Biologic therapies 
• Targeted therapies 
• Immunotherapy (other than protocol therapies) 
• Investigational therapies 
• Live vaccines 
• Tumor treating fields 
 
Permitted Medications/Medications for Management of Cerebral Edema and 
irAE  
In general, non-cancer treatments considered by the investigator to be necessary for participant’s 
welfare in keeping with community SOC, including prophylactic treatments (ie, anti-emetics) are 
allowed. 
The BSC for control of PTE or CE related sequalae after PVSRIPO infusion and/or combination 
of PVSRIPO and pembrolizumab, as needed, are allowed, and recommended as follows: 
• Preferred ≥ 2 weeks post-PVSRIPO infusion: low dose bevacizumab (7.5 mg/kg q 3 
weeks).  
o Treatment with bevacizumab for the shortest course possible is desired over 
dexamethasone use for control of cerebral edema, when deemed safe to use by the 
investigator.  
o Treatment with higher doses of bevacizumab for > 2 cycles is not permitted per 
protocol.  

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• Within 2 weeks of PVSRIPO infusion or thereafter, at the treating clinician’s discretion if 
rapid response is clinically indicated: low dose dexamethasone (≤ 4 mg/day). As low a 
dose as possible, for the shortest duration possible is desirable for managing cerebral 
edema. However, participants should primarily be managed with bevacizumab, 
thereafter.  
• Other supportive care treatments (eg, anti-epileptics for seizure). 
6.5.4.1 
Steroids 
Corticosteroids (dexamethasone recommended) are allowed for treatment of irAEs and/or PTE 
or CE with guidance that dose and duration be as limited as medically appropriate. 
Dexamethasone (ideally ≤ 4 mg/day) should be used at the lowest dose required to control 
symptoms of PTE and mass effect or other inflammatory-related conditions and be discontinued 
as soon as medically appropriate. Use of corticosteroids should be recorded in the eCRF.  
In addition, at discharge following PVSRIPO administration and after each pembrolizumab 
treatment, participants should have a filled dexamethasone (or equivalent if cannot use 
dexamethasone) prescription in hand, with instructions regarding what emerging symptoms 
would warrant immediate consult with the treating clinician to determine if immediate initiation 
of dexamethasone is warranted and/or to proceed to the clinic for consideration of bevacizumab 
infusion or other treatments, depending on the nature and severity of the event(s). 
Every attempt should be made to use the lowest dose of steroids for the shortest duration and to 
discontinue/taper steroid use as soon as is feasible. 
Risks Associated with Use: Use of corticosteroids may lead to cardio-renal, endocrine, and 
immune system and ophthalmic AEs as well as increased susceptibility to infections, including 
life-threatening infection. Abrupt withdrawal following prolonged therapy may result in 
symptoms of the corticosteroid withdrawal syndrome including, myalgia, arthralgia, and malaise. 
See the dexamethasone PI for additional details. 
6.5.4.2 
Bevacizumab 
A clinically important feature of bevacizumab is the steroid-like improvement of the disrupted 
blood-brain barrier and reduction in PTE and mass effect when use in rGBM [26-28]. Given this 
and the success utilizing bevacizumab for the management of PTE or CE and related sequalae in 
prior studies with pembrolizumab [3] and PVSRIPO [5] and the combination in rGBM patients 
treated under compassionate use, eligible participants will be allowed to initiate bevacizumab 
treatment (7.5 mg/kg q 3 weeks) as early as 2 weeks after PVSRIPO infusion, at the time of the 
first planned pembrolizumab treatment. Bevacizumab use should be reevaluated as soon as 

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possible but at a minimum, after 3 consecutive doses (9 weeks) and be discontinued as soon as 
possible at the treating clinician’s discretion.  
Intermittent, short-term, lower dose bevacizumab use is not anticipated to have an appreciable 
impact on survival outcomes based on limited anti-tumor activity [26-28]. Given the impact of 
bevacizumab on enhancing lesions [29], all radiographic response will be confirmed ≥ 8 weeks 
after discontinuation of bevacizumab to account for the known radiographic pseudoresponse and 
T2/Fluid-Attenuated Inversion Recovery (FLAIR) will be monitored over time by independent 
radiographic reviewers blinded to patient outcome and bevacizumab use.  
Branded Avastin® (bevacizumab) is preferred but if unavailable, MVASI™ (bevacizumab-awwb) 
is an acceptable alternative (check with Sponsor before utilizing any others). Bevacizumab will 
not be provided by the study. 
Risks Associated with Use: There is a warning and precaution noted in the prescribing 
information of bevacizumab regarding risks of bleeding/wound healing complications within 28 
days following major surgery. For this protocol, investigators will have the discretion to use low-
dose bevacizumab at ≥ 2 weeks following the less invasive biopsy/intracranial infusion, if such 
use is judged by the investigator to be less than the potential risk of sequalae associated with 
PTE or CE after PVSRIPO treatment alone and/or followed by pembrolizumab. Bevacizumab is 
also associated with thromboembolic and other events; see the PI.  
6.5.4.3 
Concomitant Medications for Immune-related Adverse Events 
See Section 7.5.3 for information on irAE and actions to take with pembrolizumab. For the 
management of any irAE, after the first dose of pembrolizumab, as low a dose as possible of 
dexamethasone (ideally ≤ 4mg/day), for the shortest duration possible, is desirable. 
Any irAE should ultimately be managed at the clinician’s discretion with patient safety as the 
primary consideration.  
Further, although not planned as part of the protocol, for severe cases of peritumoral edema with 
clinical symptoms requiring treatment that are not managed successfully per the BSC practices 
noted above or other measures, surgical resection of the lesion infused with PVSRIPO, 
approximately 4 weeks post PVSRIPO and approximately 2 weeks following the first dose of 
pembrolizumab, could occur at the discretion of the treating clinician and neurosurgeon. 

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7 
Safety and Pharmacovigilance 
The Investigator is responsible for the identification and documentation and reporting of AEs 
and SAEs, as provided in this protocol. During each study visit and other patient contacts (eg, 
phone contact, telemedicine visit), the Investigator or designated study personnel must assess, 
through non-suggestive inquiries of the patient or evaluation of study assessments, whether an 
AE or SAE has occurred. In addition, if the Investigator (or designee) receives a report from 
other health care providers or legally authorized representatives that is suggestive of an AE/SAE 
in the study patient, the Investigator must similarly follow up for reporting purposes. 
7.1 
Adverse Events 
An AE is an untoward or medical occurrence associated with the use of study treatment (drug, 
biologic, or device) in clinical investigation participants, which does not necessarily have a 
causal relationship with the study treatment. An AE can therefore be any unfavorable and 
unintended symptom, sign, disease or condition, or test abnormality (although diagnosis should 
always be reported as the AE if known) regardless of the relationship to study treatment. AEs 
that do not meet the definition for an SAE are considered non-serious AEs. All AEs must be 
recorded in the patient’s source documents and AE case report form. 
AEs will be assessed according to the CTCAE v5. If CTCAE grading does not exist for an AE, 
the severity of the AE will be graded as mild (1), moderate (2), severe (3), life-threatening (4), or 
fatal (5).  
All AEs will be followed until the outcome is determined by the Investigator as one of the 
following: 
• Resolved 
• Ongoing 
• Chronic/Stable 
• Death 
• Unknown 
Attribution of AEs/SAEs will be determined for each study intervention or concomitant 
medication/intervention, as applicable (ie, catheter placement, PVSRIPO, pembrolizumab, 
corticosteroids, bevacizumab). 
Attribution of AEs will be indicated as follows: 
• Definite: The AE is clearly related to the study drug(s) 

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• Probably: The AE is likely related to the study drug(s) 
• Possible: The AE may be related to the study drug(s) 
• Unlikely: The AE is doubtfully related to the study drug(s) 
• Unrelated: The AE is clearly NOT related to the study drug(s) 
Events that do not meet the definition of an AE include: 
• Non-clinically significant (as assessed by the investigator), isolated, laboratory values, 
other than those noted in Section 7.4; see Section 7.1.1 for assessing clinical significance 
of laboratory abnormalities for AE reporting. 
• Medical or surgical procedures (eg, endoscopy, appendectomy).  
o Note: The condition that leads to the procedure can be an AE. 
• Situations where an untoward medical occurrence did not occur (eg, social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of preexisting diseases/conditions present at baseline 
that do not worsen. 
• Planned hospital admissions or surgical procedures for elective procedures or for an 
illness or disease that existed before the signing of the ICF or before the participant was 
enrolled in the study will not be captured as TEAEs/SAEs.  
• However, if planned admissions or procedures occur at a time other than what was 
planned (eg, due to an exacerbation in the preexisting illness or disease), they should be 
reported as TEAEs/SAEs.  
 
Laboratory Based Abnormalities 
All protocol-specified laboratory values will be reported as outlined in Table 1 during the study, 
along with associated units and reference ranges. Results of unscheduled/SOC laboratory 
assessments should be reported as an unscheduled visit laboratory assessment only if associated 
with a TEAE. An investigator should assess the clinical significance for all abnormal laboratory 
values. In general, if either of the following conditions are met, the abnormal laboratory value 
may be clinically significant: 
• The abnormality suggests a disease and/or organ toxicity that is new or has worsened 
from baseline. 
• The abnormality is of a degree that requires additional active management, eg, change of 
dose, discontinuation of the drug, close observation, more frequent follow-up 
assessments, or further diagnostic investigation. 
Therefore, a clinically significant lab value is generally one that indicates a new disease process, 
an exacerbation or worsening of an existing condition, or requires further action(s) to be taken. 

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A lab result should not be considered in isolation, but in the context of the patient’s physical 
examination and available history (ideally including past and present medical problems, social 
history, family history, medications, and previous laboratory evaluations). 
Isolated non-clinically significant (as assessed by the investigator) laboratory values should not 
be reported as adverse events.  
Laboratory abnormalities considered clinically significant by the investigator should be reported 
as AEs (or SAEs, as applicable), although the diagnosis should always be reported as the AE if 
known (eg, treatment emergent fasting hemoglobin A1C values ≥ 7.1% on two consecutive 
laboratory evaluations would be reported as the AE of diabetes, with the abnormal A1C values 
supportive of this diagnosis). 
 
Non-Treatment Emergent Adverse Events 
Any AE occurring after a patient provides informed consent that is related to the non-SOC 
screening procedures (eg, PV vaccination booster) and biopsy procedure will be assessed, 
recorded in the patient’s source documents and the eCRF with attribution, regardless of causality 
or seriousness (non-TEAEs).  
Any AE occurring from the time of informed consent to start of PVSRIPO infusion that are not 
considered related to a study required non-SOC screening procedure, should be reported as 
medical history.  For example, if a patient had new onset seasonal allergies requiring medication 
after signing of ICF but before Screening Period 2, it would be reported as medical history.   
 
Treatment Emergent Adverse Events 
Treatment emergent AEs will be noted from the time of PVSRIPO infusion through the time the 
patient comes off study/no longer meets the requirements for the per protocol population (as 
defined in Section 8) and 30 days thereafter. Any AEs related to the catheter placement without 
PVSRIPO infusion will be summarized separately (eg, patient withdraws due to AE experienced 
after catheter placement but before PVSRIPO infusion).    
7.2 
Serious Adverse Events 
An SAE is any AE meeting the following criteria:  
Death 
An AE that results in death (note: death due to progression is not an 
AE/SAE but should be reported as noted in the eCRF completion 
guidelines). 

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SAEs must be reported by the Investigator to the Sponsor or designee within 24 h of discovery for 
all patients from the time of consent, while on study and for 30 days after 1) completion of study 
participation or 2) if patient is rendered off-study and in the follow-up period only. SAEs will be 
reported in the eCRF with instruction provided in the eCRF Completion Guidelines. 
The Investigator is required to provide an assessment of the causal relationship between the event 
and the study drug(s) at the time of the initial report. The related SAE page should be completed 
as thoroughly as possible and signed by the Investigator before transmittal to the Sponsor or 
designee. The Investigator should not wait to for additional information to fully document the 
related SAE before notification, although additional information may be requested.  
Instances of death, congenital abnormality, or an event that is of such clinical concern as to 
influence the overall safety assessment, if brought to the attention of the Investigator at any time 
after cessation of study drug(s) and linked by the Investigator to this study, should be reported to 
the Sponsor or their designee. Where applicable, information from relevant laboratory results, 
hospital case records, and autopsy reports should be obtained. 
Life-threatening AE An AE that places the participant, in the view of the Investigator, at 
immediate risk of death from the AE as it occurred (ie, does not include 
an AE that had it occurred in a more severe form, might have caused 
death). 
Required or 
prolonged 
participant 
hospitalization 
An AE that results in an initial participant hospitalization or prolongs an 
existing hospitalization of the participant. If a participant is hospitalized 
as part of the clinical use of the study treatment, the period of normal 
hospitalization will be based on the Investigator’s judgement and 
experience. Hospitalizations longer than this period will be considered 
prolonged hospitalizations. 
Persistent or 
significant 
disability/incapacity 
An AE that results in a substantial disruption of a participant’s ability to 
conduct normal life functions. 
Congenital 
anomaly/birth 
defect 
A congenital anomaly/birth defect that occurs in the offspring of a 
participant exposed to the study drug. 
Important medical 
event 
An AE that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, the event may jeopardize the participant 
and may require medical or surgical intervention to prevent 1 of the 
outcomes listed above. Examples of such “important medical events” 
include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do 
not result in participant hospitalization, or the development of drug 
dependency or drug abuse 

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The SAE/narrative description should include the following, as a minimum: 
• Time to onset following PVSRIPO and/or pembrolizumab infusion, as applicable 
• Maximum severity of signs and symptoms 
• Treatment(s) undertaken (including dose, route frequency, as applicable) 
• Action taken with study drug(s) (eg, permanently discontinued, treatment interruption) 
• Concomitant medications at the time of the event(s) 
• Time to resolution as the information becomes available 
7.3 
Definition of an Unexpected Adverse Event 
An AE or suspected adverse reaction is considered "unexpected" if it is not listed in the current 
IB or PI or is not listed at the specificity or severity that has been observed previously. In 
addition, reports which add significant information on specificity or severity of a known already 
documented AE may constitute an unexpected AE. 
The Medical Monitor or designee will evaluate expectedness of all SAEs as per the currently 
available safety information. For all events, medical and scientific judgement should be exercised 
in deciding whether expedited reporting is appropriate in other situations and should consult with 
the Sponsor Medical Monitor or designee if unclear.  
7.4 
Assessment and Definition of Dose Limiting Toxicity 
For this study, assessment of treatment emergent DLT will occur after a patient receives 
PVSRIPO and until 21 days (± 3 days) after the first dose of pembrolizumab.  
Peritumoral and CE occur frequently in rGBM and may be secondary to the disease process 
itself, surgical procedures, necrosis from previous radiation, or inflammation due to immune 
infiltration of the brain or destruction of tumor cells, which may manifest as neurologic 
dysfunction. Given that transient PTE has been observed following PVSRIPO use, the primary 
focus for DLT will be neurologic events meeting the criteria for a DLT defined as follows: 
1. ≥ Grade 3 neurologic events related to PTE or CE within the first 3 weeks of the first 
pembrolizumab administration that:  
a. Do not resolve to ≤ Grade 1 with the management practices outlined herein 
(≤ 4mg/dexamethasone or 7.5 mg/kg bevacizumab) within 3 weeks of initiating such 
treatments,  
and/or 
b. Require surgical debulking of the PVSRIPO infused tumor within 3 weeks of the first 
pembrolizumab administration 

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To assess for any other potential DLT, CTCAE v5.0 will be utilized, and the following will 
also be considered DLT if treatment related: 
1. Any of the following SAEs: 
a. Treatment-related death 
b. Treatment-related life-threatening event 
c. A medically significant condition (defined as an event that compromises patient 
safety or may require medical or surgical intervention to prevent one of the outcomes 
above). 
d. Requires inpatient hospitalization or prolongation of existing hospitalization 
e. Results in persistent or significant incapacity or substantial disruption to conduct 
normal life functions 
2. Any Grade 4 non-hematologic toxicity 
3. Any Grade 3 non-laboratory-based toxicity that is not reversible to its pre-PVSRIPO 
treatment baseline within 2 weeks of onset with the following exceptions: 
a. Grade 3 fatigue lasting ≤ 3 days or Grade 3 fatigue in a participant with Grade 1 
fatigue at baseline  
b. Grade 3 diarrhea, nausea, or vomiting without use of anti-emetics or anti-diarrheals 
per standard of care  
c. Grade 3 adrenal insufficiency due to suboptimal steroid replacement therapy  
d. Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard 
of care 
4. Grade 3 or Grade 4 non-hematological laboratory values only if meets one of the serious 
criteria outlined in 1 above or: 
a. The abnormality persists for > 1 week 
b. The abnormality results in a drug-induced liver injury 
Note: Treatment-emergent, non-clinically significant laboratory abnormalities that are treatable 
with routine measures, or reversible (≤ 1 week of onset) laboratory abnormalities in and of 
themselves (including liver function tests, uric acid, etc.), are not considered DLT.  
Exceptions (these laboratory values are DLT): 
• Grade 4 thrombocytopenia of any duration  
• Grade 3 thrombocytopenia associated with bleeding requiring a platelet transfusion  
5. Febrile neutropenia meeting following criteria: 
a. Grade 3: ANC < 1000/µl with a single temperature of > 38.3° C (101° F) or a sustained 
temperature of ≥ 38° C (100.4 degrees F) for ≥ 1 hour 
b. Grade 4: ANC < 1000/µl with a single temperature of > 38.3° C (101° F) or a sustained 
temperature of ≥ 38° C (100.4° F) for ≥ 1 h, with life-threatening consequences and urgent 
intervention indicated 

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7.5 
Adverse Events of Special Interest  
 
Cerebral Spinal Fluid Leakage or Aseptic Meningitis 
Based on communications with the FDA agreed upon in IND 014735, Serial Submission 0197, 
in the event 2 or more patients enrolled under the current inclusion/exclusion criteria relating to 
catheter placement, present with evidence of cerebral spinal fluid leakage or aseptic meningitis, 
enrollment of patients under these criteria will be paused for further evaluation. The previous 
criteria (ie, catheter tip placed ≥ 1 cm from the ventricle and corpus callosum) will be used for 
continued enrollment until this evaluation is complete. These events will not be considered DLT 
for the purpose of evaluating PVSRIPO followed by pembrolizumab use unless further 
evaluation suggests an association.   
 
Cerebral or Peritumoral Edema  
Peritumoral edema (and possibly the signs and symptoms thereof) is considered expected with 
PVSRIPO therapy in rGBM based on the mechanism of action, whereby a targeted anti-tumor 
inflammatory immune response is elicited in and around the tumor. For the recommended best 
practices to manage signs symptoms related to PTE or CE, see Section 6.5.4 (eg, low dose 
bevacizumab [7.5 mg/kg q 3 weeks] or dexamethasone [≤ 4 mg/day], along with initiation of 
other supportive care treatments, as required [eg, antiepileptics]). 
Peritumoral or CE may also be secondary to the disease process itself, the surgical procedure, 
necrosis from previous radiation, or inflammation due to immune infiltration of the brain or 
destruction of tumor cells, which may manifest as neurologic dysfunction. The timing of onset of 
such events should be considered in relation to PVSRIPO or pembrolizumab infusion when 
considering attribution of such events to these therapies (see PVSRIPO IB for guidance).  
Peritumoral or CE may present as a constellation of general signs and symptoms such as altered 
mental status, cognitive disturbance, confusion, somnolence, lethargy, fatigue, unresponsiveness, 
encephalopathy, or coma or can be more focal, depending on the patient and tumor. The 
individual signs and symptoms may include but are not limited to: seizures, dysphasia, 
paresthesia, headaches, focal neurologic deficit, ataxia, dystonia, facial muscle weakness, 
hemiparesis, pyramidal tract syndrome, hemianopia, visual field cut, blurred vision, diplopia, and 
urinary incontinence. Participants will be monitored throughout the course of the study and upon 
noting any signs or symptoms of PTE or CE, may receive an antiangiogenic agent 
(bevacizumab), steroids, receive an osmotic diuretic, and/or have surgical decompression. Edema 
that fails to respond to aggressive therapy may lead to permanent neurological impairment. The 
probability of this risk can be predicted to some degree based upon tumor size, location, 

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preoperative neurological impairment, and post-operative course prior to virus administration. 
The risks will be discussed with the patient and the patient’s family.  
SAEs considered related the local inflammatory effect on the tumor (ie, peritumoral edema) 
should be reported in a way that distinguishes it from a more generalized brain edema (eg, 
“edema cerebral (peritumoral)”. In cases where the edema is more generalized, reporting as 
“edema cerebral” would be more appropriate. In each case, the appropriate severity grade of the 
PTE or CE and the resulting symptoms/specific dysfunction should be noted in the edema-
specific AE/SAE collection forms (and narrative description for SAE related to PTE or CE) by 
severity grade along with other relevant information (eg, start and stop date of each 
sign/symptom and any other information considered relevant by the investigator). Any signs or 
symptoms considered to be out of proportion to the extent of the PTE may be reported as 
additional SAEs, if indicated.   
Except in cases of imminent life-threatening emergency, investigators should consult with the 
Sponsor Medical Monitor or designee is recommended prior to implementing anti-tumor 
treatments beyond the protocol-recommended supportive care options. 
Delays and or discontinuation of pembrolizumab treatment should occur as outlined in 
Sections 5.3 and 7.5.3 for events related to PTE and CE. 
 
Adverse Events of Immunologic Etiology Associated with Pembrolizumab 
Adverse events of an immunologic etiology have been associated with pembrolizumab exposure. 
These irAE may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. Therefore, 
early recognition and initiation of treatment is critical to reduce complications. Existing clinical 
trial data have shown that most irAEs related to pembrolizumab were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids, and/or other 
supportive care. See Section 6.5.4.3 on medication use for treatment of irAE. 
Depending on the severity of the irAE, pembrolizumab will be temporarily withheld or 
permanently discontinued. In general, for an irAE requiring dose interruptions, low-dose 
dexamethasone (≤ 4mg/day) should be initiated and tapered when the irAE is ≤ Grade 1. 
For a life-threatening irAE, IV dexamethasone should be initiated first followed by oral steroids. 
Other immunosuppressive treatment should also be initiated if the irAEs cannot be controlled by 
corticosteroids alone.   

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The next doses(s) of pembrolizumab will be withheld until the irAE has been reduced to ≤ Grade 
1 and dexamethasone dose has been tapered to ≤ 4mg/day and/or discontinued.  
Pembrolizumab should be permanently discontinued if the irAE does not resolve within 
12 weeks of last dose or dexamethasone cannot be reduced to ≤ 4 mg/day within 12 weeks. 
• With regard to events ≥ Grade 2 related to PTE or CE (eg, hemiparesis, seizure), 
pembrolizumab treatment should be held until those events resolve to ≤ Grade 1.  
Pembrolizumab should be permanently discontinued for Grade 4 PTE or CE and/or events 
≥ Grade 3 related to PTE or CE. 
Refer to the most recent Keytruda® (pembrolizumab) package insert and “Guide for 
Keytruda®” for a list of adverse reactions for which pembrolizumab should be interrupted 
or permanently discontinued along with recommended management. This may include but 
not be limited to the following: 
• Immune-mediated pneumonitis: Withhold for moderate, and permanently discontinue for 
severe, life-threatening or recurrent moderate pneumonitis. 
• Immune-mediated colitis: Withhold for moderate or severe, and permanently discontinue for 
life-threatening colitis.  
• Immune-mediated hepatitis: Monitor for changes in hepatic function. Based on severity of 
liver enzyme elevations, withhold or discontinue pembrolizumab. Consider corticosteroid 
therapy. 
• Immune-mediated endocrinopathies: 
o Adrenal insufficiency: Withhold for moderate and withhold or permanently 
discontinue for severe or life-threatening adrenal insufficiency. 
o Hypophysitis: Withhold for moderate and withhold or permanently discontinue for 
severe or life-threatening hypophysitis. 
o Thyroid disorders: Monitor for changes in thyroid function. Withhold or permanently 
discontinue for severe or life-threatening hyperthyroidism. 
o Type 1 diabetes mellitus: Monitor for hyperglycemia. Withhold pembrolizumab in 
cases of severe hyperglycemia. 
• Immune-mediated nephritis: Monitor for changes in renal function. Withhold for moderate, 
and permanently discontinue for severe or life-threatening nephritis.  
• Immune-mediated skin adverse reactions including Stevens- Johnson syndrome (SJS) and 
toxic epidermal necrolysis (TEN): Withhold for severe and permanently discontinue for 
life-threatening skin reactions.  
• Other immune-mediated adverse reactions: In organ transplant recipients, consider the 
benefit of treatment with pembrolizumab versus the risk of possible organ rejection. 

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In addition, pembrolizumab can cause severe or life-threatening infusion-related reactions, 
including hypersensitivity and anaphylaxis. 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 above, in the current pembrolizumab package 
insert, or in keeping with current medical practices when managing reactions noted during or 
after pembrolizumab infusion. 
7.6 
Notification for Serious or Unexpected Adverse Events 
The investigator, or responsible person per local requirements, must comply with the applicable 
local regulatory requirements related to the reports of SAEs to regulatory authorities and the 
IRB/ IEC.  
The Sponsor is responsible for appropriate reporting of SAEs to the necessary regulatory bodies 
where appropriate. The Sponsor will report to the Investigators all suspected unexpected serious 
adverse reactions (SUSARs) associated with PVSRIPO/PVSRIPO followed by pembrolizumab 
use. The Investigator (or Sponsor where required) must report any SUSARs to the IRB/IEC 
according to the Institution’s regulations. 
The Sponsor is responsible for the ongoing evaluation of the study drug. Any adverse experience 
associated with the use of the study drug that is both serious and unexpected must be reported. In 
accordance with the US Code of Federal Regulations, Title 21 CFR Part 312.32, and the 
International Conference on Harmonization (ICH) Guidelines for Clinical Safety Data 
Management Definitions and Standards for Expedited Reporting, the Sponsor must submit 
written documentation in the form of an IND Safety Report or SUSAR reports, respectively. All 
events qualifying as IND Safety Reports/SUSARs will be reported to the IRB/IECs. IND Safety 
Reports/SUSARs are required to be reported within 7 calendar days for life-threatening events 
and those resulting in death or 15 calendar days for all others. These timeframes begin with the 
first notification of the IND Safety Reports/SUSARs to the drug safety group from the 
Investigator. 
The Sponsor should submit to the regulatory authority all safety updates and periodic reports, as 
required by applicable regulatory requirements. 

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8 
Statistical Analyses 
This single-arm study is designed to evaluate the efficacy, safety and tolerability of PVSRIPO 
when followed by pembrolizumab treatment in patients with rGBM. Summary statistics (eg, 
n, %, CI) will be employed to describe the key findings (ORR, DOR, incidence and severity of 
DLT, Grade 3 or higher AE, etc.). 
Adverse events considered related to screening or other pre-infusion procedures that are not 
standard of care (eg, PV booster, biopsy prior to infusion, catheter placement without PVSRIPO 
infusion) will be summarized separately from TEAE (after PVSRIPO infusion), as will data from 
patients receiving only PVSRIPO and not at least one dose of pembrolizumab. The number of 
doses of pembrolizumab received and other baseline characteristics will also be explored as 
variables for safety and efficacy (eg, age, number of prior recurrences, baseline NANO and KPS, 
extent of prior resection, prior bevacizumab and chemotherapy use, tumor genetic profile).  
All patients enrolled and treated with PVSRIPO will be summarized in all analyses. In addition, 
a per-protocol analysis will also explore the impact of excluding patients meeting pre-defined 
criteria from radiographic and survival analyses as outlined in Section 8.4.6. For comparisons of 
efficacy or safety relative to PVSRIPO alone or pembrolizumab alone from other data sources, 
both the overall and per-protocol populations may be considered. 
In general, patients should follow the protocol treatment plan outlined and will be considered on 
study if there are no major protocol deviations including prohibited tumor-treatments, until the 
time of confirmed disease progression, or until the investigator and/or patient feel it is in the 
patient’s best interest to stop study treatments or study participation.  
The SAP, which will be finalized before conducting the analyses, will present details about 
planned statistical summary methods and analyses. A brief summary of the SAP is provided 
below by section. The SAP will govern in the event the protocol and the SAP differ.  
8.1 
Sample Size Considerations 
In an ongoing analysis of the Phase 1 study of PVSRIPO in rGBM, an ORR of 11% was 
demonstrated (7/61 patients achieved a CR or PR; data on file, Istari). With 30 subjects treated in 
this study, there is > 75% power to demonstrate a 20% or greater improvement in ORR (ORR > 
31%, two-sided P<0.05). 

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8.2 
Analyzed Population Sets 
All patients enrolled and treated with PVSRIPO will be summarized in all analyses. For any 
informal summary comparisons of safety or efficacy relative to PVSRIPO alone or 
pembrolizumab alone from other data sources, both the overall and per-protocol populations may 
be considered.  
A screening analysis set will include all patients who signed the ICF and include screen failures 
who failed up until PVSRIPO infusion (ie, considered a screen failure if biopsy at time of 
catheter placement does not confirm rGBM). The safety and efficacy analysis sets are described 
in Sections 8.4.5 and 8.4.6, respectively. 
8.3 
Handling of Missing Data 
Missing or implausible data noted during routine interim monitoring visits, via programmed or 
manual edit checks withing the eCRF, and during database review and cleaning will be brought 
to the attention of the Investigator or designee requiring an appropriate response (ie, 
confirmation of data, correction of data, completion or confirmation that data is not available, 
etc.). 
The database will be reviewed and discussed prior to database closure. It will be closed only 
after resolution of all remaining queries. An audit trail will be kept of all subsequent changes to 
the data. 
8.4 
Statistical Analysis Plan 
A brief description of the planned statistical analysis is provided below. The final analyses will 
be described in greater detail in the SAP, prior to conduct of the specified analyses. 
 
Disposition of Patients 
A number of tabulated summaries will be created to adequately describe the disposition of 
patients prior to study enrollment and treatment, as outlined in the SAP. 
 
Protocol Deviations 
All the protocol deviations will be provided in listing format. Number and percentage of patients 
not meeting IC/EC will be tabulated for the safety data set. 

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Demographics, Disease Characteristics and Medical History 
All demographic and medical history information will be summarized using the safety data set. 
 
Demographics 
Key demographic variables will be summarized, as outlined in the SAP. 
8.4.4.1 
Disease Characteristics 
The following disease characteristics relating but not limited to the following will be tabulated 
and may be explored as variables for safety/response: 
• Tumor mutational status, by site standard means of analysis, at diagnosis and 
recurrence/baseline including but not limited to the following should be recorded if 
available or may be assessed by central pathology laboratory on archival tissue/tissue 
obtained at baseline biopsy: 
o PV receptor (CD155) 
o EGFRvIII and wild-type EGFR status 
o MGMT promoter methylation status 
o IDH 1 and 2 
o TERT 
o PD-1/PD-L1 
Tumor treatment history: 
• Initial diagnosis; GBM or transformation from a lower grade to a higher grade, along 
with tumor characteristics (size, location, etc.) 
• Prior MRI transmitted to Sponsor or designee, if required 
• Age at diagnosis 
• Time from initial diagnosis and initial and subsequent therapies, including PVSRIPO 
• Extent of prior surgical resection 
• All prior therapies (approved/investigational) 
o Prior tumor treatments will be recorded in the relevant sections of the disease 
specific medical history 
8.4.4.2 
Medical History 
Medical history will be tabulated by number (%) of patients in the safety data set for each system 
organ class and preferred term. 

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8.4.4.3 
Prior and Concomitant Medications or Therapies 
Prior medications are defined as medications taken or therapies received by patients prior to 
PVSRIPO infusion. Concomitant medications are defined as medications taken or therapies 
received by patients during the study after first dose of PVSRIPO. Medications will be coded 
using the World Health Organization (WHO) Drug Dictionary version. Summaries will be 
performed on the Safety set.  
The number (%) of patients receiving or taking prior and concomitant medications or therapies 
will be summarized based on the WHO Anatomical Therapeutic Chemical (WHO ATC) Level 1 
and generic name. In addition, by-patient listings will be provided for the following: 
• Prior investigational agents 
• Secondary therapies (during the study) 
8.4.4.4 
Unscheduled Visits 
Data collected at unscheduled visits will be included and analyzed for both safety and efficacy 
analyses in the same fashion as the data collected at scheduled visits and will be reported in the 
eCRF, except as otherwise noted.   
Descriptive statistics (mean, standard deviation, median, minimum, maximum and quartiles) by 
nominal visit or time point for safety endpoints such as laboratory measurements and vital signs 
will include only data from scheduled visits per protocol.  
 
Safety Analysis 
The full safety analysis set will include all patients who were administered at least one dose of 
the PVSRIPO. The safety of study-required pre-infusion procedures including catheter 
placement, will also be summarized.  
Separate summaries will be prepared for the primary safety analysis set, which is patients who 
received PVSRIPO and ≥ 1 dose of pembrolizumab. Patients who received PVSRIPO alone will 
be summarized separately (secondary safety analysis). 
Summaries of TEAE will begin at the time of PVSRIPO infusion. Adverse events considered 
related to screening or other pre-infusion procedures that are not SOC (eg, PV booster, biopsy 
prior to infusion, catheter placement without PVSRIPO infusion) will be summarized separately 
(screening data set). 

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All safety endpoints for patients receiving PVSRIPO and ≥ 1 dose of pembrolizumab may be 
summarized overall and by the number of pembrolizumab treatments received while on study 
(eg, 1, 2 to 3, 4 to 6, etc.). 
Adverse events will be summarized by highest grade per patient and by attribution according to 
CTCAE v5.0, using the latest version of MedDRA preferred term as event category and 
MedDRA primary system organ class body term as Body System category. Unless otherwise 
stated, adverse events will be displayed in terms of frequency tables by treatment group by 
decreasing frequency. Each patient will be counted only once within each preferred term or 
system organ class. If a patient experiences more than one AE (or laboratory value) within a 
preferred term or system organ class for the same recording period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries of 
relationship and severity.  
Events meeting the criteria for a DLT or SAE, leading to discontinuation, resulting in death, etc., 
will be reported in additional summaries. Changes from baseline over time and abnormal 
laboratory values, vital signs and NANO and KPS will also be reported. 
Changes in toxicity grade, seriousness or outcome of AEs are recorded as separate entries in the 
eCRF with associated end and start dates (start date equals end date of previous entry). Such 
entries reporting the same event in such immediately consecutive periods will be considered as 
one event in the analysis in case of an improvement in toxicity grade. These events will be kept 
as separate records in the database to maintain the full detailed history of the events. The start 
date of the initial record in the sequence is taken as start date of the entire event. Duration of the 
AE will be adjusted accordingly in the analysis.  
 
Efficacy Analysis 
The full efficacy analysis set will include all patients who were administered at least one dose of 
PVSRIPO but patients receiving PVSRIPO alone will be analyzed separately from those who 
received PVSRIPO and ≥ 1 dose of pembrolizumab, which will be considered the primary 
efficacy analysis set. 
All efficacy endpoints for patients receiving PVSRIPO and ≥ 1 dose of pembrolizumab will be 
summarized overall and in subgroups by the number of pembrolizumab treatments received 
while on study (eg, 1, 2 to 3, 4 to 6, etc.), for those with pembrolizumab interruptions, with 
treatment-related irAE, etc. 

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In addition, a per-protocol analysis will also occur to explore the impact of excluding patients 
from radiographic and survival primary analyses who: 
• Underwent surgical resection of target lesions for control of PTE or CE or other reasons 
following-PVSRIPO infusion 
• Received > 4 mg/day dexamethasone or equivalent prior to or for > 14 days after the first 
pembrolizumab treatment 
• Received ≥ 3 consecutive treatments with bevacizumab at doses exceeding 7.5 mg/kg 
• Received other non-protocol specified anti-tumor treatments 
• Did not receive ≥ 1 dose of pembrolizumab (these patients will be replaced) 
• Had major deviations, classified as follows: 
o Did not fulfill eligibility criteria 
o Met criteria for withholding or discontinuation of study treatments but continued 
treatment 
o Received incorrect study drug or dose of study drug. 
o Timing of study drug administration outside of protocol-specified windows 
o Received prohibited concomitant medication 
o Protocol-required procedure not adhered to 
o Other 
The per-protocol analysis set will be identified prior to database lock. 
There will be 2 patient strata at enrollment: the first, based on receipt of any prior anti-
angiogenic or anti-VEGF targeted agents (eg, bevacizumab, cediranib, aflibercept, vandetanib, 
cabozantinib, sunitinib, etc.) and the second, based on prior chemotherapy use. The size of the 
stratum for VEGF targeted agents will be capped at ≤ 50% of the total population enrolled (ie, do 
not want > 50% of the patients enrolled to have failed prior VEGF targeted therapies). The size 
of the stratum for prior chemotherapy use will be ≤ 50% of the total population enrolled, 
regardless of MGMT promoter methylation status (ie, want > 50% of the patients receiving the 
combination to have failed prior chemotherapy use). Enrollment and eligibility criteria will be 
monitored to meet these goals. Data will be analyzed together and separately, by these strata. 
Responses may also be summarized in by subgroup analyses including but not limited to baseline 
NANO score and KPS, prior bevacizumab and chemotherapy or other tumor treatment 
use/failure, extent of surgery at diagnosis (GTR, STR), MGMT promoter methylation status 
and/or other tumor genetic factors at diagnosis and baseline, lesion cross-sectional area at 
baseline, time from initial diagnosis to baseline, number of prior progressions, age, and sex. 

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For any informal summary comparisons of safety or efficacy relative to PVSRIPO, 
pembrolizumab or other ICI alone or in combination from other data sources, both the overall 
and per-protocol populations may be considered.  
8.4.6.1 
Objective Response Rate and Disease Control Rate 
Given PVSRIPO’s pattern of response and mechanism of action (direct tumor cell killing 
followed by adaptive anti-tumor immune response), PVSRIPO can trigger an inflammatory 
immune response that is observed on imaging, which can make distinguishing between the 
inflammatory immune response and progressive disease difficult. This is anticipated to occur to a 
similar or possibly greater extent when followed by pembrolizumab treatment. 
In the Phase 1 and Phase 2 rGBM PVSRIPO clinical trials, an initial increase in the extent of 
FLAIR abnormalities was observed after PVSRIPO, which resolves over time. In addition, an 
initial increase in size of the enhancing lesion with multiple cystic degeneration was observed 
(“swiss cheese” or “honeycomb” appearance), as well as an extension of enhancing disease 
toward previously non-enhancing infiltrative disease, followed by a tumor retraction; see Figure 
4. Depending on the size of the tumor, the inflammatory changes could be observed up to 12 
months post-PVSRIPO infusion.  
This immunoprogressive appearance can resolve and patients may go on to have an ORR and 
achieve long-term survival [5]. However, the time to response is delayed, as noted for other 
immune-therapies [27]; the median time to response in the Phase 1 study based on an ongoing 
analysis was 15.4 months (range 5.7 to 29.7 months; data on file, Istari). In addition, areas of 
new enhancement in the vicinity of the target lesion and in previously non-enhancing T2/FLAIR 
and response tracking, where previously non-enhancing/infiltrative disease enhances and 
subsequently resolves, has been noted with PVSRIPO in the Phase 1 and Phase 2 rGBM studies 
within the first 12 months post-infusion and is being independently assessed by central 
radiographic reviewers (data on file, Istari; see example in Figure 5). This immunoprogressive 
type of radiographic appearance has been described with other immunotherapeutics [1, 30-32]. 
Given this and the potential use of low dose bevacizumab for managing mass effect related to 
PTE, adjustments to define radiographic response, disease control and progression are required, 
as has been noted with other oncolytic viruses [30]. Therefore, the number and percent of 
patients meeting criteria for a confirmed response (CR or PR) and disease control (confirmed 
CR, confirmed PR or SD for ≥ 6 months), as well as confirmed progression will be based on the 
criteria outlined in Table 3.  In addition, an exploratory analysis will evaluate response via 
iRANO criteria. 

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Table 3 
Criteria for Determination of Response/Progression with PVSRIPO Followed by 
Pembrolizumab  
Response  
Criteria 
1. Complete  
• 
Disappearance of all enhancing disease and meets criteria in # 4 below 
2. Partial 
• 
≥ 50% reduction of biperpendicular diameter of enhancing disease and meets 
criteria in # 4 below 
3. Stable Disease 
• 
Does not qualify for CR or PR above AND, 
• 
No increase of biperpendicular diameter of total enhancing disease > 25%, 
AND  
• 
Meets criteria in # 4 below 
4. Must be met for all 
responses above: 
• 
Response persists for ≥ 4 weeks 
• 
Response persists for ≥ 8 weeks post-discontinuation of bevacizumab (once 
confirmed off bevacizumab, response duration will be reported as when 1st 
observed when response 1st noted) 
• 
No greater than physiologic steroids (≤ 4 mg/day dexamethasone or equivalent) 
for CR; stable/improved steroids for PR and SD. 
• 
Stable/improved clinically1 
Immunoprogression 
• 
Increase in enhancing lesion size (with or without new lesions/enhancement 
into T2/FLAIR), within 12 mos of PVSRIPO infusion that responds 
radiographically to steroids (≤ 4 mg/day dexamethasone or equivalent) or 
bevacizumab (≤ 7.5 mg/kg q3 weeks) or a combination of both within 3 months 
of noting appearance of radiographic progression)  
AND either: 
• 
Absence of significant clinical decline 
OR  
• 
If significant clinical decline is present, it is responsive to post-infusion 
interventions including steroids (≤ 4 mg/day dexamethasone or equivalent) or 
bevacizumab (≤ 7.5 mg/kg q3 weeks) or a combination of both within 3 months 
of radiographic progressive-type appearance (ie, ≥ 25% increase of 
biperpendicular diameter of enhancing disease/new lesions/worsened 
T2/FLAIR)   
Progression 
• 
Does not meet criteria for immunoprogression  
AND  
• 
≥ 25% increase of biperpendicular diameter of enhancing disease from the 
smaller of baseline or post-infusion nadir (enhancing at baseline plus any new 
enhancement) and/or worsened T2/FLAIR, confirmed on a subsequent scan 
performed at least 3 months later (unless clinical deterioration prevents 
confirmatory scan). If confirmed, progression date is the date that progression 
was first observed.  
Investigator reported results may be verified by independent central radiographic reviewers 
blinded to patient outcome and possibly bevacizumab use. Response will be summarized at 
_____ 
1 Not inclusive of clinical deterioration clearly due to an intercurrent illness or condition not directly related to the 
patient’s tumor. 

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regular intervals including those achieving a response by 6, 12 and 24 months post-PVSRIPO 
infusion. 
Given that the NANO scale has been shown to provide a more detailed and objective measure of 
neurologic function for predicting the prognosis of glioblastoma patients especially at the time of 
progression [33], the NANO scale will be utilized to explore clinical neurologic function as a 
correlate of response, especially with regard to immunoprogression and/or confirmed 
progression, along with KPS. 
Final criteria for determining response and progression will be outlined in the SAP and the SAP 
will prevail in the event differences are noted.  
Figure 4 Example of Initial Increase in Lesion Size with PVSRIPO Treatment Followed 
by Retraction  
 
In Figure 4 above, note the ≥ 25% increase in infused lesion size (at months 4 and 11) after 
PVSRIPO treatment followed by retraction, beginning around 14 months post-infusion. 
 

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Figure 5 Example of New Enhancement/Disease Tracking after PVSRIPO Treatment, 
Which Resolves over Time  
 
In Figure 5, note the appearance of new enhancement over time, including into previously non-
enhancing T2/FLAIR, that resolves over time. Also note the reduction in mass effect, beginning 
at month 1 post-infusion, which is more prominent at month 4 (2nd row). The ventricle, nearly 
closed at baseline due to tumor mass effect on the ventricular space (white arrow), is open at 4 
months (2nd white arrow), despite new enhancement into previously non-enhancing disease. This 
disease tracking/areas of new enhancement around the previously non-enhancing infiltrative 
disease, continues through month 16 post-PVSRIPO infusion but the reduction in mass effect on 
the ventricle is noted through 25 months. This observation supports the notion that the new 

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enhancement is not new active disease, which would be expected to exert pressure on and close 
the ventricle, but rather is indicative of immunotherapeutic response and disease tracking.  
8.4.6.2 
Duration of Response and Durable Radiographic Response 
The DOR is defined as time from first confirmed response until confirmed PD or death, 
whichever comes first.  
A DRR is defined as a radiographic response that persists for ≥ 6 months. 
The DOR and DRR for those meeting the criteria for confirmed response (CR or PR) with and 
without those achieving SD will be calculated. Endpoints as evaluated by iRANO and inclusive 
of SD will be utilized to describe these endpoints for overall DCR.  
8.4.6.3 
Progression Free Survival 
If calculable, PFS will be based on the time of first PVSRIPO infusion to death or unequivocal 
confirmed progression, based on the definition of progression noted in Table 3. 
8.4.6.4 
Landmark Survival 
Landmark Survival: the proportion of patients alive at ≥ 6, ≥12, ≥18  and ≥ 24 months from time 
of first PVSRIPO infusion.   
8.4.6.5 
Overall Survival 
Overall Survival is defined as time from first PVSRIPO infusion to death from any cause, or last 
follow-up if patient is alive. Kaplan-Meier estimates (product-limit estimates) will be presented 
with a summary of associated statistics including the median survival time with two-sided 95% 
CIs. The survival rates will be estimated throughout the study through a maximum of 24 months, 
with corresponding two-sided 95% CIs. 
9 
Ethical Considerations 
9.1 
Institutional Review Board or Independent Ethics Committee 
The protocol, the ICF and patient assent documents (as applicable), relevant supporting 
information and all types of patient recruitment or advertisement information for this study must 
be approved by the appropriate IRB/IEC before the study is initiated. Copies of the Letter of 
Approval from the IRB/IEC, which contains specific identification of the documents approved, 
must be received by the Sponsor prior to shipment of study drug supplies to the investigational 
site. Any amendments to the protocol, as well as a change of Principal Investigator, must also be 

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approved by the IRB/IEC and documentation of this approval must be provided to the Sponsor 
prior to implementing changes in the study. The IRB/IEC utilized must comply with current ICH 
GCP. The IRB/IEC must supply to the Sponsor or their designee, upon request, a list of the 
IRB/IEC members involved in the vote and a statement to confirm that the IRB/IEC is organized 
and operates according to ICH GCP and applicable laws and regulations. 
Records of IRB/IEC review and approval of all documents pertaining to the study must be kept 
on file by the Principal Investigator and are subject to inspection by a regulatory authority at any 
time. IRB/IEC re-approval is required every 6 months or annually as required by local 
regulation. Where required, the Principal Investigator is to notify the Sponsor, in writing, of the 
approval to continue the study. 
The Investigator’s responsibilities regarding the IRB are as follows: 
• Obtain IRB/IEC approval of the protocol, ICF, and any advertisements for patient 
recruitment prior to their use. 
• Obtain IRB/IEC approval for any protocol amendments and revisions to the ICF before 
implementing the changes. 
• Provide the IRB/IEC with any required information before and during the study. 
• Submit progress reports to the IRB/IEC, as required, during the conduct of the study; 
request re-review and approval of the study, as needed; provide copies of all the IRB/IEC 
re-approvals and relevant communication to the Sponsor. 
Notify the IRB/IEC within 10 days of all serious and unexpected AEs related to the study 
investigational product that are reported to the Investigator by the Sponsor if required. The 
Investigator is responsible for updating the IRB/IEC on the progress of the study and of any 
changes made to the protocol at least once a year or at regular intervals as deemed appropriate. 
The Investigator must also keep the IRB/IEC informed of any AEs, according to the IRB/IEC 
policy. 
9.2 
Ethical Conduct of the Study 
The Investigator(s) will conduct the study in accordance with this protocol, the Declaration of 
Helsinki, ICH, GCP and all other applicable laws and regulations. The Investigator(s) and the 
Sponsor will sign the protocol and study contract, to confirm agreement. The Investigator(s) will 
not implement any amendment (deviation or changes of the protocol) without agreement by the 
Sponsor and approval of the associated IRB, IEC or equivalent, except where necessary to 
eliminate immediate hazard(s) to study participants, or when change(s) involve only logistical or 
administrative aspects of the study. 

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9.3 
Data and Safety Monitoring Board (DSMB) 
A DSMB will be engaged to assess the safety of the interventions during the study. The DSMB 
will provide recommendations about stopping or continuing enrollment in the study. Evaluations 
will be conducted by the DSMB after the initial patients undergo DLT assessment during the 
safety lead in period and for the evaluation of SUSAR throughout the study, as specified in the 
DSMB charter. The charter will prevail in the event any differences are noted in protocol and 
charter. To contribute to enhancing the integrity of the trial, the DSMB may also formulate 
recommendations relating to the selection, recruitment, and retention of participants and their 
management. 
9.4 
Protocol Revisions and/or Deviations 
The protocol may be revised for any number of reasons (eg, to expand the study, to modify the 
planned treatment or follow-up in consideration of safety or efficacy from this study or other 
sources). All changes to the prior version of the protocol will be outlined in a summary section 
for all amendments. The amended protocol (along with any amended ICF, if applicable) must be 
approved by the designated IRB/IEC or other institutional local regulating authorities, as 
required, prior to implementation of the changes, except in the case where immediate changes 
are required to prevent harm to current or future patients.  
A list of protocol deviations will be maintained by the Sponsor or their designee(s). Deviations 
should be reported to the relevant IRB per IRB guidelines, and those required for reporting per 
ICH and/or Sponsor or their designee’s guidelines/Standard Operating Procedures (SOP) will be 
included in the clinical study report. Such deviations may include but are not limited to: 
• Patients that are dosed on the study despite not satisfying the inclusion and exclusion 
criteria 
• Patients that develop withdrawal criteria whilst on the study but are not withdrawn 
• Patients that receive the wrong treatment or an incorrect dose 
• Patients that receive an excluded concomitant medication 
• Deviation from ICH GCP 
9.5 
Patient Information and Consent 
The Investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation in layman’s terms regarding the nature of 
the study, along with the aims, methods, objectives, and any potential risks. The ICF must be 
appropriately signed and dated by the patient or the patient’s legally authorized representative 
and the person obtaining the consent (if required by the IRB) prior to conducting/obtaining any 

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study-related assessments including the discontinuation of any medications prohibited for the 
study. 
Each patient must be provided with a statement that the investigation involves research and that 
the IRB/IEC has approved solicitation of patients to participate; a fair explanation of the 
procedures to be followed and their purposes, including identification of any procedures which 
are experimental; a description in lay language of any possible side effects; a description of any 
attendant discomforts and risks reasonably to be expected; a description of any benefits 
reasonably to be expected; a disclosure of any appropriate alternative procedures that might be 
advantageous for the patient; an offer to answer any inquiries concerning the procedures, and 
instruction that the person is free to withdraw consent and discontinue participation in the project 
or activity at any time without prejudice to the patient. Payment to research participants for 
participation in the study is considered compensation for the investment of time and for incurred 
costs, and not a payment nor an incentive. The method and manner of compensation should 
comply with applicable regulatory requirements. All information concerning payment, including 
the schedule of payments, must be set forth in the ICF, including a disclosure that the 
Investigator is being paid to perform the stated research. A patient (or the patient’s legally 
authorized representative) must give written consent to participate in the study. This ICF must be 
dated and retained by the Principal Investigator as part of the study records. A copy shall be 
given to the person signing the form. The informed consent process must be documented in the 
patient’s source documents.  
The original and any amended signed and ICF must be retained at the study site; and a copy must 
be given to the patient or patient’s legally authorized representative(s). 
The ICF shall also contain the patient’s authorization for the use and disclosure of his/her 
protected health information (PHI) in connection with the study. The authorization shall include 
at a minimum a clear description of the following: the duration of the authorization, the patient’s 
right of access to the PHI (or any suspension thereof during the course of the study), type of 
information to be used/disclosed in the study, the names or classes of parties that may use or 
disclose the PHI, the purpose of the use/disclosure of PHI, the extent of the patient’s right to 
revoke the authorization, the extent to which participation in the study is conditioned on signing 
the authorization, and the potential for re-disclosure of PHI. 
The Investigator agrees that the Sponsor and its employees or agents will have the right to review 
and audit pertinent medical records and source documents relating to this clinical study (see 
Sections 10.1 and 10.2). As part of the informed consent process, the ICF will include a 
statement from each patient participating in the study permitting the release of his/her medical 

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records as necessary for inspection by authorized personnel of the Sponsor, FDA or other 
regulatory authorities, IRB, IEC, or equivalent and the staff managing the clinical study.  
In the United States (US), per US law, the release of medical records and the review of the 
contents will comply with the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). 
9.6 
Personal Data Protection and Confidentiality 
Anonymity of patients participating in this study will be maintained. Only the patient study 
number should appear on any study documents submitted to the Sponsor. Every effort will be 
made to maintain the confidentiality of documents that identify the patient by name (eg, signed 
ICF, laboratory reports, clinic charts), except to the extent necessary to allow auditing by the 
FDA, or other regulatory authorities.  
10 
Quality Control and Quality Assurance 
10.1 
Audits and Inspections 
At its discretion, Istari Oncology (or designee) may conduct a quality assurance audit of this 
study. If such an audit occurs, the Investigator agrees to allow the auditor direct access to all 
relevant documents and the schedule his/her time and the time of his/her staff to permit meetings 
with the auditor to discuss findings and relevant issues. 
In addition, regulatory agencies may conduct a regulatory inspection of this study. If such an 
inspection by a regulatory authority is announced, the Investigator will immediately inform Istari 
(or designee). If such an inspection occurs, the Investigator agrees to allow the inspector direct 
access to all relevant documents and to schedule his/her time and the time of his/her staff to 
permit meetings with the inspector to discuss findings and any relevant issues.   
The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
participants enrolled (ie, signing informed consent and undergoing study procedures) have been 
protected, that enrolled participants are appropriate for the study, and that all data relevant for the 
evaluation of the investigational product have been process and reported in compliance with the 
planned arrangements, the protocol, the investigational site, and IRB/IEC SOPs, ICH GCP and 
applicable regulatory requirements. 

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10.2 
Study Monitoring 
This study will be monitored by Istari, or its designee, in accordance with ICH GCP and 
applicable regulations. By signing this protocol, the investigator agrees to periodic, on-site 
and/or remote monitoring of all appropriate study documentation. 
The progress of the study will be monitored by periodic on-site and/or remote visits and frequent 
communications between the Sponsor or designee(s) and the Investigator (either by phone, 
email, or post). 
During these contacts, the monitor will perform the following activities per the Study Monitoring 
Plan: 
• Check and assess the progress of the study 
• Review study data collected 
• Conduct source document verification 
• Identify any issues and address their resolution 
The objectives of monitoring procedures are to verify that data are authentic, accurate, and 
complete; that the safety and rights of participants are being protected; and that the study is 
conducted in accordance with the currently approved protocol (and any amendments), ICH GCP, 
and all applicable regulatory requirements. 
 
Source Document 
Source documentation consists of, but is not limited to, in-patient hospital charts, clinic notes, 
out-patient records, original tests results, laboratory data, worksheets, investigational product 
accountability records, consent forms, etc. Source documents must be available for review and 
inspection during on-site and/or remote monitoring of the study by Istari Oncology, their 
designees, IRB/IEC and/or appropriate regulatory authorities. 
 
Case Report Form  
Patient data will be collected in an eCRF via electronic data capture (EDC). The EDC system 
will be Part 11 compliant and will have a documented audit trail for all changes made to the 
eCRF.  
The Investigator or designee must enter all required patient data using the specified data 
collection method defined by Istari in a reasonable timeframe after data are obtained (eg, within 
48 h; exception is SAE reporting; see Section 7.2). The Investigator must sign and date a 
declaration on the eCRF attesting to their responsibility for the quality of all data entered and that 

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the data represents a complete and accurate record of each patient’s participation in the study. 
Details on use of the EDC are provided in the eCRF Completion Guidelines. 
10.3 
Quality Laboratory Standards 
Other than research samples, clinical laboratory tests are conducted as per SOC and standards are 
in keeping with the qualified individual site laboratory quality standards and procedures. 
Research laboratory samples and procedures may be monitored and/or audited in keeping with 
pre-specified monitoring/audit plans by the Sponsor or their designee. Laboratory normal ranges 
should be provided to the Sponsor or their designee for all laboratories utilized as part of the 
SOC assessments in this study. 
10.4 
Data Management 
Data management will be performed in accordance with the SOP of Istari or its designee. Patient 
data will be collected in an eCRF. Data will be reviewed and validated. Data clarifications will 
be requested of the Investigator or his/her designee, and the database will be edited appropriately 
prior to database hard lock. Selected variables will be coded. The database will be authorized for 
release when all data management quality control procedures are completed. 
11 
Study Administration 
11.1 
Participating Sites/Study Centers 
Participating centers will be evaluated by the Sponsor or their designee by completion of formal 
site feasibility and site-qualification assessment, including but not limited to review for 
acceptable facilities, laboratories, adequate operating procedures, staff and investigator 
qualifications, and patient population. These may be abbreviated if the center has participated in 
a clinical study with the Sponsor or their designee and/or in a related indication with the 
investigational product within a 12-month period. 
The Investigator and essential support staff will review current ICH GCP guidelines and all 
aspects of protocol application and study management with the Sponsor or their designee. It is 
the responsibility of the Investigator to ensure training of ancillary study staff. 
11.2 
Required Documents Prior to Study Initiation 
Required documentation on file with the site and/or Sponsor or their designee prior to 
authorizing shipment of investigational protocol to the site will be in keeping with ICH GCP 

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guidelines/standards and the Sponsor or their designee’s SOP. Review by the Sponsor/their 
designee is required before the trial formally begins recruitment at each site. 
11.3 
Clinical Trial Supplies 
Clinical trials supplies should not be discarded or destroyed without proper accountability and 
authorization by the Sponsor or their designee. Any supplies provided to the site for the conduct 
of the trial may be returned to the Sponsor or their designee or may be authorized for destruction 
or shipment to 3rd parties, at their request and cost.  
11.4 
Investigator Site File 
The investigational site will maintain a specific study file. This file is patient to inspection as 
described in Section 10 of this protocol. This file may contain, but is not limited to the 
following: 
• Protocol and protocol amendments 
• IB 
• IND Safety Reports 
• IRB/IEC approval 
• IRB/IEC approved sample ICF 
• IRB/IEC (or privacy board) waiver of authorization (if applicable) 
• IRB/IEC correspondence 
• IRB/IEC membership list 
• Signed Form FDA 1572 with corresponding curriculum vitae 
• Communications (letters, memos, meeting notes, printed emails) 
• Site signature log 
• Delegation of authority log 
• Study drug accountability records (receipt and dispensing) 
• Laboratory normal ranges and certification 
• Laboratory director’s curriculum vitae 
• SAE reports (as applicable) 
• Patient identification log 
• Patient screening / enrollment log 
• Informed consent log 
• Data captured in electronic data  
• Investigator(s) financial disclosure statement 

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11.5 
Study Completion 
Upon completion of the study (including early discontinuation by the investigator, Sponsor, local 
IRB/IEC, or other regulatory authorities (eg, FDA, European Medicines Agency [EMA]), the 
following activities, when applicable, must be conducted by the monitor in conjunction with the 
investigator, as appropriate: 
• Return of all study data to Istari (or designee) 
• Data clarifications and/or resolutions 
• Accounting, reconciliation, and final disposition of used and unused study drug 
• Review of site study records for completeness 
In addition, Istari reserves the right to temporarily suspend or prematurely discontinue this study 
either at a single site or at all sites at any time and for any reason. If such action is taken, Istari 
will discuss this with the investigator (including the reasons for taking such action) at that time. 
Istari will promptly inform all other investigators and/or institutions conducting the study if the 
study is suspended or terminated for safety reasons and will also inform the 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. 
11.6 
Final Report 
Istari or their designee will be responsible for generating a final clinical study report. Istari 
acknowledges the importance of public disclosure/publication of information collected or 
generated by the Institution and Principal Investigator. All data generated from this study shall 
be held in strict confidence along with all information furnished by Istari. Independent analyses 
and/or publication of these data by the Investigator or any member of his/her staff are not 
permitted without prior written consent of Istari, in keeping with the executed clinical trial 
agreement. The draft of the publication and the lead authors will be determined by a 
Sponsor/Investigator publication committee or similar. 

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11.7 
Retention of Study Records 
Essential documents as described above should be retained for one of 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 however if required by applicable 
regulatory requirements or by the executed clinical trial agreement with the Sponsor. It is the 
responsibility of Istari 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. 
11.8 
Confidentiality and Publication 
The Investigator and other study site personnel will keep confidential any information provided 
by Istari (including this protocol) related to this study and all data and records generated in the 
course of conducting the study, and 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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12 
References 
1. 
Okada, H., et al., Immunotherapy response assessment in neuro-oncology: a report of the 
RANO working group. Lancet Oncol, 2015. 16(15): p. e534-e532. 
2. 
Brown, M.C., et al., Cancer immunotherapy with recombinant poliovirus induces IFN-
dominant activation of dendritic cells and tumor antigen-specific CTLs. Sci Transl Med, 
2017. 9(408). 
3. 
Cloughesy, T.F., et al., Neoadjuvant anti-PD-1 immunotherapy promotes a survival 
benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat 
Med, 2019. 25(3): p. 477-486. 
4. 
de Groot, J., et al., Window-of-opportunity clinical trial of pembrolizumab in patients 
with recurrent glioblastoma reveals predominance of immune-suppressive macrophages. 
Neuro Oncol, 2019. 
5. 
Desjardins, A., et al., Recurrent Glioblastoma Treated with Recombinant Poliovirus. N 
Engl J Med, 2018. 379(2): p. 150-161. 
6. 
McGranahan, T., et al., Current State of Immunotherapy for Treatment of Glioblastoma. 
Curr Treat Options Oncol, 2019. 20(3): p. 24. 
7. 
Weenink, B., et al., Immunotherapy in Glioblastoma: Current Shortcomings and Future 
Perspectives. Cancers (Basel), 2020. 12(3). 
8. 
Nayak, L., et al., The Neurologic Assessment in Neuro-Oncology (NANO) scale: a tool to 
assess neurologic function for integration into the Response Assessment in Neuro-
Oncology (RANO) criteria. Neuro Oncol, 2017. 19(5): p. 625-635. 
9. 
Harder, B.G., et al., Developments in Blood-Brain Barrier Penetrance and Drug 
Repurposing for Improved Treatment of Glioblastoma. Front Oncol, 2018. 8: p. 462. 
10. 
Sim, H.W., E.R. Morgan, and W.P. Mason, Contemporary management of high-grade 
gliomas. CNS Oncol, 2018. 7(1): p. 51-65. 
11. 
Nduom, E.K., M. Weller, and A.B. Heimberger, Immunosuppressive mechanisms in 
glioblastoma. Neuro Oncol, 2015. 17 Suppl 7: p. vii9-vii14. 
12. 
Brown, C.B., et al., Convection-Enhanced Delivery in the Treatment of Glioblastoma. 
Semin Oncol Nurs, 2018. 34(5): p. 494-500. 
13. 
Saito, R. and T. Tominaga, Convection-enhanced Delivery of Therapeutics for Malignant 
Gliomas. Neurol Med Chir (Tokyo), 2017. 57(1): p. 8-16. 
14. 
Darvin, P., et al., Immune checkpoint inhibitors: recent progress and potential 
biomarkers. Exp Mol Med, 2018. 50(12): p. 1-11. 

LUMINOS-101 
Version 4.0: 26May2021 
PVSRIPO 
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Page 96 
15. 
NCCN. National Comprehensive Cancer Network Guidelines Version 1.2019, Anaplastic 
Gliomas/Glioblastoma.  [cited 2019 May 06]; Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. 
16. 
Zhao, J., et al., Immune and genomic correlates of response to anti-PD-1 immunotherapy 
in glioblastoma. Nat Med, 2019. 25(3): p. 462-469. 
17. 
Clinicaltrials.gov.  [cited 2020 April 16]; Available from: https://clinicaltrials.gov/. 
18. 
Dobrikova, E.Y., et al., Attenuation of neurovirulence, biodistribution, and shedding of a 
poliovirus:rhinovirus chimera after intrathalamic inoculation in Macaca fascicularis. J 
Virol, 2012. 86(5): p. 2750-9. 
19. 
Gromeier, M., et al., Intergeneric poliovirus recombinants for the treatment of malignant 
glioma. Proc Natl Acad Sci U S A, 2000. 97(12): p. 6803-8. 
20. 
Reardon, D.A., et al., Safety of pembrolizumab in combination with bevacizumab in 
recurrent glioblastoma (rGBM). Journal of Clinical Oncology, 2016. 34(15_suppl): p. 
2010-2010. 
21. 
Reardon, D.A., et al., Phase II study of pembrolizumab or pembrolizumab plus 
bevacizumab for recurrent glioblastoma (rGBM) patients. Journal of Clinical Oncology, 
2018. 36(15_suppl): p. 2006-2006. 
22. 
Aiken, R., et al., ATIM-33: Interim results of a phase 2 multi-center study of oncolytic 
adenovirus DNX-2401 with pembrolizumab for recurrent glioblastoma; CAPTIVE 
STUDY (KEYNOTE-192). Neuro-Oncology, 2019. 21(S6): p. vi8-vi9. 
23. 
Hagel, S., et al., External ventricular drain infections: risk factors and outcome. 
Interdiscip Perspect Infect Dis, 2014. 2014: p. 708531. 
24. 
Kunwar, S., et al., Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel 
wafers for recurrent glioblastoma. Neuro Oncol, 2010. 12(8): p. 871-81. 
25. 
EORTC. EORTC Quality of Life Group Website. 2021  [cited 2021 April 22]; Available 
from: https://qol.eortc.org/. 
26. 
Gramatzki, D., et al., Bevacizumab may improve quality of life, but not overall survival in 
glioblastoma: an epidemiological study. Ann Oncol, 2018. 29(6): p. 1431-1436. 
27. 
Lesser, G.J., Bevacizumab and Glioblastoma: The Ecstasy and the Agony. Oncology, 
2015. 29(10): p. 728-9. 
28. 
Weathers, S.P. and J. de Groot, VEGF Manipulation in Glioblastoma. Oncology, 2015. 
29(10): p. 720-7. 

LUMINOS-101 
Version 4.0: 26May2021 
PVSRIPO 
Istari Oncology, Inc. 
Confidential 
Page 97 
29. 
Arevalo, O.D., et al., Assessment of Glioblastoma Response in the Era of Bevacizumab: 
Longstanding and Emergent Challenges in the Imaging Evaluation of Pseudoresponse. 
Front Neurol, 2019. 10: p. 460. 
30. 
Lang, F.F., et al., Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: 
Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma. J Clin 
Oncol, 2018. 36(14): p. 1419-1427. 
31. 
Pollack, I.F., et al., Antigen-specific immune responses and clinical outcome after 
vaccination with glioma-associated antigen peptides and polyinosinic-polycytidylic acid 
stabilized by lysine and carboxymethylcellulose in children with newly diagnosed 
malignant brainstem and nonbrainstem gliomas. J Clin Oncol, 2014. 32(19): p. 2050-8. 
32. 
Prins, R.M., et al., Gene expression profile correlates with T-cell infiltration and relative 
survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin 
Cancer Res, 2011. 17(6): p. 1603-15. 
33. 
Lee, J., S.H. Park, and Y.Z. Kim, Prognostic Evaluation of Neurological Assessment of 
the Neuro-Oncology Scale in Glioblastoma Patients. Brain Tumor Res Treat, 2018. 6(1): 
p. 22-30. 
 
 
 
 

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Version 4.0: 26May2021 
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